Type IV hypersensitivity reaction
`
`Investigations
`Alanine Aminotransferase Increased
`
`Lipase increased
`Aspartate Aminotransferase Increased
`Eosinophil Count Increased
`Granulocyte Count Decreased
`Hepatic Enzyme Abnormal
`Hepatic Enzyme Increased
`Liver Function Test Abnormal
`
`Neutrophil Count Decreased
`Platelet Count Decreased
`
`Lymphocyte count increased
`White blood cell count increased
`
`Monocyte count increased
`Basophil count increased
`White blood cell morphology abnormal
`Biopsy liver abnormal
`Biopsy kidney abnormal
`Biopsy lung abnormal
`Immunology test abnormal
`Biopsy skin abnormal
`Urinary casts
`
`Musculoskeletal and connective tissue disorders
`Arthritis
`
`Myositis
`Polyarthritis
`Joint swelling
`Joint warmth
`
`Arthralgia
`Arthropathy
`
`Neoplasm, benign, malignant and unspecified
`Pseudolymphoma
`
`Renal and urinary disorders
`Nephropathy toxic
`Nephritis
`Nephropathy toxic
`Renal failure
`Proteinuria
`Hematuria
`
`Oliguria
`Nephrotic syndrome
`Nephritis allergic
`Nephritic syndrome
`Nephritis interstitial
`Eosinophilic cystitiSa
`
`

`

`Respiratory, thoracic and mediastinal disorders
`Interstitial lung disease
`Pneumonitis
`Alveolitis
`
`Alveolitis allergic
`Eosinophilic bronchitiSa
`Eosinophilic pneumoniaa
`
`Skin and subcutaneous tissue disorders
`
`Eosinophilic cellulitiSa
`
`Laboratory value criteria
`Eosinophils % 210%
`Eosinophils absolute 20.5G/L
`Neutrophils absolute <l .SG/L
`Platelets SI OOG/L
`ALT ZZXULN
`AST ZZXULN
`
`
`ALT=alanine aminotransferase; AST=aspartate aminotranseras; iv=intravenous;
`LCM=lacosamide; MedDRA®=Medical Dictionary for Regulatory Activities;
`SOC=system organ class; ULN=upper limit of normal
`a Preferred term is included in the MedDRA Version 11.0 SOC of ‘Blood and
`
`lymphatic disorders’ in the document provided by the Division. For this table,
`however, the preferred term is listed under the Primary SOC for
`MedDRA Version 9.1 (which is utilized in the original submission and this
`response).
`
`APPEARS THPS WAY
`ON ORlGlMAL
`
`23
`
`

`

`Appendix 4. Adverse events suggestive of fever, rash, or lymphadenopathy (Group
`B) in subjects treated with LCM as submitted on (08/14/08 submission)
`
`MedDRA® SOC/Preferred term
`
`Blood and lymphatic system disorders
`Lymphadenitis
`Lymphadenopathy
`Lymphadenopathy Mediastinal
`
`General disorders and administration site conditions
`
`Pyrexia
`
`Immune system disorders
`Drug rash with eosinophilia and systemic symptoms:
`
`Skin and subcutaneous tissue disorders
`
`Dermatitis Allergic
`Rash
`
`Rash Erythematous
`Rash Generalised
`Rash Macular
`
`Rash Macular—Papular
`Rash Morbilliform
`
`Rash Papular
`Rash Pruritic
`Rash Psoriaform
`
`Drug Eruption
`Uriticaria
`
`Toxic skin eruption
`Exfoliative rash
`Skin exfoliation
`Rash vesicular
`
`
`iv=intravenous; LCM=lacosamide; MedDRA®=Medical Dictionary for Regulatory
`Activities; SOC=system organ class
`a Preferred term is included in the MedDRA Version 11.0 SOC of ‘Skin and
`
`subcutaneous tissue disorders’ in the document provided by the Division. For this
`table, however, the preferred term is listed under the Primary SOC for
`MedDRA Version 9.1 (which is utilized in the original submission and this response).
`
`APPEARS THIS WAY
`0N ORlGlNAL
`
`

`

`Appendix 5. Summary table of potential cases of multiorgan hypersensitivity identified
`in lacosamide trials, using the FDA suggested approach. Cases added in 8/08 are bolded.
`Subjects with new or revised narratives based on identification of a potential case of mum-organ
`hypersensiiifiqr using the Division-directed algorithm
`AE oufmme
`New or
`Basis of identification“: AE or lab
`Narrative
`CTD
`
`
`vaine criteria
`subject
`integrated raised
`
`
`number
`database.
`narrative
`
`subject
`number
`
` Phase 1
`
`588008953 Revised
`
`
`Group A: Joint swelling
`
`
`
`Remveredfresoived
`
`Group B: Rash pruriiie (18 Oct
`2909),
`
`Rash pruritir (19 Oct 2000},
`
`
`
`Rash prnritic (19 Oct 2000),
`
`
`
`6403820?6-‘
`
`646832876 Reused
`
`6411189204
`
`641030204
`
`641080501
`
`641080501 New
`
`
`
`
`
`
`Recoveredl'resoived
`Reeeverech’resuived
`
`Rash prui’itic (29 Oct 2000)
`Reeeveredfiresoh’eii
`
` . Receveredlresoived
`Rash (26 Oct 2098)
`
`Recoveredfresoived
`Group A: Hypersensitivity
`
`
`Recoveredfresoived
`Group B: Skin exfoiiatien
`
`
`
`
`Receiveredg’resniveé
`Group A: Art'hi‘algia
`
`
`
`Receveredfresoived
`Group B: Lymphadenopathy
`
`
`
`Group A: Neutrophils absolute
`NA (Ea?) value)
`
`
`
`
`<1 .5G/L
`
`
`Recoverediresolved
`
`Group B: Lymphadenopathy
`
`
`
` 836000010 836000019 New Group A: ALT increased Resolved
`
`Gmup B: Rash
`Resolved
`
`
`
`
`Group A: Neutmphils absolute
`NA {lab value)
`<11ij
`
`
`
`
`
`
`
`
`
`
`
`
`Partial—onset seizures
`
`607001454
`
`507001434 Revised
`
`
`
`
`
`
`
`615016052
`
`615013.028
`
`Group B: Rash erythematous
`
`598003003
`
`Group A: Eosmophfls absolute
`20 5oz}.
`
`Not yet completely
`resoived
`
`NA (rat; value)
`
`667012486 New
`
`Receveredfresuived
`
`Guoup B: Dermatizis allexgic
`
`Recoveredfresolved
`
`
`
`25
`
`

`

`
`Appendix 5. Cont.
`AE- outcome
`Basis of'idenfificaiion’: A}: oriab
`
`
`CID
`New or
`Warmth-e
`subject
`integrated
`revised
`
`
`number
`dafabase
`narrative
`
`513133" eat
`
`number
`
`
`
`
`
`value criteria
`
`
`
`
`
`
`667310192 Revised
`[667016102
`Group A: Arthralgia
`Recoveredh‘esoix-‘ed
`Group B: Rash (05 Mar 2GB3),
`fiecoveredfi‘esoived
`
`Rash (39 Apr 2003)
`Recoveretia’resolved
`
`6670}1095 Revised
`{SEENHGGSt
`GroupA: Hypersensitivity
`A‘Eecoveredl'resak-‘eé
`
`
`
`
`
`
`Group B: Rash
`Recox’ereiifresolved
`66701 ISOI Revised
`667011801
`Group A: Eosinophii count increasedf'iecoverediresolveé
`
`
`
`
`
`Eosinophiis % 310%,
`NA (lab value) '
`
`Eosinophiis aesolute 130.5GI‘L
`NA (lab value)
`
`
`Group B: Lymphadenopathy
`Recoverediresolved
`Group A: Joint swefling
`'fi7011814
`667011814 Revised
`Recoveredfresoived
`
`
`
`
`
`
`
`
`Group B: Rash
`Recoveredlremlveii
`66701351i Revised
`GroupA: Eosinophiis %210%~ AfiA (lab value)
`667013511
`NA (lab value)
`
`
`Eosinophiis absoiute 20.5611:
`
`
`Neutrophiis absolute 451.561L
`
`Recoveredfresolved
`
`Group B: Rash
`
`Recoveredfresolveé
` V55100804 Revised
`Group A: Leukopenia
`
`Recoveredlresolved
`
`
` Group 13: R3511
`
`755124101
`355124101 Revised
`NA (lab value)
`NA (lab value)
`Group A: Eosinophils % 210%,
`
`
`
`Neutrophiis absolute fiISGfL
`
`Recoveredfresolved
`
`Group B: Rash
`
`
`Recoverediresolved
`
`
`
`NA (lab value)
`
`Neutrophiis absoiute <1} .SGIL
`
`Recoveredfresolveo
`Group B: Rash
`
`
`L
`
`756012005
`
`Bosinophii count increased...
`
`Group A: Neutropenia,
`
`754013005 Revised
`
`Recoveredfresolved
`
`NA {lab vaiue)
`
`26
`
`

`

`subj ect
`number
`
`Group A: Eosinophils absolute
`20.591.
`
`
`75401220}
`
`
`
`756016195
`
`754915205 New
`
`Group AzArthmlgia
`
`
`
`
`
`757150001
`
`667017720 Revised
`
`NA (1313122211123)
`
`mp
`
`
`
`
`
`
`
`
`Appendix 5. Cont.
`CTD
`Narrafive
`New or
`Basis of identification“: All 01' 1a!)
`
`
`
`
`revised
`vaiue criteria
`51ij ed
`integrated
`
`
`
`
`(Iataba se
`number
`narrative
`
`
`
`
` NA (lab value)
`
`
`
`Recovered’resoived
` Group B: Pyrexia,
`'White blood ceil count increased
` Recoveredfresolved
`
`'7 5601 2462
`754012402
`Revised
`Group A: W'hite blood cell count
`Recm el eéfresnhed
`
`
`
`
`
`
`increased
`
`----——
`
`
`
`
`
`
`
`
`AST ZZXULN.
`NA (lab value)
`
`
`Hepatic enzyme incxeased
`Not recorveredfnot
`
`resolved
`
`
`
`Group B: Pyrexia
`
`742016303
`742016303 Revised
`
`
`
`
`
`
`
`
`27
`
`
`614001807 Revised
`
`
`Group A: ALT 22mm
`
`
`
`614001200 Revised
`
`614001807
`
`65016693
`
`-6
`
`74‘2012?05
`
`742012705 Revised
`
`Group A: ALT ZEXULN,
`
`NA Gab value)
`
`745111802
`
`i’681i1802 Revised
`
`resolved
`
`Group B: Rash
`
`Recoverecvresoived
`
`

`

`
`
`Appendix 5. Cont.
`Narrative
`CTD
`
`New or
`
`subject
`number
`
`integrated
`database
`
`revised
`narrative.
`
`Basis of identification“: AE or fab
`value criteria
`
`AE outcome
`
`subject
`number
`
`745114?18
`
`?68I14718
`
`3345174208
`
`742014208
`
`
`
`Group A: Eosinophils absoiute
`2056?L
`
`NA(1ab value)
`
`Group B: Rash papulax
`
`Recm eredfresoh ed
`
`20.56%.
`
`Group B: Rash
`
`.
`
`?451?5804
`
`742015804
`
`Group A: Eosinophils 96230918,
`
`NA (3313 value)
`
`'
`
`Bosinophiis absolute 20.56%
`
`768E09E09 Group A: Eosinophils absolute
`
`7451?6209
`
`742016209
`
`
`
`7346014104
`
`743014104
`
`
`
`768108312
`
`768108312
`
`768109109
`
`Group A: Eosinophils absoiut‘e
`20.5631.
`
`NA (fab vaiue)
`
`Group B: Rash generafiseé
`
`Recovereéx’resolved
`
`Group A: ALT EQXULN,
`
`AST EQXULN:
`
`NA (lab value)
`
`NA (lab mine)
`
`Eosinophiis absolute 20.56103,
`
`NA (Lab value)
`
`Hepatic enzyme. incxeased
`
`Not recoverewnot
`reach-Ed
`
`Group A: AST EZKULN,
`
`Eosiuophiis absolute 30.5CHL,
`
`NA (lab value)
`
`NA (lab value)
`
`Hepatic enzyme increased
`
`Recoveringfresoiving
`
`
`
`Group B: Pyrexia Recoveredkesolved
`
`2056/1
`
`Group B: Rash
`
`NA (lab value)
`
`Not recoxaerodfnot
`resolved
`‘
`
`28
`
`

`

`Appendix 5. cont.
`Narrative
`CTD
`
`subject
`number
`
`integrated
`database
`
`New or
`revised
`narrative
`
`Basis of identification“: AE- or lab
`value criteria
`
`AE outcome
`
`sub} est
`number
`
`
`7681097122
`
`768109712
`
`J.
`
`76810980?
`
`763109807
`
`Not recoveredfnot
`Group A: Haemamfia
`resoivezi
`Recovered!resoived
`
`Group B: Rash (30 Mar 2005),
`Recoveredfresoh‘ed
`Rash (31 31131‘ 2005)
`Recoveredfresoh-‘ed
`
`Group A: Arthmlgia (18 3133’ '
`2005):
`
`Arthmlgia (‘20 31a}; 2005),
`
`Recoveredfresoh’ed
`
`Group A: Hepatic enzyme increased
`
`
`Not recoveredmot
`Arthralgia {24 Why 2005)
`resoived
`Recoveredfresoh-‘ed
`
`Group B: Pyrexia (13 Riay 2005),
`Recoveredi'resolved
`Pyrexia (20 313}? 2605)
`768111003
`
`Group A: Eosinophils % 210%,
`
`NA (fab value)
`
`768111003
`
`Eosinophils absolute EOSGEL
`
`Group B: Rash (I 1 Aug 2005),
`
`Rash (25 Aug 2005),
`
`Rash (10 Sep 2005)
`
`NA (tab vaiue)
`Recovered/resolved
`
`Recoveredfresolved
`
`Recovered/resolved
`
`768112501
`
`768112501 Revised
`
`Group A: Eosinophiis % 210%,
`
`NA (iab value)
`
`83 0 3 02604
`
`830102604
`
`Revised
`
`830105613
`
`830105613
`
`Neuropathic pain of mixed origin
`611001024
`611001024 Revised
`
`Eosinophils absolute 205le
`
`Group B. Rash pruntic
`
`Group A: Eosinophiis absolute
`3:0ij
`
`Group B: Rash
`
`NA (fab value)
`Recoveredfresolved
`
`NA (Iab vaiue)
`
`Recoveredfresolved
`
`NA (lab vaiue)
`Group A: ALT ZZXULN
`Recoverecil'resolveci
`
`Group B: Dermatitis afiergic
`
`Recoveredx‘resolved
`
`Group B: Rash pmritic
`
`Recoveredfresolved
`
`AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotranserase; DNP=diabetic
`neuropathic pain; Iab=laboratory; NA=not applicable; ULN=upper limit of normal
`a Basis of identification is ‘Group A+B’, in which a subject was reported to experience an AB or have a lab
`value suggestive of internal organ involvement (Group A) and at least 1 AE suggestive of fever, rash, or
`lymphadenopathy (Group B) within 28 days in order for a case to be identified as potential multi-organ
`hypersensitivity. b Narrative has been updated based on inclusion of additional AE preferred terms
`requested by the Division. c In the response to the 12 Jun 2008 request, subject was identified in the
`table based on selected MedDRA preferred terms of medical importance. Based on the request of the
`Division to add hepatitis and hypersensitivity to Group A, the subject has been moved to this table
`based on the Division-directed algorithm and thus no longer appears in the table based on selected
`MedDRA preferred terms of medical importance. d Subject was randomized to placebo.
`
`Note: Based on the data cut-off for the 120-day safety update, 12 Jun 2007.Source: Sponsor’s
`table, 8/18/08 submission.
`
`29
`
`

`

`Appendix 6. Summary table of potential cases of multiorgan hypersensitivity identified
`in lacosamide trials, using the sponsor’s important medical event approach (8/08).
`
`Nana the
`
`subj eet
`member
`
`588008061
`
`388008061
`
`Revissed
`
`Hepatitis (suspect on drug induced
`hepatitis)
`
`
`
`Recmere(1,-1’resoiveClz
`
`
`Hypersensitivity (hypersensitivity)
`
`Recoveredz’resolved
`
`Hypersensitivity (28 Apr 2003}
`(aiiergies)
`
`Recoverediresoix'ed
`
`New
`754013507 New
`
`Hypersensitivity {allergies} ‘
`
`
`Recoveredfresoived
`
`755012601
`-
`75601500»
`
`754013601 New
`7—
`34015005 Revised
`
`Hypersensitivity (increase. afiergies)
`
`Recoveredfresolved
`
`Hypersensitivity (environmental
`aiiergies)
`
`Net recoveredfnot'
`resoived
`
`754015608 Revised
`
`Hmaersensitivity (aliergic Ieactien)
`
`Recoveredfresoived
`
`
`Basis of identification“:
`AE autmme
`CT!)
`New or
`
`
`
`
`
`integrated raised
`R’IedDRAs E’referred Term
`
`
`
`
`narrative.
`(reported term}
`database
`
`
`
`snbj eet
`
`
`mimiier
`
`Phase. 1 ’
`
`
`
`
`$87 0080 16
`5 87008016 Revised
`Hypers ensitiviry (impressicm of
`Recoveredfresoived
`
`increased sensitivity)
`.
`
`
`
`
`640032076 New
`640082076
`Parfiat-onsat seizures
`
`515010976
`667013301
`
`Hypersensitivity (09 Mar 2003)
`Recoveredé‘resoived
`
`(allergie s),
`
`
`
`
`
`
`?56015608
`DNP
`
`614001308
`
`614001308
`
`\ew
`
`614001426
`
`2
`'.
`_ 14001426 Rewsed
`
`
`
`Hypersensitivity {exacerbation of
`afiergies)
`
`Recoveredr’resolved
`
`
`
`
`
`Hypersensitivity (SOB secondary to
`aiiergies)
`
`Recoveredt’resoived
`
`742014104
`
`742014104 Revised
`
`Hypersensitivity (allergic reaction)
`
`Reecvered’resolved
`
`745 104201
`
`768 1 04201 Revised
`
`Anaphyiactic reactien (amphylaxis)
`
`Recovered}resolved
`
`3’45108305
`,
`
`7681 083 05 Rewsed
`
`Hypersensmmty (exacerbation of
`allergies)
`
`Recovereda’resoived
`
`745 1 15009
`
`7681 1 5009
`
`’\ eu.
`
`
`
`Hypersensitivity (envirenmentai
`aiiergies)
`
`
`Not recoveredfnot
`resolved
`
`
`
`
`
`
`30
`
`

`

`New or
`
`b
`
`Appendix 6. Cont.
`
`Narrative
`CTD '
`Basis of identifica tion"’
`
`
`
`
`MedDRA’S el-efermi Term
`subject
`integrated revised
`
`
`
`
`number
`database
`narrative
`(reported term}
`
`
`
`
`subject
`
`
`
`number
`
` Hypersensitivity {imermittent
`
`environmental aliergies)
`
`
`
`T43012806
`
`743172806
`
`Recoveredfresolved
`
`’368110402
`
`768110402
`
`Hypersensitivity (nasai allergy)
`
`Reecveredr’res’olved
`
`
`
`
`
`
`
`
`763 3 13 302 ,
`
`7681 1 3 3 02 New
`
`768114108
`
`?68114108
`
`830111810
`
`
`
`330111310
`
`7
`
`Recover-edfresolved
`
`Recoveredfresolved
`
`Hypersensitivity (allergic reaction)
`
`Recoverediresolved
`
`
`Hypersensitivity (allergic
`
`reaction?generalized swelling)
`
` Hypersensitivity {worsening of
`
`
`environmentai allergies)
`
` Myocarditis {toxic damage of
`
`
`myocard)
`
`
`
`AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotranserase; DNP=diabetic
`neuropathic pain; lab=laboratory; NA=not applicable; ULN=upper limit of normal
`a Basis of identification is ‘Medical importance’, which is an AB of hypersensitivity, anaphylactic reaction,
`hepatitis, or myocarditis any time after Baseline (start of trial medication).
`b Subjects meeting the criteria because of a medically important event may have also had an AB or lab
`value within Group A or Group B; however, as this was not the basis of identification, it is not identified in
`the table. Information regarding additional AEs or lab values is provided in the narrative.
`c The outcome of this AB is given as “not yet completely resolved” in the SP588 clinical trial report. The
`outcome is reported as “recovered” in this table because more information about this case has become
`available outside the database showing that the AE was resolved.
`d Subject was randomized to placebo
`Note: Includes all Phase 1 LCM trials, all oral and intravenous (iv) Phase 2 and 3 lacosamide trials in
`subjects with partial-onset seizures, and all oral Phase 2 and 3 LCM trials in subjects with neuropathic pain
`(ie, DNP, post-herpetic neuralgia, and neuropathic pain of mixed origin).
`Note: Based on the data cut-off for the 120-day safety update, 12 Jun 2007.
`Source: Sponsor’s table, 7/16/08 submission.
`
`APPEARS HHS WAY
`
`ON OREGWM
`
`31
`
`

`

`'_
`
`Z
`
`- Page(s) Withheld
`
`Trade Secret / Confidential (b4)
`
`/Draft Labeling (b4) -
`
`Draft Labeling (b5)
`
`Deliberative Process ”(b5)
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Maria Villalba
`
`9/26/2008 03:59:53 PM
`MEDICAL OFFICER
`
`Sally Yasuda_
`9/29/2008 12:35:46 PM
`INTERDISCIPLINARY
`
`

`

`Safety Team Leader Memo
`NDA 22-253, -254, 6?
`
`M4)
`Review and Evaluation of Clinical Data
`
`Safety Team Leader Memorandum
`
`NDA:
`Drug:
`Route:
`Indication:
`
`22-253, 22-254 Lg,
`Lacosamide (VIMPAT)
`
`Oral (tablets
`Partial Onset Seizures
`
`lV
`
`Schwartz Biosciences
`Sponsor:
`Review Date: 7/7/08
`
`“(4)
`
`Reviewer:
`
`Sally Usdin Yasuda, Safety Team Leader
`Neurology Drug Products, HFD-l20
`
`1. Background
`
`Lacosamide has been proposed as adjunctive therapy of partial onset seizures in patients
`2 16 yo The Sponsor has also proposed lacosamide for management of neuropathic
`pain associated with diabetic peripheral neuropathy in NDA N“ , that indication is
`being reviewed by HFD-l70. The mechanism of action of lacosamide in either indication
`has not been fully characterized; it enhances slow inactivation of voltage-gated sodium
`channels.
`
`The Sponsor has proposed the use of lacosamide (LCM) for partial onset seizures given
`orally in doses up to "“ mg/day, beginning with initial doses of 100 mg/day given as
`twice daily dosing. Intravenous LCM infusion was evaluated for temporary replacement
`of the oral dose in patients who are unable to take oral products. The Sponsor’s
`recommendation for switching from oral LCM is that the initial total daily intravenous
`dosage should be equivalent to the total daily dosage and frequency of the oral
`formulation, and that it should be infiised over a period of at leastg‘f‘ininutes.
`
`M4}
`
`This memorandum primarily summarizes the primary safety concerns from the safety
`team’s review of the lacosamide NDAs (22-253, 22-254. .4...,._ _ for adjunctive therapy
`for partial onset seizures. Dr. Villalba conducted the primary safety review for HFD-
`120.
`In addition to evaluating the safety database in the epilepsy population, Dr. Villalba
`has also summarized the results of a consult from Dr. Stephen Grant of the Division of
`Cardiovascular and Renal Products (DCRP) regarding PR prolongation and cardiac
`safety, as well as the pertinent safety results from the diabetic peripheral neuropathy
`(DPN) submission in ND;A —"
`. that was formally reviewed by Dr. Prokovnichka
`from the Division of Anesthesia, Analgesia and Rheumatologic Products (DAARP).
`Please refer to Dr. Villalba’s review for detailed safety considerations.
`
`2. Summary of Findings from the Safety Review
`
`2.] Sources ofData
`The clinical data are from studies submitted as part of the NDAs. Dr. Villalba’s review
`covered safety for NDA 22-253 (tablets), 22-254 (IV infusion) v—\_J
`.
`,1. She
`
`M4)
`
`bill)
`
`

`

`Safety Team Leader Memo
`NDA 22—253, -254. ===1
`
`be»
`
`has focused on safety in the phase 2/3 epilepsy studies (oral tablet and IV). The Phase
`2/3 epilepsy studies with the oral tablet are referred to as EP 81 (three placebo controlled
`studies) and EP S2 (includes EPSl and open label studies). Dr. Villalba has also
`reviewed safety in phase 1 studies and in the phase 2/3 studies with the oral capsule that
`were not included in the ISS safety pool. In addition, Dr. Villalba discusses pertinent
`safety findings in the DPN population, as identified in the DAARP review. For details
`regarding exposure in the safety pool, please refer to Dr. Villalba’s review.
`
`2.3 Significant Safely Findings
`
`2.3.1 Deaths
`
`Dr. Villalba notes that there were 9 deaths, all in patients taking LCM, across 1327
`subjects in the Phase 2/3 LCM partial onset seizure population. One of these occurred
`in the LCM-treated group in EP S1 (1/944=0.1%). There were no deaths in the Phase 1
`studies, Phase 2/3 trials with IV infusion, or oral capsule studies. Of the 9 deaths, 4 were
`considered possible sudden unexpected death in epilepsy (SUDEP) and 1 was a
`completed suicide. Suicidality will be discussed later in the review. The other 4 deaths
`included 1 road traffic accident, 1 due to intracranial hypertension, 1 glioblastoma, and 1
`cerebral hemorrhage thought secondary to injury during an epileptic seizure. Dr. Villalba
`believes that there is not a pattern suggesting that the 9 deaths were drug-related. I agree.
`
`In EP Pool S2, the estimated rate of SUDEP is 0.002 per patient year. As Dr. Villalba
`has discussed, the rate of SUDEP in the present LCM application is in the range expected
`in this population, based on that described in the LAMICTAL label (0.0005 for the
`general population of patients with epilepsy to 0.005 for patients with refractory epilepsy
`in patients not receiving LAMICTAL).
`
`In addition to the deaths in the epilepsy population, there were 15 deaths across 1566
`subjects in the Phase 2/3 LCM DPN population. No deaths occurred on placebo (0/291).
`Four were in the controlled studies (4/1023). Eight were cardiac-related (3 were in the
`placebo controlled studies), 1 was a completed suicide (72 days after last dose of LCM),
`1 was the result of head trauma/subdural hematoma/cardiopulmonary failure, and 5 were
`cancer—related (ovarian, pancreatic, bronchial, colon, and leukemia). The cardiac deaths
`(ventricular fibrillation, myocardial infarction, heart failure (n=2), myocarditis, cardiac
`arrest (n=2), and sudden death) occurred in patients with previous cardiovascular history,
`including diabetes plus hypertension, coronary artery disease, cerebrovascular disease, or
`peripheral vascular disease. In two of the cases of cardiac death (ventricular fibrillation
`and cardiac arrest), Dr. Prokovnichka did not believe that the relationship to LCM could
`be ruled out given the limited information provided.
`
`‘An additional death was reported in the DPN population. This death was due to
`myocarditis/toxic hepatitis and occurred 2 1/2 months following the last time LCM was
`dispensed for this patient, and the last date of administration was unknown. According to
`the sponsor at a teleconference on 6/12/08, a 3-month supply had been dispensed. The
`patient had taken LCM for more than 1 year. The toxic hepatitis was said to be alcoholic,
`although it is stated that the subject did not have a history of alcohol abuse. There is no
`
`

`

`11(4)
`
`Safety Team Leader Memo
`NDA 22-253, -254, *—
`
`further information available in the submission and the sponsor is not able to provide
`more details. We are concerned that this case could be consistent with a multi—organ
`hypersensitivity reaction.
`
`2.3.2
`
`Other Serious Adverse Events
`
`Overview ofEP S1 and SZ - Dr. Villalba notes that in placebo-controlled trials (EP Pool
`S1), the rate of treatment emergent (TE) serious adverse events (SAE) was 6.5% in LCM-
`treated subjects compared to 3.8% in subjects on placebo. Dr. Villalba does not find a
`clear dose-response for SAEs among LCM-treated patients. The most frequently
`reported TE SAEs in the epilepsy population were in the Nervous System disorders
`System Organ Class (SOC) (2.1% for LCM and 1.6% for placebo), with the most
`frequent preferred term (PT) being convulsion for both LCM and placebo-treated patients
`(0.8% for placebo and 0.8% across LCM doses). The next most frequent TE SAEs were
`in the Psychiatric disorders SOC (0.7% for LCM and 0 for placebo—treated patients). The
`psychiatric disorders included 1 case of hallucinations and 3 cases of psychosis. There
`was 1 case each of suicide, and suicide attempt. The most frequent PTs in EP Pool S2
`were convulsions (7.9%) and dizziness (2.9%). As Dr. Villalba notes determination of
`causality is difficult.
`
`DPN Database - Dr. Villalba notes that in the DPN database, the highest proportions of
`SAEs were in the cardiac disorders SOC (angina, coronary artery'disease, A-fib, a-flutter,
`and bradycardia) and the Nervous system disorder SOC (loss of consciousness and
`transient ischemic attack). SAEs in the DPN population were higher in the LCM treated
`patients (7.5%) compared to placebo (5.2%). The frequency of the cardiac SAEs was
`similar between LCM and placebo treated patients, although most of the cardiac
`conduction/rhythm abnormalities recorded as SAEs were reported from subjects treated
`with LCM. Other significant AEs that were observed to occur more frequently in patient
`receiving LCM vs placebo were syncope related events (7.3% vs 2.4%, respectively).
`
`Bradycardia - In the Phase 2/3 infusion studies there was 1 SAE of bradycardia reported.
`Dr. Villalba describes this case in detail in her review, and I will summarize it here. This
`was a 48 yo. white male with a prior history of hypertension who was also taking the
`ACE inhibitor perindopril, the beta-blocker acebutolol, and carbamazepine. After
`completing the 12-week treatment phase with oral LCM 200 mg/day he was rolled over
`into the open label extension. He had been in the OLP for approximately 6 months and
`had been taking oral LCM 300 mg/day for 74 days prior to enrolling in the IV trial. The
`AE occurred 7 minutes into the 3rd infusion of LCM 150 mg given over 15 minutes.
`Heart rate (HR) pre-dose was 62 bpm with a BP of 120/80; HR dropped to 26 bpm with a
`blood pressure of 100/60 mm Hg and there was no prolongation of PR or QRS. The
`LCM infusion was stopped due to the AE and the ECG changes were reported to be
`resolved 4 minutes after onset. Dr. Villalba notes that the plasma concentrations of LCM
`in this subject were less than 9 itle after the first 2 doses and after the infusion was
`stopped.
`'
`
`

`

`Safety Team Leader Memo
`NDA 22—253, -254, “=’
`
`M4)
`
`Two of the Sponsor’s cardiologists evaluated the case and diagnosed it as either
`bradycardia with junctional escape, or AV block with sinus exit block. Dr. Stephen
`Grant, the FDA cardiologist who evaluated this case, believes it is likely a vasovagal
`reaction. Dr. Villalba believes that a relationship between the infusion of the drug and
`the profound bradycardia is biologically plausible. She refers to the time course of the
`event, as well as the known PR and QRS prolongation observed in nonclinical studies in
`dogs at doses equivalent to 300 mg bid in humans (and with plasma concentrations of
`approximately 14.5 ug/ml). Dr. Villalba notes that taking a beta blocker may have
`predisposed this subject to the LCM effects on the heart rate.
`I agree with her
`assessment.
`
`Hepatitis/Nephrz'tz's/Multi—Organ Hypersensitivity - Dr. Villalba describes in detail a case
`of symptomatic hepatitis/nephritis occurring 12 days after the final dose of lacosamide in
`a healthy volunteer. Increased liver enzymes (AST/GOT >3OX ULN; ALT/GPT >10X
`ULN) along with proteinuria and casts (unknown values) were reported. No bilirubin
`was measured at the time of this AE.‘ Transaminases were returning to normal
`approximately 1 week later. There is a discrepancy regarding the bilirubin levels at the
`time that the transaminases were returning to normal, with levels of 22 mg/dl reported in
`the 188 but 22 umol/l (1.3 mg/dl) reported to the FDA in a later communication.
`Because there is no confirmed bilirubin value at the time of the AE, a Hy’s law case
`cannot be ruled out. Approximately 1 month after the patient became symptomatic,
`laboratory values normal. Viral causes for hepatitis were ruled out. A gastroenterologist
`diagnosed acute drug-induced hepatitis without any sequelae. A dermatologist interpreted
`this event as a possible delayed allergic reaction toward the trial medication. Dr.
`Villalba believes that drug induced hepatitis, or even a multi-organ hypersensitivity
`syndrome, cannot be ruled out, and notes that the fact that the drug was stopped because
`of study completion may have prevented the patient for having more severe/irreversible
`hepatic damage.
`I agree.
`
`Dropouts and Other Significant Adverse Events
`2.3.3
`Overall, 17.1% in the LCM group in EP Sl had treatment emergent AE that led to drop
`Out compared to 4.9% on placebo. Across the placebo controlled trials in EPSl, there
`was a dose-dependent increase in premature discontinuations based on SOC. The
`majority of discontinuations due to AEs'occurred during the titration period. The most
`common PTs leading to discontinuation were dizziness, ataxia, convulsion, and tremor;
`the overall rate for convulsion was similar for LCM and placebo. Other AEs that led to
`dropout were nausea, vomiting, diplopia, blurred vision and fatigue, and these showed a
`dose-response. The overall rate of dropouts in EPS2 was similar to EPSl . Similar events
`led to drop out in the DPN database. Syncope led to dropout in both the EP and DPN
`populations and will be discussed later.
`
`2.3.4 Common Adverse Events
`
`Among the most common adverse events in EPSl were dizziness, ataxia, nystagmus, and
`balance disorder that are also associated with other antiepileptic drugs. Common adverse
`events in the DPN population were similar to the epilepsy population.
`
`

`

`Safety Team Leader Memo
`NDA 22-253, —254, - “a“
`
`KR“!
`
`Laboratory findings
`2.3.5
`Evaluation of routine chemistry, hematology laboratory measurements and urinalyses did
`not reveal major issues of clinical concern in patients with partial-onset seizures, other
`than the previously identified case of hepatitis and increases in transaminases and GGT
`that will be discussed in section 2.3.6 of this memo.
`
`In EPSl neutropenia occurred in 1.3% of the total LCM group and 1.1% for placebo.
`There were 3 cases of treatment emergent neutropenia with granulocyte count < 1500/L
`that all occurred in the IV LCM group in SP616 and no cases on placebo or after oral
`administration in Study SP616 (7.8% in the IV infusion group vs 0% in the oral LCM
`group). SP616 was a phase 2/3 infiasion study that was an extension to an open label
`study with the oral tablet. Pre-infiJsion neutrophil counts were available for 2 of the 3
`patients; one had a neutrophil count of 2.3 and the other had a neutrophil count of 1.7
`prior to the infusion. In the phase 2/3 study SP757, the rate of neutropenia was similar to
`that in EPSl (1.3%). According to Dr. Villalba’s review, several patients had baseline
`neutropenia in both SP616 and SP757, and that it was unknown whether it was acquired
`during EPS2 or prior to lacosamide. The clinical significance of these observations is
`unclear.
`
`2.3.6 Adverse Events of Interest
`
`Based on non-clinical and clinical trial data, and safety considerations related to other
`AEDs, evaluation was performed for AEs related to cardiac and ECG abnormalities,
`syncope, abnormal liver fiJnction, rash, seizure, memory impairment, suicidality, and
`weight change.
`
`Cardiac AEs
`
`Consistent with conduction effects identified in the nonclinical program, LCM has a
`dose-related effect on the cardiac conduction system. In the thorough QT (TQT) study a
`dose-related increase in PR interval was observed. The maximum mean changes in PR
`interval on Day 6 (steady-state) were observed at 1 hour post-dose and were 6.3ms,
`13.6ms, and 18.2ms in the placebo, LCM 400, and LCM 800 groups, respectively. (No
`subject in any treatment group in the TQT study had QRS > 120 msec during the
`treatment phase). No evidence of orthostatic hypotensionr was observed. Evaluation of
`vital signs at protocol—specified time points in the clinical trials and in the TQT study
`suggests little or no effect on SBP, DBP, or heart rate with the proposed therapeutic doses
`of LCM oral tablet in the epilepsy population. Orthostatic changes were not measured in
`phase 2/3 studies.
`
`The TQT study demonstrated a shortening of the QTc. At Tmax on day 6, the mean
`change in QTcI from baseline for LCM 400 mg/day compared to placebo was -9.4 msec
`with an upper one-sided 95% CI of —4.2; for 800 mg/day the values were -7.4 and -3.3
`msec, respectively. According to the IRT review of the TQT study, adequate data upon
`which to base a recommendation regarding labeling for products that shorten the QT
`interval do not currently exist.
`‘
`
`_
`
`

`

`Safety Team Leader Memo
`NDA 22-253, -254, ’-"’
`
`“gig
`
`As Dr. Villalba has reviewed, the percentage of patients with any potentially cardiac-
`related AEs is 5.0% for LCM and 2.3% for placebo in EP Pool 81. The difference is
`driven by a higher rate of rhythm and conduction disorders, mainly PR and QRS
`prolongation‘in the LCM group. There were 4 cases of first degree AV block in the LCM
`group (0.4%) vs 0% on placebo.1 Three subjects taking LCM presented conduction
`disorders that led to dropout (2 cases of bradycardia and 1 PR prolongation in a patient
`with sick sinus syndrome) in EPSl. There were no cases of second degree AV block or
`serious arrhythmias in EPSl or EPSZ. In the DPN database, there was 1 case of second
`degree AV block in a patient with prolonged PR at baseline taking LCM 400 mg daily
`during the DPN open label studies, and an additional patient who had second degree AV
`block during telemetry monitoring after a syncopal episode during LCM titration with a
`dose of 600 mg. No QRS prolongation was observed in the DPN controlled database.
`In the placebo controlled studies in DPN there were 5 AEs of first degree AV block, 4 of
`atrial fibrillation, 3 of atrial flutter, and 1 nodal rhythm, all in the LCM treatment group.
`No such cases were observed in the placebo group.
`
`Of note, a case of 1St degree AV block occurred in a healthy volunteer when LCM was
`added to digoxin in a drug interaction study.
`
`Smcope
`Dr. Villalba has reviewed cases of syncope in the epilepsy population and summarized
`the discussion of syncope in the DPN population. Overall the rate of syncope in the
`controlled phase of the epilepsy and neuropathic pain