CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICATIONNUMBER:
`NDA 22-253 & 22-254
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEWg S 2
`
`

`

`MEMORANDUM TO FILE
`
`Dissolution Specification or Lacosamide Tablets (NDA 22-253 and NBA (-
`TV
`
`'
`
`-
`
`Drug name, substance, dosage
`form and strength
`
`Sponsor
`
`Clinical Division
`
`
`
`
`
`
`
`
`NDA 022-253 and
`
`
`r—f—
`
`
`
`
`
`film-coated
`Vimpat,
`Lacosamide
`
`tablets (50-, 100-, 150-, 200-, 250— and
`300-m 0
`
`Schwarz Biosciences, Inc.
`Research Trianle Park, NC
`Division of Neurology Products and
`Division of Anesthesia,
`
`Anal-esia and Rheumatolo- Products
`
`
`
`
`
`
`
`
`33W '
`
`M4)
`
`'The purpose of this memorandum to file is to clarify and consolidate the ONDQA
`recommendation for dissolution specification for the lacosamide tablets.
`
`In my April 4, 2008, dated review of this submission, l had provided the following
`section to support dissolution specification for lacosamide tablets:
`’
`
`mmmminmmpemmmalmweemmmwwmm
`adhasedmflmsbrnMeddahflefoflwhgdbsolufimmeflwdformebmfidetabletsis
`acceptable:
`
`USPApparatusNPadrfle)
`Testmefiumzllj NHCl,900mL
`Turpentine: 37°C 0.5“0
`
`Q=—- at 30 nin
`
`Forthe CMC review including complete product quarrty assessment and specification for the lacosamide
`dosage forms. please see Dr. Prafull ShiIunam’s review.
`
`lnfiieNDAaWIamnfidedmolufiontesfingwascamedmtatSOrpmpaddlerotafionspeed,the
`Spampmposos "rpmforthe dissolution specilimtion, however, consisterrtwitlfihesulmissimthe
`Spamslnddmintainfireofiginalpadrflespeedofflmmfordissolufimtecfirg.
`
`W4)
`
`Consistent with the above comments, the primary quality reviewer, Dr. Prafull
`Shiromani, had also requested additional information from the Sponsor (including
`those related to dissolution and stability testing of the lacosamide tablets).
`
`

`

`The Sponsor responded to the IR letter on April 29, 2008. Dr. Shiromani’s May
`20, 2008, dated review, encompassing evaluation of the updated dissolution test
`results obtained at both 50 rpm and —- rpm (as part of the updated 24 month
`stability data from twelve primary stability batches and additional supportive
`data), indicates that the Q value of -* ‘at 30 min with a paddle speed of 50 rpm
`is acceptable for ensuring product quality.
`
`This reviewer agrees with Dr. Prafull Shiromani’s extensive chemistry review of
`the dissolution test results obtained from stability batches. The Q value of =-
`at 30 min is acceptable (instead of -‘ at 30 min) based on dissolution test
`results that indicate that as long as the test is carried out with a
`—-==s
`.paddle
`speed (50 rpm vs. —-—- rpm) and according to the above test conditions (USP
`Apparatus 2, and 900 mL of 0.1 N HCI media), the dissolution test is suitable for
`quality assessment of the lacosamide tablets.
`
`' For product specification of the lacosamide tablets, including in vitro dissolution,
`please see Dr. Shiromani's May 20, 2008, dated Chemistry Review.
`
`“4)
`
`3(4)
`
`Signature;
`
`Arzu Selen, Ph.D.
`Associate Director, Biopharmaceutics
`Office of New Drug Quality Assessment
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature. -
`»
`
`' Arzu Selen
`
`6/27/2008 11:15:26 AM
`BIOPHARMACEUTICS
`
`

`

`- CLINICAL PHARMACOLOGY REVIEW
`
`NDAs
`Submission Dates:
`
`Type:
`Generic Name:
`Brand Name:
`
`Drug Class:
`Proposed Indications:
`
`Clinical Divisions:
`
`OCP Division:
`Reviewers:
`
`Team Leader:
`PM Reviewer:
`PM Team Leader:
`
`Dosage Form:
`Strengths:
`Route of Administration:
`
`Propsoed Dosing regimens:
`
`22—253, “"7
`9/28/2007; 11/26/2007; 12/13/2007; 5/27/2008
`
`13(4)
`
`505(b)(1)
`Lacosamide
`VIMPAT
`
`Other antiepileptics
`NDA 22-253: For the treatment of Epilepsy as adjunctive
`therapy in patients with partial onset seizures aged 16 years
`and older
`
`NDA _* . For the management of neuropathic pain
`associated with diabetic peripheral neuropathy
`NDA 22—253: Neurology Products (DNP)
`NDA ’ _,...
`. Anesthesia, Analgesia and Rheumatology
`Products (DAARP)
`Clinical Pharmacology 2 (DCP2)
`Lei Zhang, Ph.D.
`Emmanuel O. Fadiran, R.Ph., PhD.
`
`Suresh Doddapaneni, Ph. D.
`Hao Zhu, Ph.D.
`
`Joga Gobburu, Ph.D.
`Film Coated Tablets
`
`50, 100, 150, 200, 250, and 300 mg
`Oral
`
`NDA 22-253: Starting dose is 100 mg (50 mg twice daily)
`and the recommended maintenance dose of lacosamide is
`
`200-400mg per day. Maximum dose is -=-‘ mg/day.
`
`{ H
`
`11(4)
`
`Schwarz Biosciences, Inc
`IND ~==~
`
`
`Applicant:
`Relevant IND:
`
`Type of Submission; Code
`
`505 (b)(1); IS W“
`
`~
`
`.
`
`_
`
`

`

`TABLE OF CONTENTS
`
`1 EXECUTIVE SUMJVIARY ...................................................................................................... 3
`
`1.1
`1.2
`1.3
`
`RECOMMENDATIONS ...................................................................................................... 3
`PHASE IV COMMITMENT ................................................................................................ 3
`SUMMARY OF CLINICAL PHARMACOLOGY FINDINGS .......................................... 4
`
`2 QUESTION BASED REVIEW ........................................................................................... 14
`
`2.1 GENERAL ATTRIBUTES ................................................................................................ 14
`2.2 GENERAL CLINICAL PHARMACOLOGY ................................................................... 17
`2.3
`INTRINSIC FACTORS ...................................................................................................... 31
`2.4
`EXTRINSIC FACTORS .7.................................................................................................... 43
`2.5 GENERAL BIOPHARMACEUTICS ................................................................................ 52
`2.6 ANALYTICAL ................................................................................................................... 57
`
`3 DETAILED LABELING RECOMMENDATIONS ......................................................... 62
`
`4 APPENDICES ................................................................................ . ..................................... 75
`
`4.1
`4.2
`
`PROPOSED PACKAGE INSERT FROM THE SPONSOR .............................................. 75
`INDIVIDUAL STUDY REVIEWS ............................................................................................ 1 14
`
`In Vitro Metabolism/Transport Studies and In Vivo ADME ................................. 114
`4.2.1
`4.2.1.1 In Vitro Metabolism/Transport Study Review for Lacosamide ......................... 114
`4.2.1.1.] In vitro metabolism oflacosamide ................................................................. 114
`4.2.1.1.21n vitro induction and inhibition of CYP isoforms .......................................... 120
`4. 2. 1 . 1.3 In vitro transport processes ............................................................................ 130
`4. 2. 1. 1.4 Plasma protein binding ................................................................................... 135
`4.2.1.2 In Vivo ADME Study—Study SP619 .................................................................. 140
`4.2.2
`Single- and Multiple—Dose PK Studies in Healthy Subjects ................................... 145
`4.2.2.1 Dose proportionality studies—Single dose ......................................................... 145
`4.2.2.1.] Study SP835 .................................................................................................... 145
`4.2.2.1.2Study SP587 .................................................................................................... 148
`4.2.2.2 Dose Proportionality Studies—Multiple Doses .................................................. 151
`4.2.2.2.] Study SP836 .................................................................................................... 151
`4.2.2.2.2 Study SP588 .................................................................................................... 154
`4.2.3
`Special Population Studies ...................................................................................... 158
`4.2.3.1 Renal Impairment—Study SP641
`................. 158
`4.2.3.2 Hepatic Impairment—Study SP642 ..................................................................... 1 74
`4.2.3.3 Age and Gender—Study SP620 ........................................................................... 184
`4.2.3.4 Race—StudySP661...
`....191
`4.2.4
`Food Effect Study
`199
`4.2.4.1 Study SP600 ......................................................................................................... 199
`4.2.5
`In Vivo Drug Interaction Studies ............................................................................ 201
`4. 2. 5. 1 Omeprozole— Study SP863 ................................................................................. 201
`4.2.5.2 Digoxin—Study SP644 ........................................................................................ 211
`
`
`NDA
`Lacosamide Film-Coated Tablets
`
`-
`
`50, 100, 150, 200, 250, 300 m
`Original NDA Review
`
`g
`
`.
`
`~
`\
`b(4)
`
`2
`
`

`

`4.2.5.3 Metformin—Stuajl SP660 .................................................................................... 219
`4.2.5.4 Oral Contraceptive—Study SP599 ...................................................................... 230
`THROUGH QT STUDY CONSULT REVIEW ........................................................................... 239
`4.3
`4.4 OCP FILING AND REVIEW FORM ........................................................................................ 271
`
`1 EXECUTIVE SUMMARY
`
`Lacosamide (LCM) is a new molecular entity being developed as adjunctive therapy in the
`treatment of partial-onset seizures in patients with epilepsy aged 16 years and older and for the
`management of neuropathic pain associated with diabetic peripheral neuropathy (DPN). The
`proposed dose regimen is 50 to 200 mg twice daily, not to exceed -—— mg per day.
`
`,
`b“)
`
`The precise mechanism by which lacosamide exerts its antiepileptic and analgesic effects in
`humans remains to be fully elucidated. Preclinical experiments suggest that lacosamide has a
`dual mode of action: In Vitro electrophysiological studies have shown that lacosamide selectively
`enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of
`hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing while exerting no
`effects on physiological neuronal excitability. Additionally, lacosamide binds to collapsing
`response mediator protein-2 (CRl\/IP-2), a phosphoprotein which is mainly expressed in the
`nervous system and is involved in neuronal differentiation and control of axonal outgrowth.
`CRMP-2 expression was found to be dysregulated in the brain of epileptic patients as well and in
`
`There are, F’dosage forms of lacosamide products: film-coated tablet, solution for injection,
`“f Tablet is for
`epilepsy (NDA 22-253) and DPN ———’-=——, indications,
`
`and the later “formulations are for epilepsy ______._,_ (NDA 22-254
`
`‘
`
`M4)
`
`is reviewed by the
`The epilepsy indication (NDA 22—253, NDA 22-254
`Division of Neurology Products (DNP) and the neuropathic pain indication (NDA / ,4) is
`reviewed by the Division of Anesthesia, Analgesia and Rheumatology Products (DAARP).
`
`
`
`1.1 RECOMMENDATIONS
`
`The Office of Clinical Pharmacology / Division of Clinical Pharmacology-2 (OCP / DCP-2) has
`reviewed NDA 22-253 and NDA —=-=~
`Clinical Pharmacology information submitted on
`September 28, 2007 and finds it acceptable provided that a mutually satisfactory agreement can
`be reached between the sponsor and the Agency regarding the language in the package insert.
`
`M4)
`
`1.2
`
`PHASE IV COMMITMENT
`
`To better understand drug interaction potential for lacosamide, the Sponsor is recommended to
`
`NDA -———
`
`-
`
`Lacosamide Film—Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`_
`
`~
`_
`“(4)
`
`3
`
`

`

`provide the following data as a Phase 4 commitment:
`
`0 Determine which enzymes may be involved in the metabolism of lacosamide in addition
`to CYP2C19.
`
`1.3
`
`SUMMARY OF CLINICAL PHARMACOLOGY FINDINGS
`
`More than 30 in vivo pharmacokinetic studies and in vitro metabolism/transport study reports
`have been submitted in support of clinical pharmacology for this NDA.
`
`These studies were cross-referenced among fflDAs and were reviewed by four reviewers in
`OCP: Dr. Tandon in DCPl (NDAs 22-253, 22-254, *===='
`, 1 and Dr. Zhu in
`Pharmacometrics (NDAs 22-253 anc fi—a ), and Drs. Fadiran and Zhang in DCP2 (NDAs 22-
`253 anr‘
`\=— This review by Drs. Fadiran and Zhang comprehensively covers all the general
`Clinical Pharmacology aspects pertinent to NDAs 22-253 anr‘
`-==-—‘ and has adequate detail to
`stand on its own. Detailed reviews of the individual studies are captured'in this review, reviews
`by Dr. Tandon (DCPl) and Dr. Zhu (Pharmacometrics). The following table lists the location of
`reviews of individual studies.
`
`
`M43
`
`Study Number
`
`Location of Review
`
`
`Brief Description
`
`In vitro study reports
`
`In vitro
`’
`
`DCP2
`metabolism/Transport
`
`DCP2
`In vitro inhibition/induction
`
`
`
` Plasma protein binding
`DCP2
`
`In vivo metabolism
`14C-radiolabel study in
`
`
`
`DCP2
`human
`
`
`
`
`
`Dose-proportionality
`Single dose—tablets
`
`Multiple dose-tablets
`
`Single dose-IV
`
`Special populations
`Renal Impairment
`Hepatic Impairment
`CYP2C19 EM vs. PM
`
`
`
`Age and gender
`Race
`
`Drug interaction studies
`Digoxin
`Metformin
`
`
`
`
`Omeprazole
`Oral contraceptive
`NDA
`==—=-
`
`4
`
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`'
`
`1‘4)
`
`

`

` Effect on valproic acid
`
`Valproic acid effect
`
`Cabamezapine effect
`
`Effect on cabamezapine
`
`Comparative BE
`
`iv solution vs. tablet
`DCPl
`
`
`iv solution vs. tablet
`DCPl
`
`Food effect-tablet
`SP600
`DCP2
`__—
`
`
`___
`
`Population PK in healthy
`
`Pharrnacometrics
`
`
`
`
`DCP2: this review; DCPl: Dr. Tandon’s review (dated June 10, 2008); Pharmacometrics: Dr. Zhu’s review (dated
`June 5, 2008); QT-IRT: Appendix 4.3 of this review (dated July 25, 2007).
`
`Absoerion, Distribution, Metabolism and Elimination
`Following oral administration, lacosamide is absorbed with a Tmax of approximately 0.5 to 4
`hours after dosing. The elimination half-life is approximately 13 hours. Steady state plasma
`concentrations are achieved after 3 days of repeated administration (twice daily).
`Pharmacokinetics of lacosamide is dose proportional at the therapeutic dose range. Food does not
`affect lacosamide PK.
`’
`
`Absolute bioavailability of lacosamide was determined to be ~100% indicating an almost
`complete absorption of LCM after oral administration.
`
`After IV administration as well as after oral administration, the Vd of LCM was between
`approximately 40 and 60 L, indicating that lacosamide is distributed in the total body water. .Less
`than 15% of LCM is bound to plasma proteins.
`
`In vitro incubation with human liver microsomes, hepatocytes, kidney microsomes, and plasma
`showed a low metabolic turnover of lacosamide (<4% at 4 hours). Two metabolites, SPM 12809
`(desmethyl) and SPM 6912 (desacetyl) were found in trace quantities (<3 %). However, the
`human radiolabeled ADME study (SP619) suggested that lacosamide was metabolized in vivo.
`Only 40% of unchanged LCM was recovered in urine and about 30% of the dose was recovered
`in urine as SPM 12809, the major metabolite. Another 20% of dose was recovered as a polar
`fraction. Investigations with [14C]-lacosamide labeled either at the carboxylic or at the benzylic
`carbon atom suggest that the polar fraction may be a desbenzylamine derivative. SPM 12809 is
`not pharmacologically active. Levels of SPM 12809 in plasma and urine were confirmed in
`several PK studies. Exposure of SPM 12809 is approximately 10% of the parent compound in
`plasma.
`
`The maximum plasma concentration of SPM 12809 occurs later than the parent, LCM. At
`steady state, Tmax of SPM 12809 at steady state occurs between 1.8 and 4 hours after dosing
`(range: 0.5-12 hours). The terminal half-life of SPM 12809 is between approximately 15 and 23
`
`NDA "’
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`3(4)
`
`5
`
`

`

`hours and is not altered by different doses or by multiple dosing.
`
`The relative contribution of P450 isoforms in the oxidative metabolism of lacosamide is not
`clear. The Sponsor determined that lacosamide is a CYP2C19 substrate and formation of SPM
`12809 is via this pathway. The Sponsor did not study other CYP isoforms in the recombinant
`systems. The role of other enzymes in lacosamide metabolism is unknown. POP-PK data
`analysis showed a 20% decrease in exposure in the presence of cabamazepine, phenytoin or
`phenobarbital which may indicate an induction effect. As of note, all these three drugs are
`CYP3A inducers. Whether the data imply that CYP3A may be involved in metabolism of LCM
`remains to be determined. The Sponsor conducted an interaction study with carbamazepine in v
`healthy subjects and data did not show effect of carbamazepine on lacosamide. Metabolite, SPM
`12809, was not monitored in the study.
`
`Renal is the major clearance pathway for lacosamide as 95% of dose was recovered in urine
`either as lacosamide (40%) or metabolites.
`
`The renal clearance of lacosamide (~ 2 L/hr) was less than GFR indicating that it was net
`absorbed in the kidney. It is unknown which transporter may be responsible for reabsorption of
`lacosamide.
`
`,
`SQecial P02ulations
`Renal Impairment (Study SP641): Systemic exposure of lacosamide (AUC) increased with
`increasing degree of renal impairment. Renal function was classified based on estimated
`creatinine clearance according to the FDA 1998 renal guidance. Mean AUC increased 27%,
`23%, and 59% in subjects with mild, moderate, and severe renal impairment compared to
`subjects with normal renal function, respectively (Table 1). AUC values were more variable for
`patients with severe renal impairment, and AUC in some patients were 2-fold higher than AUC
`in subjects with normal renal function. Renal clearance of lacosamide decreased with increasing
`degree of renal impairment. For Cmax, only a slight difference was observed. The terminal half-
`life of lacosamide in plasma (Ti/2) was prolonged in subjects with severe renal impairment
`(approximately 18 hours) in comparison with normal renal function subjects (approximately 13
`hours).
`'
`
`The plasma concentrations of the metabolite, SPM 12809, also increased with increasing degree
`of renal impairment. The increases were more profound than lacosamide. AUC increased 4-fold
`in patients with severe renal impairment compared to normal renal function subjects.
`
`Results from subjects with endstage renal disease (ESRD) receiving hemodialysis showed that
`under a 4-hour dialysis starting 2.5 hours after dosing, AUC(O-tz) of LCM and SPM 12809 was
`approximately 50% lower in ESRD subjects receiving hemodialysis after a single oral dose of
`100 mg LCM Compared with dosing on a dialysis-free day (Table l). Cmax was less affected by
`dialysis than AUC, probably because the maximum plasma concentration was reached before the
`start of dialysis in most subjects (i.e., Tmax < 2.5 hours).
`
`Pharmacokinetics of LCM was similar in severe renal impairment patients and ESRD patients.
`
`NDA II—I
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`“\A‘
`
`'
`
`6
`
`

`

`Based on the results ofthis study, dose adjustment for patients with mild or moderate renal
`impairment may not be needed. However for patients with severe renal impairment or ESRD
`patients, the highest doses should be reduced to "’ of the highest doses recommended in
`patients who have normal renal function due to a mean 60% increase in AUC and highly variable
`exposure data.
`
`M4)
`
`For patients with ESRD who are on hemodialysis, due to the decreased plasma concentrations of
`lacosamide under dialysis conditions, dose adjustment needs to be considered in clinical practice
`for patients under dialysis.
`In addition, hemodialysis can be considered as an effective treatment
`to reduce lacosamide plasma concentrations, for instance in case of overdosing.
`
`Hepatic Impairment (Study SP642): Plasma concentrations of lacosamide were apprOximately
`50-60% higher in the subjects with moderate hepatic impairment (Child-Pugh Classification B)
`compared to subjects with normal hepatic function (Table 1). Half-life was prolonged and the
`amount of lacosamide excreted into urine within 0-12 hours after administration was reduced by
`approximately 20-30% in the subjects with hepatic impairment. The Tmax was comparable
`between the 2 groups. Plasma concentrations of the main metabolite of lacosamide, SPM 12809,
`were approximately 40-5 0% lower in subjects with hepatic impairment compared to healthy
`subjects.
`
`Similar to recommendation for severe renal impairment patients, the highest doses in moderate
`hepatic impairment patients should be reduced to "‘ of the highest doses recommended in
`patients who have normal hepatic function.
`
`m4?
`
`PK of lacosamide has not been studied in mild or severe hepatic impairment patients. Caution
`should be exercised as metabolism of lacosamide is anticipated to be altered in these subjects.
`Consider contraindication in severe hepatic impairment patients.
`
`Gender and Age (Study SP620): Exposure of LCM was higher in elderly male and female
`subjects compared with young male subjects. In terms of age effect, elderly male subjects
`showed ~3 0% higher AUC than young male subjects. In terms of gender effect, elderly female
`subjects showed ~15% higher AUC than elderly male subjects (Table I). When taking body
`weight differences into considerations, the difference between genders went away, however,
`there was still 20-25% difference between elderly and young subjects. Because of the high
`solubility of LCM in water, an increased LCM concentration in elderly subjects could result
`from the reduced body water in this age group. In addition, an influence of reduced renal
`filnction in elderly subjects could not be excluded.
`
`30% higher exposure in elderly may not warrant a dose adjustment based on age. However,
`caution should be exercised because elderly patients usually may also have impaired renal or
`. hepatic function that leads to increased lacosamide exposure.
`
`Age and sex do not influence exposure in patients with partial seizure based on population PK
`analyses results.
`
`NDA "F
`Lacosamide Film-Coated Tablets
`
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`51(4)
`
`7
`
`

`

`Race (Study SP661): A slightly higher exposure (measured as AUCx,ss) of LCM was observed
`in Asian and Black compared with White subjects (increase of approximately 10%) (Table 1).
`The body weight was slightly higher in the group of White subjects, and after normalization to
`body weight (AUCI,Ss,norm) the exposure for the 3 ethnic groups Was similar.
`
`With respect to SPM 12809, mean AUC and Cmax were approximately 30% to 50% lower in
`Asian and Black subjects compared with White subjects. This difference is not considered
`clinically relevant because the exposure of SPM 12809 is lower in Blacks and Asians compared
`' with White subjects and SPM 12809 has no known pharmacological activity.
`
`No dose adjustment is needed based on race.
`
`Pediatric Patients: The pharmacokinetic profile of lacosamide in pediatric patients has not been
`established. The Sponsor requested a deferral for initiating the pediatric development program
`for lacosamidewm
`
`CYP2C19 Polymorphism (Study SP643): Plasma concentrations of lacosamide were
`comparable (not more than 10% difference) between poor metabolizers (PMS) (n=4) and
`extensive metabolizers (EMS) (n=8) (Table 1), however, there were noticeable differences (75—
`80% difference) between PMS and EMS with respect to AUCS of the metabolite SPM 12809. PM
`and EM were classified based on genotype. PMs were homozygous for nonfunctional alleles and
`EMS were either heterozygous or homozygous for wild-type alleles. . The data confirmed that
`CYP2C19 is involved in SPM 12809 formation. As level of SPM 12809 is low compared to
`lacosamide, dose adjustment based on CYP2C19 genotype is not needed.
`
`Refer to Table 1 for summary of findings on effect of intrinsic factors on lacosamide exposure.
`
`APPEARS THlS WAY
`0N 0018128311.
`
`EEC/dug Film-coated Tablets
`
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`b(4§
`
`8
`
`

`

`
`
`Dosage Adjustment
`
`_
`
`same
`
`Table 1. Influence of intrinsic factors on lacosamide ex osure.
`Intrinsic Factors
`Lacosamide
`Cmax Ratio
`AUC Ratio
`
`
`0
`doses
`
`
`
`(906 CI)
`(90%CI)
`evaluated
`
`
`Compare to
`Reviewer
`Sponsor’s
`Compare to
`
`respective
`Recommen-
`proposal
`respective
`controls
`
`
`controls
`dation
`
`
`
`
`100 mg
`1.0955
`1.2682
`No dose
`same
`Renal
`Mild
`
`smgle dose
`(0.8972, 1.3375)
`(1.0601,
`adrizjtegzrr‘t ‘8
`Impa‘m‘em
`(CLcr 50-‘80
`
`
`
`
`mL/min)
`1.5172)
`y
`Control:
`
`
`
`
`Normal (CLcr
`. Moderate
`1.1356
`1.2247
`No dose
`>80 mL/min)
`adjustment is
`
`
`(CLcr 30-50
`(0.9301, 1.3866)
`(1.0237,
`necessary
`mL/min)
`1.4651)
`
`. Severe
`1.1223
`1.5903
`
`
`/ f
`
`(CLcr < 30
`(0.9192, 1.3703)
`(1.3293,
`-
`.
`/
`mL/mm)
`1.9025)
`
`I
`
`i
`
`Treatment -
`B/Treatment A
`0.5369
`
`(0.5060,
`0.5697)
`
`1.61
`(1.36-1.91)
`
`
`
`
`
`
`
`
`
`
`ESRD patients Treatment
`Treatment
`=single
`B/Treatment A
`0n
`
`
`
`hemodialysis
`dose of
`0.8757
`
`
`
`(CLcr < 30
`100mg .
`
`
`
`(0.7573, 1.0126)
`mL/min)
`lacosamlde
`
`
`on a
`
`dialysis-free
`day
`
`(1 day
`
`before
`
`dialysis);
`
`Treatment
`
`B=single
`
`dose of
`
`100mg
`
`lacosamide
`
`2.5 hours
`
`before start
`
`
`of dialysis
`
`
`
`Hepatic
`Moderate
`100 mg
`1.50
`
`Impairment
`(Child-Pugh
`twice daily
`(1304.73)
`
`
`
`
`B)
`Control:
`
`
`Normal
`
`
`
`I
`
`I
`'
`
`5;
`i
`
`_
`
`The maximum
`
`dose shouldbe
`f
`k
`ept e-d of
`.max1mum dose
`recommend for
`patients with
`normal organ
`function.
`The maximum
`dose should be
`kept "' of
`.
`max1mum dose
`recommend for
`patients with
`normal organ
`function.
`
`h‘4}
`
`II (4)
`
`The maximum
`dose in rfrliild and
`,,
`epatic
`impairment
`patients should
`be kept N of
`maximum dose
`recommend for
`
`normal organ function.
`
`patients with
`
`NDA "‘
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`3‘49
`
`.9
`
`

`

`Elderly (Male)
`
`100 mg
`twice daily
`
`1.33
`
`(1.16,1.43)
`
`(118,150)
`
`Female
`
`(Elderly)
`
`1.19
`
`1.13
`
`(107,131)
`
`(1.00,1.28)
`
`adjustment is
`necessary
`
`No dose
`
`adjustment is
`necessary
`
`Control:
`
`Young (Male)
`
`Gender
`
`Control:
`
`Male (Elderly)
`
`Lacosamide
`should be
`contraindicated
`
`in patients with
`severe hepatic
`impairment.
`No dose
`
`adjustment but
`dose titration
`
`with caution.
`
`200 mg
`twice daily
`
`CYP2C 19
`
`CYP2C19 PM
`
`Polymorphism
`
`vs.
`
`CYP2C19 EM
`
`200 mg
`twice daily
`
`1.0100
`
`1.1037
`
`No dose
`
`(0.8883,
`1.1483)
`
`1.0282
`
`(0.9043, 1.1690)
`
`(0.9795,
`1.2435)
`
`1.1150
`
`(0.9896,
`1.2562)
`
`adjustment is
`necessary
`
`No dose
`
`adjustment is
`necessary
`
`No dose
`
`adjustment is
`necessary
`
`Drug interactions
`The potential for drug interactions was evaluated in eight in vivo clinical pharmacology studies
`which incorporated an evaluation of the relevant in vitro DDI results (omeprazole), drugs that
`can be expected to be coadministered with lacosamide (digoxin, metforminxoral contraceptive,
`cabamazepine, and valproic acid).
`
`
`
`
`
`drus
`.
`Digoxin, Oral contraceptive, Omeprazole,
`Metformin, Cabamazepine, Valproic Acid,
`
`
`
`
`
`Potential for other drugs to affect
`lacosamide
`
`(
`
`Omeprazole, Metformin, Cabamazepine,
`Valproic Acid
`
`
`
`
`
`Cabameazpine and valproic acid interaction studies were mainly for the epilepsy indication and
`were reviewed by Dr. Tandon under NDA 22-253.
`
`Lacosamide did not show to affect PK of digoxin and omeprazole (Table 2). Lacosamide
`increases Cmax of ethinylestridiol in oral contraceptive (~20%) (Table 2). Its effect on
`metformin was] dependent on the sequence in which the subjects received metformin. The effect
`of lacosamide on metformin PK showed different trend for Group I (started with lacosamide on
`Day 1) and Group 2 (start with metformin on Day 1): Group 1 showed decreased exposure and
`__.-
`Group 2 showed increased exposure of metformin in the presence of lacosamide (Table 2). PD
`NDA __ _ _
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`11(4)
`
`10
`
`

`

`of metformin was not studied. However, these changes were in the range of 15 to 20% and the
`overall magnitude of change on metformin PK is not considered clinically relaVent.
`
`Metformin did not affect PK of lacosamide (Table 3). The administration of 40 mg omeprazole
`once daily multiple-dose treatment did not influence the pharmacokinetics of 300 mg LCM
`single-dose treatment but reduced the formation of SPM 12809 by approximately 60%. This
`indicates that CYP2C19 is responsible for the formation of SPM 12809. The findings are similar
`to what was found in Study 643 (CYP2C19 polymorphism study).
`
`Refer to Table 2 for summary of findings on effect of lacosamide on concomitant drugs exposure
`and Table 3 for summary of effect of concomitant drugs on lacosamide exposure.
`
`Table 2. Influence of lacosamide on concomitant dru_
`Concomitant
`Lacosamide
`Concomitant
`Cmax Ratio
`Medication
`doses
`medication
`dose
`evaluated
`
`(90% CI)
`
`ex I osure.
`AUC Ratio
`
`(90%c1)
`
`Dosage Adjustment
`
`. w/wo
`lacosamide
`
`w/wo lacosamide
`
`Reviewer
`Recommen
`
`40 mg single
`dose
`
`300 mg twice
`daily
`
`200 mg twice
`daily
`
`1.0976
`
`(0.9963, 1.2092)
`
`Sponsor’ s
`proposal
`
`No dose
`
`adjustment
`is
`necessary
`
`1.0241
`
`No dose
`
`1.1049
`
`(0.9793,
`1.2466)
`
`1.0487
`
`(0.9592,
`1.1465)
`
`(0.9792, 1.0709)
`
`adjustment
`is
`necessary
`
`
`Metformin
`
`500 mg three
`times a day
`(0, 6, and 12
`hr)
`
`200 mg twice
`daily
`
`Group 1
`0.8782
`
`Group 1
`0.8675
`
`None
`
`
`
`-dation
`
`Oral
`Contra-
`
`ceptive
`
`(Micro-
`gynon)
`
`Valproate
`
`levonor
`
`gestrel
`
`0.03 mg
`
`3 cycles
`
`0.15 mg
`
`3 cycles
`
`200 mg twice
`daily
`
`(the 3rd cycle)
`
`200 mg twice
`daily
`
`(the 3rd cycle)
`
`titrated from
`300 to 600
`mg
`
`_
`
`titrated from
`100 to 400
`mg
`
`1.01
`
`1.04
`
`(0.97-1.07)
`
`(0.99—1.09)
`
`(0.768, 1.004)
`
`(0.773, 0.973)
`
`Group 2
`1.1725
`
`Group 2
`1.1939
`
`(1.026, 1.340)
`
`1.205
`
`(1.064, 1.339)
`1.113
`
`(1.106,1.312)
`
`(1.052, 1.177)
`
`1.120
`
`1.092
`
`(1.053,1.192)
`
`(1.046, 1.140)
`
`No dose
`
`adjustment
`is
`necessary
`
`No dose
`
`adjustment
`is
`necessary
`
`No dose
`
`adjustment
`is
`
`NDA -—""
`Lacosamide Film-Coated Tablets
`
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`tit“)
`
`11
`
`

`

`----- necessary -
`same
`
`0.91
`
`0.88
`
`No dose
`
`(0.87—0.98)
`
`(0.84-0.92)
`
`adjustment
`1s
`
`necessary
`
`Carbamazepine
`
`
`
`titrated from
`
`titrated from
`200 to 400
`200 to 400
`mg
`mg
`
`0.95
`0.97
`
`
`
`Carbamazepine-
`epoxide
`
`
`
`
`(0.87-1.05)
`(0.89-1.04)
`
`
`
`Table 3. Influence of concomitant drugs on lacosamide ex
` Concomitant
`Concomitant
`Lacosamide
`Cmax Ratio
`Medication
`medication
`dose
`
`doses
`evaluated
`
`(90% CI)
`w/wo
`lacosamide
`
`nosure.
`
`AUC Ratio
`Dosage Adjustment
`
`(90%CI)
`w/wo lacosamide
`
` Reviewer
`
`Omeprazole
`
`Metformin
`
`300 mg single
`dose
`
`500 mg three
`times a day (0,
`6, and 12 hr)
`
`200 mg twice
`daily
`
`Valproate
`
`titrated from
`
`300 to 600 mg
`
`0.9958
`
`(0.9474,
`1.0467)
`
`Group 1
`1.1427
`
`1.1330
`
`(1.1015,1.1654)
`
`Group 1
`1.0964
`
`(1.044, 1.250)
`
`(1.062, 1.132)
`
`Group 2
`1.0228
`
`Group 2
`1.0280
`
`(0.935, 1.119)
`
`(0.996, 1.061)
`
`1.01
`
`1.00
`
`(0.96-1.07)
`
`(0.98-1.03)
`
`Carbamazepine
`
`titrated from
`
`200 to 400 mg
`
`1.075
`
`1.011
`
`(0.98-1.170)
`
`(096-1065)
`
`Recommen
`-dation
`
`Sponsor’s
`proposal
`
`No dose
`
`adjustment
`is
`necessary
`
`No dose
`
`adjustment
`is
`
`necessary
`
`No dose
`
`adjustment
`is
`necessary
`
`No dose
`
`adjustment
`is
`necessary
`
`QTc Prolongation Potential (QT-IR T consult review!
`The Sponsor conducted a Thorough QT study (SP640). The study report was reviewed by the
`QT—IRT (interdisciplinary team) under IND 57, 939. Their review found that both lacosamide
`and SPM 12809 did not prolong QTc but shortened QTc. For lacosamide, at Tmax on day 6, the
`mean change after administration of lacosamide 400 mg/day in QTcI from baseline compared to
`
`NDA "‘—
`
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 'mg
`Original NDA Review
`
`0(4)
`
`12
`
`

`

`placebo was —9.4 with an upper one-sided 95% CI of —4.2; for 800 mg/day the values were —7.4
`and —3.3, respectively. Shortening of the AAQTcI intervals were also observed on day 1 and day
`3. The ICH E14 guideline makes no recommendation for the development or labeling of
`products which shorten the QT interval because adequate data upon which to base a
`recommendation do not currently exist. As of note, the supra-therapeutic dose chosen for this
`study is only 33% higher than the highest proposed dose of 600 mg/day. The subject exposures
`in this study may not cover the increases in lacosamide concentrations due to moderate to severe
`hepatic or severe renal impairment (AUC increased 50-60%).
`
`Pogulation PK and Exgosure—Resgonse (PM review:
`Population PK has been conducted in both healthy and patient populations. PK parameters are
`comparable between healthy subjects and patient population.
`
`Across the pivotal trials for DPN,M
`
`see PM review for more details.
`
`BCS Classification
`Data were submitted to support a BCS class 1 classification of the drug and was deemed
`appropria