Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, -254, v" sacosamide for the treatment of partial-onset seizures
`
`h(4)
`
`Table 24: Seizure—related AE dropouts in LCM in EP 81, treatment phase
`Placebo
`
`
`LCM (mg/day)
`(N=364)
`,
`
`
`
`
`
`n (%)
`LCM Total
`200
`400
`
`(N=270)
`(N=47l)
`(N=944)
`
`
`
`n (%)
`n (%)
`n (%)
`
`
`
`Any
`2(0.7)
`4(l.1)
`
`Convulsion
`2 (0.7)
`4 (1.1)
`
`
`0
`Status eppileticus
`
`Source, Summary of Clinical Safety, Table EP.6.29.l.
`
`10(2.l)
`8
`2
`
`12 (1.3)
`10
`2
`
`600
`(N=203)
`n (%)
`
`The overall rate of cases of seizure activity leading to discontinuation in this database is similar
`between placebo and LCM treated patients. It is unclear why LCM 400 appears to have a higher
`rate than the LCM 200 and LCM 600 groups. The listing of cases in which seizure activity led to
`a study discontinuation is presented as follows:
`
`Table 25. Lacosamide. Dropouts due to seizure-related adverse event EP Pool S]
`
`Re] st
`
`Placebo
`
`frequency
`
`aggravated
`
`Convulsion
`
`100 Yes
`
`sequelae
`
`Placebo
`
`Convulsion
`
`2 No
`
`R R
`
`No
`
`Yes
`
`No
`
`R
`
`1 Yes
`
`aggravated
`
`
`
`ag_ravated
`
`
`
`--———---m
`R m
`seizures
`aggravated
`
`Flurry of
`Convulsions
`
`
`
`Placebo Convulsion
`
`No
`seizures
`aggravated
`
`
`
`
`Seizures
`Convulsions
`
`
` Convulsion
`755118104
`Placebo
`increase
`
`
`
`- Increased
`Convulsions
`
` Convulsion
`
`aggravated
`667011910 LCM 200
`number of $2
`
`‘
`Convulsions
`Seizures
`
`
`Convulsion
`No
`aggravated
`increase
`755118617 LCM 200
`200
`
`
`
`
`Convulsion
`400
`Seizures
`Seizures
`667010404 LCM 400
`Yes
`R
`
`
`
`
`orsening Sz
`Convulsions
`
`
`
`
`Convulsion
`hange in "aura"
`aggravated
`
`
`
`
`Status
`Status
`Status
`
`
`
`
`epilepticus
`epilepticus
`epilepticus
`754010107 LCM 400
`31 Yes
`
`
`
`Increased 82
`
`
`Convulsions
`frequency,
`
`
`hOSpitalization
`Convulsion
`
`
`667015009
`
`754012010
`
`
`
` 754018303
`
`
`667014801
`
`LCM 400
`
`
`
`754013604 LCM 400
`
`
`
`
`
`
`
`
`
`754017202 LCM 400
`
`754019001
`
`LCM 400
`
`755108202 LCM400
`
`seizures
`Increased Sz
`
`frequency
`Hospitalization
`statuseppiletic
`
`Seizure
`Convulsions
`
`aggravated
`Status
`eppileticus
`
`Convulsion
`
`21 No
`
`R
`
`Convulsion
`Status
`epilepticus
`
`20 No
`
`123 Yes
`
`
`
`
`755118106 LCM 400
`
`increase
`
`755118211
`
`LCM 400
`
`increase
`
`
`
`aggravated
`
`'
`
`Convulsion
`
`
`'R
`3 No
`Convulsion
`aggravated
`
`
`31 No
`
`54
`
`
`
`
`
`
`
`
`
`
`0
`
`100
`
`400
`
`100
`
`

`

`Clinical Safety Review
`Lourdes Villalba, MD.
`NDA 22-253, -254, #- Lacosamide for the treatment of partial-onset seizures
`
`11(4)
`
`9
`
`i Outcome Increase of
`
`TrtGrou
`
`AE term
`
`LLT
`
`Convulsions
`
`PT
`
`'
`
`Serious
`
`Convulsion
`aggravated
`seizures
`755118613 LCM 400
`LLT= MedDRA lower level term. Source: AE datasets in EP 81.
`
`The mean and median doses at the time of the onset of the AE of seizure among patients
`randomized to LCM were 208 mg/day and 200 mg/day, respectively. No seizure-related events
`occurred in patients while receiving 500 and 600 mg/day. This is reassuring, as higher doses of
`LCM do not seem to be associated with an increased risk of seizures leading to dropout.
`
`- Dropouts due to AEs in other SOCs
`
`Table 26 summarizes PT terms for AEs in other SOCs with >1% incidence of discontinuations.
`
`Table 26. Lacosamide NDA. Patients who discontinued from EP Pool 81, by preferred term in selected
`SOCsl, during the treatment phase by randomized dose.
`
`LCM (mg/day)
`600
`(N=203)
`n %
`
`200.
`_(N=270)
`n %
`
`400
`(N=471)
`n %
`
`LCM Total
`(N=944)
`n %
`
`MedDRA
`System Organ Class
`
`-
`
`
`Placebo
`(N=364)
`n M)
`
`Gastrointestinal disorders
`
`3 (0.8)
`
`3 (1.1)
`
`15 (3.2)
`
`12 (5.9)
`
`30 (3.2)
`
`11 (2.3)
`8 (1.7)
`1
`l
`l
`
`'
`
`0
`
`13 (2.8)
`
`10 (2.1)
`
`Vomiting
`Nausea
`Flatulence'
`Diarrhea
`Pancreatitis
`
`Abdominal pain/ abd pain upper
`D mouth
`
`Eye disorders
`
`'
`
`Diplopia
`Vision blurred
`Photopsia
`
`3
`1
`1
`0
`0
`
`l
`0
`
`1 (0.3)
`
`1
`0
`0
`
`General disorders and admin site condit.
`
`1 (0.3)
`
`Fatigue
`Asthenia
`Chest pain
`Malaise
`
`Feeling cold
`Feeling abnormal
`Feeling drunk
`
`1
`0
`0
`0
`
`1
`0
`0
`0
`
`0
`0
`
`55
`
`
`
`
`
`
`
`
`6 (3.0)
`8 (3.9)
`
`18 (1.9)
`17 (1.8)
`2
`1
`1
`
`1
`1
`
`10 (4.9)
`
`28 (3.0)
`
`4 (2.0)
`6 (3.0)
`0
`
`8 (3.9)
`
`3 (1.5)
`4 (2.0)
`1
`0
`
`18 (1.9)
`10 (1.1)
`1
`
`16 (1.7)
`
`6
`4
`3
`2
`
`1
`1
`1
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, -254. "" Lacosamide for the treatment of partial-onset seizures
`
`.
`
`“(4)
`
`
`LCM (mg/day)
`600
`(N=203)
`n (%
`
`200
`(N=270)
`
`400
`(N=471)
`%)
`
`LCM Total
`(N=944)
`n (%
`
`MedDRA
`System Organ Class
`
`Placebo
`(N=364)
`n (%)
`
`
`Psychiatric disorders
`
`Depression/depr. Suicidal /suic. attempt
`Confusional state/Mental status changes
`Insomnia
`Tearfulness
`
`Bradyphrenia
`Euphoric mood
`Ps chotic disorder
`
`OOOOOOOO
`
`
`
`15(1-6)
`
`l 0 l 1 1 O 0
`
`10(2.1)
`3
`
`Skin and subcutaneous tissue disorders
`
`Rash
`Pruritus
`
`Hyperhidrosis
`Night sweats
`A Urticaria
`
`1 SOCS with 2 1% discontinuations (other than the Nervous System) in at least one treatment group. Note:
`Treatment Phase includes both Titration and Maintenance Phase data. Note: 11 = Number of subjects who
`reported at least one event during the phase. % = Percent with respect to the number of subjects in Pool 81.
`Source, Summary of Clinical Safety, Table EP.6.29.l.
`
`Most of the GI and eye disorders leading to dropout are likely related to LCM. The cases of
`pancreatitis and peritonitis have been mentioned under SAEs and did not appear to be drug
`related. Asthenia, fatigue, malaise have been observed in phase 1 studies and are likely related
`to LCM. Psychiatric ABS and Skin rash and hypersensitivity will be discussed later under section
`7.1.4 (AE of interest).
`
`A table summarizing AE that led to discontinuations in SOCS that had an incidence <1 .0% in EP
`81 is in Appendix 7.
`‘
`
`There were few dropouts due to cardiac disorders in the epilepsy population. They all occurred in
`the LCM treatment group. These cases are discussed in Section 7.1.4.1.of this review (AE of
`interest, Cardiac AEs).
`
`Of note, in the placebo-controlled DPN studies five patients discontinued the study because of
`syncope/loss of consciousness. All five cases occurred in the LCM treatment group at doses of
`400 and 600 mg/day (5/ 1023= 0.5% among LCM-treated patients and 0% among placebo). For
`details the reader is referred to Dr. Pokrovnichka’s clinical review.
`
`56
`
`

`

`Clinical SafetyiReview
`Lourdes Villalba, MD.
`NBA 22—253, -254,
`’— Lacosamide for the treatment of partial—onset seizures
`
`”(4)
`
`7.1.3.3 Adverse events leading to dose reduction in EP 81
`
`On Feb 19, 2008, at the FDA’s request, the sponsor submitted a summary table of TEAE that led
`to either dose reduction or discontinuation in all three placebo controlled studies (See Table
`below).
`
`This analysis (by randomization dose) shows a dose response in terms of AE leading to dose
`reduction particularly for those SOCs with the larger numbers of events. Overall approximately
`half ofAE that required dose reduction underwent discontinuation. Depending on the SOC, a
`different fraction of cases that underwent dose reduction ended up requiring discontinuation.
`The SOC that most led to dose reduction/discontinuation was the Nervous System Disorders
`SOC (18.6%) followed by Eye disorders (7.2%) and GI disorders (5.1%). Approximately half of
`the patients who required dose reduction ended up being withdrawn from the studies.
`
`Comment: A summary tablefor AE that led to dose reduction in the epilepsy studies by
`randomization dose was submitted with the original application for SP 754 and SP 755
`only. Dose reduction in study SP667 (US and non- US) had not been not prospectively
`identified/analyzed Information fiom all three studies was submitted later in February
`2008.
`
`A summary of TAE that led to dose reduction or dropout in EP Pool 81, treatment phase, by
`SOC and randomization dose is presented in the next table.
`
`APPEARS THIS WAY
`
`0N ORlGINAL
`
`57
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, -254, f" Lacosamide for the treatment of partial-onset seizures
`
`Table 27. TAE that led to dose reduction or discontinuation in EP Pool 81, treatment phase, by SOC and
`randomization dose
`
`MedDRA
`
`System Organ Class
`
`$3364)
`
`
`
`200
`
`(N=270)
`n %
`
`400
`
`(N=471)
`n(%
`
`600
`
`(N=203)
`n(%)
`
`LCM Total
`
`(N=944)
`n %
`
`Any system organ class
`
`26 (7.1)
`
`42 (15.6)
`
`141 (29.9)
`
`94 (46.3)
`
`277 (29.3)
`
`Blood and lymphatic system disorders
`
`Cardiac disorders
`
`Bar and labyrinth disorders
`
`Endocrine disorders
`
`0
`
`0
`
`0
`
`0
`
`2 (0.7)
`
`1 (0.2)
`
`1 (0.4)
`
`3 (0.6)
`
`0
`
`0
`
`3 (0.3)
`
`4 (0.4)
`
`5 (1.9)
`
`12 (2.5)
`
`6 (3.0)
`
`23 (2.4)
`
`1(0.4)
`
`0
`
`0
`
`1(0.1)
`
`Eye disorders
`
`1 (0.3)
`
`9 (3.3)
`
`32 (6.8)
`
`27 (13.3)
`
`68 (7.2)
`
`Gastrointestinal disorders
`
`4 (1.1)
`
`7 (2.6)
`
`23 (4.9)
`
`18 (8.9)
`
`48 (5.1),
`
`General disorders and admin site condit.
`
`4 (1.5)
`
`17 (3.6)
`
`12 (5.9)
`
`33 (3.5)
`
`Hepatobiliary disorders
`
`Infections and infestations
`
`Injury, poisoning and procedural complic.
`
`Investigations
`
`2 (0.5)
`
`0
`
`0
`
`0
`
`. 1(0.3)
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.5)
`
`2 (0.2)
`
`5 (1.1)
`
`1 (0.5)
`
`6 (0.6)
`
`1 (0.4)
`
`5(19)
`
`3 (0.6)
`
`7(1.5)
`
`2 (1.0)
`
`3(1.5)
`
`6(0.6)
`
`15(16)
`
`Metabolism and nutrition disorders
`
`0
`
`2 (0.7)
`
`1 (0.2)
`
`1 (0.5)
`
`4 (0.4)
`
`g Musculoskeletal and connective tissue dis.
`
`1 (0.3)
`
`1 (0.4)
`
`3 (0.6)
`
`3 (1.5)
`
`7 (0.7)
`
`Neoplasms benign, malignant and
`Unspecified (incl cysts and polyps)
`
`Nervous system disorder
`
`Psychiatric disorders
`
`Respiratory, thoracic and mediastinal dis.
`
`1 (0.3)
`
`1 (0.4)
`
`0
`
`0
`
`1 (0.1)
`
`14 (8.0)
`
`21(7.8)
`
`84 (17.8)
`
`71 (35.0)
`
`176 (18.6)
`
`0
`0
`
`3 (1.1)
`0
`
`14 (3.0)
`1(02)
`
`5 (2.5)
`0
`
`22 (2.3)
`' 1(0.1)
`
`Skin & SC tissue disorders
`
`Vascular disorders
`
`2 (0.5)
`0
`'7 (1.5)
`1 (0.5)
`8 (0.8)
`
`
`
`
`001 (0.4)1(0.3) 1 (0.1)
`
`Source: February 19, 2008 response to FDA request for information.
`
`'58
`
`

`

`_
`Clinical Safety Review
`Lourdes Villalba, MD.
`NDA 22—253, -254, “Lacosamide for the treatment of partial-onset seizures
`
`b
`(4)
`
`I
`
`- AE dropouts in EP Pool 82
`
`As seen in Table 28, overall, a similar percentage of subjects prematurely discontinued from the
`trials due to a TEAE in EP Pool S2 in comparison to EP Pool 81 for most SOCs.
`
`Table 28. Rate of Discontinuations due to TEAEs in EP Pool SI and 82, treatment phase
`
`MedDRA
`
`.
`
`System Organ Class
`
`EP Pool 81
`
`EP Pool 82
`
`LCM Total
`(N=944)
`n (%)
`
`LCM Total
`(N=1327)
`n (%)
`
`Any system organ class
`
`161 (17.1)
`
`243 (18.3)
`
`
`
`
`
`Blood and lymphatic system disorders
`
`Cardiac disorders
`
`Bar and labyrinth disorders
`
`Eye disorders
`
`Gastrointestinal disorders
`
`General disorders and admin site condit.
`
`Hepatobiliary disorders
`
`Infections and infestations
`
`Injury, poisoning and procedural complic.
`
`Investigations
`
`Metabolism and nutrition disorders
`
`Musculoskeletal and connective tissue dis.
`
`Neoplasms benign, malignant and unspec.
`
`Nervous system disorder
`
`Psychiatric disorders
`
`Renal and urinary disorders
`
`3 (0.3)
`
`4 (0.4)
`
`13 (1.4)
`
`28 (3.0)
`
`30 (3.2)
`
`16 (1.7)
`
`2 (0.2)
`
`'
`
`1 (0.1)
`
`4 (0.4)
`
`9 (1.0)
`
`2 (0.2)
`
`5 (0.5)
`
`1 (0.1)
`
`93 (9.9)
`
`15 (1.6)
`
`Respiratory, thoracic and mediastinal dis.
`
`'
`
`Skin & SC tissue disorders
`
`Vascular
`
`2 (0.2)
`
`7 (0.5)
`
`15 (1.1)
`
`34 (2.6)
`
`34 (2.6)
`
`24 (1.8)
`
`2 (0.2)
`
`2 (0.2)
`
`11 (0.8)
`
`13 (1.0)
`
`2 (0.2)
`
`7 (0.5)
`
`5 (0.4)
`
`130 (9.8)
`
`26 (2.0)
`
`2 (0.2)
`
`4 (0.3)
`
`10 (0.8)
`
`-
`
`11 (0.8)
`
`Pool 82: Patients allowed to change dose of LCM and concomitant AEDs, or have surgery;
`some patients in Pool S2 had been on LCM for up to 5 V2 years. Source: Sponsor’s tables
`EP 6.29.1 and 6.29.2. Cases with incidence <0.l% are not included in this table. Patients
`
`with AE leading to early discontinuation by dose at onset are presented in the following
`table.
`
`39
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, -254. / Lacosamide for the treatment of partial-onset seizures
`
`h(4)
`
`The most common AE that led to discontinuation for “LCM total” in the EP 82 Pool were in the
`Nervous System disorders (9.1%), G1 (2.6%), Eye (2.6%), General disorders and administration
`site conditions (1.8%) and Psychiatric disorders (1.7%).
`
`AE leading to dropout in EP S2 by dose at the onset of the AE are presented in Appendix 8.
`The analysis shows that, 1%, 2%, 3%, 4%, 2%, 2%, and 0% developed a Nervous System
`disorder AE while receiving the 100 mg/day, 200 mg/day, 300 mg/day, 400 mg/day, 500
`mg/day, 600 mg/day and >600 mg/day doses, respectively in the EP S2 Pool, with a suggestion
`of a dose response from 100 to 400 'mg/day doses. However, when looking at discontinuations by
`modal dose (the most commonly received dose, data not shown), the incidence for the nervous
`system disorders was 28% for 100mg/day (i.e. 22 events among 79 patients who received 100
`mg/day), 20% for 200 m/day, 1% for 300 mg/day, 8% for 400 mg/day, 7% for 500 mg/day, 4%
`for 600mg/day and 0 for >600 mg/day.
`
`The study design hampers the interpretation ofthe open label data. It is unclear what
`the best way to look at these data is. Both approaches (modal and by dose at onset)
`involve confoundingfactors.
`
`Preferred terms for AE that led to discontinuation within the Nervous System disorders during
`the treatment phase in Pool S2 by dose at onset of the AE are presented in the following table.
`
`APPEARS nus WAY
`0N ORIGINAL.
`
`60
`
`

`

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`Eowmzw8:23.5722:Enougntnouwmcb3»862:2:£42«now—2:025:53.:no8:038:65202888.56N2a.;
`
` A (
`
`‘1000000000
`
`VN
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, -254 ’— Lacosamide for the treatment of partial-onset seizures
`
`“(4)
`
`Dizziness was the mot common cause of discontinuation due to AB in EP Pool S2 (as well as EP
`S1), followed by ataxia (coordination abnormal). When looking at any seizure-related AE
`(including the PT cenvulsion, grand mal seizure, status epilepticus and complex partial seizures)
`by dose of onset in the S2 Pool (Table 29), the rates of discontinuation due to any seizure activity
`were as follows:
`
`‘
`
`LCM 100 mg/d: 0.2% (4/1323)
`LCM 200 mg/d: 0.5% (7/1297)
`LCM 300 mg/d: 0.3% (3/1164)
`LCM 400 mg/d: 0.6% (6/1076)
`LCM 500 mg/d: 0 (0/525)
`LCM 600 mg/d: 0.2 % (1/525)
`LCM >600 mg/d: 0.5% (1/208)
`LCM any dose: 1.6% (21/1327)
`
`There is no evidence of a dose response for discontinuations due to seizure related AEs in the S2
`Pool by close at time of AB onset.
`
`Review of datasets submitted on January 2008, as part of 120—day SUR indicates that a few more
`events leading to discontinuation occurred by the time of the cutoff date of June 2007, but the
`safety profile was consistent with the original submission.
`
`0 AE leading to discontinuation in trials SP 586 and SP598 (oral capsule formulation)
`
`In SP586, no subject had a TEAE that led to discontinuation from the trial. Two subjects
`(Subject 3004, Subject 4001) withdrew early from SP598 due to AEs. The reported
`TEAEs were dizziness (moderate intensity; possibly related) and asthenia (mild intensity;
`possibly related). The dose at onset for both subjects was LCM 400mg/day.
`
`0 AE leading to discontinuations in LCM IV studies
`
`0 Phase 1, single dose, IV LCM studies (4 studies)
`
`In SP65 8, the events were mild nightmares/moderate anxiety, severe epiglottitis, and a moderate
`common cold. In SP643 one had an increase of QTc from Baseline Z60ms 4 hours after the start
`of infusion during treatment with iv LCM 200mg. The narrative of the case from study SP 643 is
`as follows:
`
`-Subject # 643-10020 was a 35 year old Caucasian male, who received 200 mg of IV LCM on the .
`morning of.9/ 16/02. The subject had been previously identified as a CYP2C19 poor metabolizer; was a
`smoker for 18 years and smoked 5 cigarettes/day. The infusion started at 7:30 AM. Three baseline 12-
`lead ECGs were recorded pre-dose, with the following QTc readings: 412 ms, 362 ms and 376 ms (a
`median 376 ms, was used for comparison). The automated QTc readings following the infusion are
`presented below:
`
`62
`
`

`

`Clinical Safety Review
`Lourdes Villalba, MD.
`NDA 22-253, -254, ALacosamide for the treatment of partial-onset seizures
`
`6(4)
`
`
`
`4 hours
`after
`
`8 hours
`after
`
`12 hour
`afier
`
`
`
`
`Median
`starting
`starting
`starting
`starting
`
`
`Heart rate (bpm)
`42
`52
`58
`74
`56
`
`
`
`140
`138
`PR (msec)
`138
`132
`148
`132
`
`
`398
`QT (msec)
`454
`446
`416
`402
`422
`
`
`|
`QTc (B) (msec)
`390
`376
`405
`4442
`4233
`4094
`
`RR (msec) 1064—] 1336 1232 1054 802 904
`
`
`
`
`
`' Mean/median 383/376 msec.
`2 change from mean baseline= 97 ms. 3 change from median/mean baseline
`QTc= 47 ms.
`4 change from mean/median baseline QTc= 33 ms.
`
`Screening
`4/9/02
`
`Pre-dose
`4/1 6/02
`
`] hour
`after
`
`
`
`The subject did not report any AEs. No clinically relevant findings were observed in labs and vital signs
`during the trial period 1 and the safety follow up examination on 9/23/02. The subject was withdrawn
`from the study according to the protocol. However, the manual evaluation by a cardiologist after the end
`of the trial revealed that the increase in QTc from Baseline was <60ms.
`
`As noted in this table, the patient had baseline sinus bradycardia, but during the
`infusion his HR increased to 78bpm, coincidentally with a prolongation ofthe
`QT0. Although the manual reading ofthe QTc prolongation was <60 msec, the
`exact value was not provided According to the table above, the change was 54
`ms.
`
`0 IV LCM in phase 2/3 partial onset seizures studies
`
`There were 2 subjects (both in the 15-minute infusion duration group) who experienced TEAEs
`that led to early discontinuation from SP757.
`
`- Subject 757-170106 discontinued the trial because of the SAE of bradycardia. Two cardiologists
`concluded that “This AE can be reasonably interpreted as sinus bradycardia with sinus pause and
`junctional escape. Alternatively, there is a pattern to the P wave intervals that suggests sinus
`exit block, and possible P waves without QRS complexes that suggest blocked AV conduction.”
`The event is described in detail in the Serious AEs section of this review.
`
`- Subject 757-70111 discontinued prematurely due to ECG QT correct interval prolonged. She was a
`35-year-old white female with a medical history of depression, diabetes mellitus and hypertension.
`She entered the DB SP755 trial on 25 Jan 2005 and was randomized to oral placebo. After completing
`12 weeks she enrolled in the open-label SP774 trial, and began oral LCM 200 on 28 Jul 2005. She
`continued participation in the SP774 trial, and also enrolled in the open-label SP757 trial on 29 Mar
`2006. At the time of enrollment in the SP757 trial, she had been on LCM 200 for 244 days. A per the
`CRF, at the time of the AE of electrocardiogram QT corrected interval prolonged (QTc =507 ms), the
`subject was receiving LCM IV infusion #7 (100 mg BID). ECG done at screening and before and
`after the first IV infusion (Mar 30, 2006 in the morning) were read as normal. The ECG before the
`second infusion (Mar 30, 2006 in the evening) was read as normal, but the ECG done at 7.5 min into
`the infusion and all ECGs thereafter were read as “abnormal, not clinically relevant.” The exact
`nature of the abnormality is not stated in the CRF.
`
`63
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, -254: —. Lacosamide for the treatment ofpartial-onset seizures
`
`”(4)
`
`At the 02 Apr 2006 pre-dose time point, her QTc(B) was 490 ms at 07:02. The LCM infusion began
`at 08:01 at a rate of 0.67mL/minute (min) to be administered over 15 minutes. Approximately 8
`minutes into the infusion #7, on day #4, the subject’s QTc(B) increased to 507ms. The infusion was
`stopped at 08:09 due to the AE. As per the narrative she had a blood pressure of 110/60mmHg and a
`heart rate of 82bpm at 08:09, and did not experience any clinically relevant symptoms. The AE was
`reported to be resolved approximately 2 hours later at 10:02 (see the following table of values). The
`subject withdrew from the SP757 trial and restarted her oral LCM (100mg) the evening of 02 Apr
`2006. ECG measurements on day at screening and day#4 are presented in the following table.
`
`
`QTcB, ?R imen31s QRS intennis, anti ECGfindings foréquject 170111
`Date
`\isii.’
`LC"Idose
`ECG
`findings
`
`Rel:five
`(mgidzigt)
`anett
`impai-:l
`iern-R531
`Day or
`(ms)
`(ms)
`(ins)
`Time point
`SPFSS Double—Blind
`
`"isiz 3
`33 Mar 2005
`{Basefinem
`
`7““ J” l f“
`
`
`
`SP757 Open—Label
`Norma}. l'
`gree. AV
`Mock, NCR
`Abnormal,
`
`Fabian-ml,
`AbnormaL
`
`Abumnm},
`
`
`
`NOR
`
`End ofm'ai
`
`
`AV=auimmaimlar; ECqueznozerfiiog-ram; it=imrxvanoug LC}§=lzco-smxide; :u'anxizmtes; NCRatx
`dinksliyzéewm; QTcB=QT imam] using 3214:! m‘reclim
`Nate: Time point was time zelafi're to sun ofiv infusion.
`Nora: Retarivednywas dateofeznlnsximrelativeto dateof:rz'nl meditation 52m.
`Note: Baseline: was defied as he average ofthe 3 paedose Baseline Visit values for SP?SS.
`
`-
`Best Poss'ble CO
`
`Concomitant medications at the onset of the event included insulin; amiloride/ hydrochlorothiazide,
`piroxicam, citalopram, sulpiride, valproate sodium and lamotrigine. The investigator considered the
`AE to be possibly related to LCM.
`
`This patient developed QTc prolongation during the IV infusion #7. The QTc
`at screening to SP 75 7 was 416 ms. The patient hadpresented intermittent PR
`prolongation during the oral LCM study.
`
`0 Phase 1 studies with the oral formulation
`
`A summary ofthe cases that lead to withdrawal with the phase 1 oral formulation studies is
`presented as follows:
`
`64
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22—253, -254, ; Lacosamide for the treatment of partial—onset seizures
`
`11(4) '
`
`
`Table 30. Dropouts during phase 1 studies with LCM oral tablet
`
`
`
`
`
`ID
`
`Age/
`gender
`
`Preferred term
`
`outcome
`
`
`
`
`
`
`
`
`
`Relationship as
`LCM dose
`at ’AE onset per investigator
`mg/day)
`
`
`LCM 400
`836-18
`32 M
`First degree heart block
`probable
`resolved
`
`
`
`(PR=24O ms)
`
`
`
`
`73 M
`620-12837
`Extrasystoles
`Not related
`unknown
`
`
`
`76 M
`LCM 100
`620-16228
`Dyspepsia,
`Unlikely, possible,
`resolved
`tremor, HTN
`unlikely
`
`
`
`0
`620-17917
`Arrhythmia
`Not assessable
`resolved
`
`
`
`602-8010
`LCM 400
`Urinary tract infection
`Unlikely
`resolved
`618-8019
`Erythematous rash
`0
`Not related
`resolved
`
`863-80011
`T wave inversion
`100
`Possible
`resolved
`
`
`599-8024
`Eosinophilia
`Not related
`unknown
`
`
`599-8030
`23 F
`Infection
`Not related
`ongoing
`
`640—82044
`22 F
`Syncope/Mallory Weiss
`Not related
`resolved
`
`
`syndrome
`
`19 F Neck pain Not related640—82088 resolved
`
`
`
`
`
`
`
`
`——
`
`-day 3-, prior to taking
`On —=2
`- Subject # 836—18 started LCM 200 mg twice daily on
`his morning dose, he had heart block of severe intensity. It resolved the same day about 4.5 hours
`later. He did not take further doses, however, he experienced 3 additional episodes on November 21,
`23 and 24, and lasted 4.5, 2 and 15 hours, respectiVely. He did not receive any particular treatment.
`On November 23 he also experienced elevated ALT <2xULN.
`Comment: this event might be related to LCM although it resolved at Tmax and
`recurred when the drug should have been washed out.
`
`13(6)
`
`- Subject# 863-80011 was randomized to sequence A—B on 9/1/05. On 9/3/05 while on Treatment A
`in Treatment Period 1 (single dose omeprazole 40 mg, multiple dose LCM 100-300 mg, twice daily)
`he experienced T wave inversion. The ECG finding was not accompanied by subjective symptoms
`and occurred at irregular intervals. The subject was withdrawn from the trial at the sponsor’s request,
`on 9/7/05. The AE was considered resolved at the safety follow up visit on 9/21/05.
`
`the finding ofintermittent T wave inversion in the ECG in a healthy
`Comment:
`volunteer appears related to LCM The clinical significance ofthis change is
`unclear, but T wave inversion is sometimes a sign ofischemia.
`
`
`In summary, the rate of AE leading to dropout in EPISI was 17.1% on LCM and 4.9% on
`placebo. The analysis of these events by randomization dose suggests a strong dose response
`(28.6% dropped out from the LCM 600 randomization group, as compared to 17.2% in the LCM
`400 group). The analysis by dose at onset of the AE also shows a dose response up to LCM 500.
`As discussed earlier, interpretation of dose response in this database isalimited by the titration
`study design and by fewer patients exposed to LCM 600 mg/day. Half of the AE leading to
`dropout were in the Nervous System disorders SOC (18.6%) and were mostly due to dizziness
`
`65
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, -254, —- Lacosamide for the treatment of partial-onset seizures
`
`11(4)
`
`and cerebellar disorders (ataxia, nystagmus, tremor and balance disorders), which have been
`
`previously identified in the LCM non-clinical studies and in clinical studies with other AEDs.
`
`7.1.4
`
`Other Search Strategies — Adverse events of interest.
`
`Based on non—clinical and clinical trial data as well as safety considerations related to drug class,
`the sponsor pre-specified certain AEs as “other significant AEs”. These AE were related to
`cardiac and ECG abnormalities, syncope, abnormal liver function, rash, seizure, memory
`impairment, suicidality and weight change.
`
`7.1.4.1 Cardiac and potentially cardiac AEs
`
`Because of the mechanism of action (interference with slow sodium channels) and the non-
`clinical findings, ECG evaluation was one of the pre—specifled “other adverse events of interest”
`in the clinical program. The non-clinical findings are summarized from the sponsor’s Cardiac
`Report as follows:
`
`In Vitro investigations of the cardiovascular effects of LCM showed that LCM reduced
`the action potential duration in cardiac tissue and inhibited sodium current in isolated
`cells starting at concentrations which are achieved with the highest recommended dose in
`the clinic. In vivo studies showed decreased cardiac conduction. LCM induced short-
`
`lasting hypotensive effects with decreases in systolic left ventricular pressure and
`reduced cardiac output in anesthetized instrumented dogs and monkeys. These effects
`started at the time of maximal drug plasma levels (Tmax), ie, 2 to 5 minutes after IV
`application, at plasma levels found in humans after 300mg bid (14.5 i 1.7ug/mL) and
`were accompanied by an increase in PR interval and QRS complex duration
`(approximately 5% and 10%, respectively). At all doses tested a slight but statistically
`significant increase of heart rate (3 -7%) was determined. The cardiodepressant effects,
`hemodynamic changes and cardiac conduction effects were dose related. Atrial
`conduction was affected at lower doses than ventricular conduction. At higher doses
`(15-45mg/kg) severe conduction disturbances such as AV block, AV dissociation and
`nodal rhythm were observed, with marked reductions in blood pressure and cardiac
`output.
`
`Standard lZ-lead ECGs were performed at protocol-specified time points during all clinical trials
`included in this application. For phase 2/3 studies ECGs were evaluated by independent blinded
`analyses by central ECG readers. Additional details about the timing of ECGs in each protocol
`are presented in section 7.1.9 of this review.
`
`ECG abnormalities were evaluated by analyzing treatment emergent adverse events under the
`Investigations/ ECG investigations HLGT and the Cardiac disorders SOC, as well as ECG
`analyses in EP Pool 81 and $2.
`I
`
`66
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, —254,
`1—— Lacosamide for the treatment ofpartial-onset seizures
`
`53(4)
`
`o ECG related treatment emergent AEs in the Investigations SOC in EP SI
`
`A summary of AE under the MedDRA ECG Investigations HLT is presented below.
`
`Table 31. Adverse events under MedDRA Investigations SOC, ECG investigations HLT
`
`
`
`
`
`
`
`MedDRA PT involving ECG
`Placebo
`LCM mg/daY) .
`
`
`(N=364)
`200
`,
`400
`600
`LCM Total
`
`
`
`
`
`(N=203)
`(N=944)
`(N=270)
`(N=471)
`
`
`n (%)
`n (%)
`
`
`
`
`Any
`0 (0)
`4 (0.7)
`8 (0.9)
`
`
`ECG abnormal
`0
`0
`l
`
`
`0
`ECG QT corrected interval prolonged
`
`0
`ECG QRS complex abnormal
`
`
`ECG QRS complex prolonged
`0
`
`ECG T wave abnormal
`O
`
`
`
`ECG PRprolongation
`Source: Reviewer’s analysis. AE datasets.
`
`0
`
`
`
`1
`1
`1
`1
`
`
`
`0
`
`The analysis ofVAE reported under the Investigations SOC/ ECG investigations HLT, reveals 8
`cases involving ECG abnormalities in the EP Pool 81 (all on LCM) with an overall incidence of
`0.9% for LCM (8/944) and 0% for placebo (0/364). A listing of these cases is presented below.
`
`Table 32. Pool EP 81. PT terms under the HLT ECG investigation
`
`ID
`
`667015502
`
`
`
` F
`400
`45
`667015022
`
`QTC—change from baseline equals 60 ms
`M
`200
`29
`
`
`
`QTC change from baseline e uals 60 ms
`
`
`
`
`
`
`
`667017204
`
`200
`
`754011401
`7
`
`54016020
`
`600
`
`600
`
`754017602
`
`754018501
`755106406
`
`600
`
`600
`400
`
`
`
`
`41
`
`45 M
`
`49
`
`23 M
`
`‘ 38-
`61
`
`Abnormality in ECG (SAE & droout)
`Prolonged QTC interval (Drug withdrawn
`because of rotocol violation *
`
`
`
`
`
`
`
`
`Low QRS voltage (ALSO RBBB)
`T wave (non-specific) abnormality per ECG
`(01-jun-05)
`
`
`
`Elevated QRS com-lex 111 ms (ECG)
`
`
`
`PR time rolongation (SAE & dro out)
`Source: 188 AB dataset EP Pool 81. *Narrative/CRF not available among discontinuations due to AE;
`available under “other significant AB”.
`1 Dose at time of AE onset.
`
`The mean and median dose taken among those who were taking LCM was 220 and 200 mg/day,
`respectively. Except for one case that occurred during maintenance (ID# 667015022) all other
`cases occurred during titration. Three cases required drug withdrawal and two were considered
`serious. All cases recovered.
`
`Narratives of cases requiring discontinuation are as follows:
`
`67
`
`

`

`Clinical Safety Review
`Lourdes Villalba, MD.
`NDA 22-253, -254, A :Lacosamide for the treatment of partial-onset seizures
`
`“‘4‘
`
`Subject # 667017204 was a 41—year-old white female with a history of hypertension. She entered the
`trial on 23 Sep 2002 with partial seizures. The subject was randomized to LCM 200 on 18 Nov 2003.
`On 16 Dec 2002, she developed chest pain and “ECG abnormal”. At that time, the subject was still on
`placebo. She was discontinued from the study on 06 Jan 2003. The chest pain was considered
`resolved on 17 Dec 2002. The abnormality in ECG was considered resolved on 06 Jan 2003.
`
`This event occurred while the patient was on placebo, therefore, it is not related to LCM
`use. The narrative and CRF are unclear as to the nature ofthe ECG abnormality. A copy
`ofthe ECG is not included.
`
`Subject #754011401 was a 45 year old male with history of hypertension, diabetes mellitus,
`depression and obesity, randomized to LCM 600 on May 19, 2004. He discontinued because of a
`baseline pre-dose QTc prolongation. The narrative and CRF explain that the patient was randomized
`“in error”, and that the OTC prolongation was not evident until final ECG reading, therefore, the
`reason for discontinuation for this patient was Protocol violation. The following values were taken
`from the ECG datasets:
`
`
`
`In this patient, the ”QTc prolongation ”preceded use ofLCM Additionally, in May 25,
`the QTc had shortened by 58 ms from pre-dose values and that he hadfirst degree A V
`block. N0 follow up on this patient has been provided
`
`Subject 755106406 was a 61—year-old white male with medical history of obesity, myocarditis,
`hypercholesterolemia, apnea, and sick sinus syndrome with a pacemaker in place. He was randomized
`to LCM 400 on 09 Mar 2005. On 09 Mar 2005, during the Baseline Visit of the Titration Phase, the
`subject experienced ECG PR prolongation (211-216ms). The subject received his trial medication and
`began taking it on schedule achieving the randomized maintenance dose of LCM 400 mg/day. On 06
`April the investigator referred the subject to a cardiologist 2005 due to the PR interval value of 294ms
`and other ECG findings. The cardiologist recommended discontinuing the trial medication. The
`subject therefore withdrew from the trial and took his last dose of trial medication on 09 May 2005.
`The trial medication remained blinded. The subject did not experience any cardiac symptoms and no
`therapeutic measures were used to treat the AB. The investigator subsequently reported that the PR
`interval prolongation did not abate after withdrawal of trial medication, and had completely resolved
`on 31 Aug 2005 after the cardiologist had adjusted the