TROBALT 100 MG

1986- ו"משתה )םירישכת( םיחקורה תונקת יפל ןכרצל ןולע

דבלב אפור םשרמ יפ לע תקוושמ הפורתה

Retigabine 50 mg הליכמ ג"מ50 TM טלבורט

Retigabine 100 mg הליכמ ג"מ100 TM טלבורט

Retigabine 200mg הליכמ ג"מ200 TM טלבורט

Retigabine 300 mg הליכמ ג"מ300 TM טלבורט

Retigabine 400 mg הליכמ ג"מ400 TM טלבורט

ג"מ100 TM טלבורט ג"מ50 TM טלבורט

לופיט תלחתה תזירא

Retigabine 50 mg and Retigabine 100 mg הליכמ

תופוצמ תוילבט

6ףיעסב תטרופמ םיפסונה םיביכרמה תמישר

ליכמהזןולע.הפורתבשמתשתםרטבופוסדעןולעהתאןויעבארק

ואאפורהלאהנפ,תופסונתולאשךלשיםא.הפורתהלעיתיצמתעדימ

.חקורה לא

הלולעאיה.םירחאלהתואריבעתלא.ךתלחמבלופיטלהמשרנוזהפורת

.המוד םתלחמ יכ ךל הארנ םא וליפא םהל קיזהל

?הפורתה תדעוימ המל.1

לעתלעופאיה.םיסוכרפתודגונתוארקנהתופורתתצובקלתכיישטלבורט

.)םייטפליפא םיפקתה( םיסוכרפל תמרוגה חומב רתי תוליעפ תעינמ ידי

ליגמםירגובמבםיסוכרפתעינמלתופסונתופורתםעבולישבתנתינהפורתה

.היספליפאמ םילבוסה65דע18

הפורתב שומישינפל.2

דחאלכלואליעפהרמוחל)יגרלא(שיגרהתאםאהפורתבשמתשהלןיא

.)6ףיעסב םיטרופמ( הפורתה הליכמ רשא םיפסונה םיביכרמהמ

הפורתב שומישל תועגונה תודחוימ תורהזא

תויעבמלבוסךנהםאתעדלךירצךאפורהפורתבלופיטהתלחתהינפל

.דבכ וא הילכ

.תתחפומ הנמ ךל תתל טילחהל יושע אפורה הז הרקמב

.65ליג לעמ םירגובמלו18ליגלתחתמםידלילתצלמומהניאהפורתה

בל תויעב

:םיאבה םירקמב דחוימב .בלה בצק לע עיפשהל הלולע טלבורט

תורחאתופורתלטונהתאםא

בלבהיעבךלשיםא

םדב הכומנ םויזנגמ וא ןגלשאתמרךלשיםא

יאצויםייונישלבלתמשםאוא,ךילעםילחהלאמדחאםאאפורלרפס

ךרטצתוןכתיי.)ידמתויטיאואתוריהמתומיעפןוגכ(ךלשבלהבצקבןפוד

.טלבורט תליטנ ןמזב )ג.ק.א תקידב ללוכ( םיפסונ םיבקעמ

תודבאתה וא תימצע העיגפ לע תובשחמ

טלבורטןוגכםיסוכרפתודגונתופורתבולפוטרשאםישנאלשןטקרפסמ

הלאתובשחמךבתולועםא.תודבאתהואתימצעהעיגפלעתובשחמווח

.דימ אפורה םע רשק רוצ ,ןותנ ןמז לכב

ןתש וא םד תקידב עצבל ךירצ התא םא

ךירצהתאםא.תומייוסמתוקידבלשתואצותלעעיפשהלהלוכיטלבורט

חקולךנהשהקידבהלעהרוהרשאםדאלרפס:ןתשואםדתקידבתושעל

טלבורטו תורחא תופורת

תופורתללוכתורחאתופורת,הנורחאלתחקלםאוא,חקולהתאםא

עדיילשידחוימב.חקורלואאפורלךכלערפס,הנוזתיפסותוםשרמאלל

:חקול התא םא חקורה וא אפורה תא

שמשמה(םדבןיסקוגידהתומרתאתולעהלהלולעטלבורט-ןיסקוגיד

.)בל תויעבב לופיטל

אמגודל(םימייוסמהמדרהירמוחלעעיפשהלהלוכיטלבורט-המדרהירמוח

תאעדייתיללכהמדרהתחתחותינרובעלדמועהתאםא.)םוידוסלאטנפויט

.טלבורט לטונ ךנהש דעומ דועבמ אפורה

לוהוכלא תכירצו טלבורטב שומיש

הנשמטוקנ.ךתייארבשוטשטלםורגלהלולעטלבורטםעלוהוכלאתייתש

.ךילע ועיפשי לוהוכלאו טלבורט דציכ עדתש דע תוריהז

הקנהו ןוירה

תוחיטבהיבגלעדימןיא.אפורתארוהבקרוךאןוירהןמזבטלבורטלוטילשי

,ןוירהתעינמלהנימאהטישבשמתשהלךיילע.ןוירהבםישנבטלבורטלש

.טלבורטב תלפוטמ תאש ןמזב ןוירהל סנכהלמ ענמהל ידכ

םאואןוירהבתויהלהלוכיתאשתבשוח,ןוירהבךניהםאךלשאפורליחווד

םאקרןוירהןמזבטלבורטבשמתשהלךיילע.ןוירהלסנכהלתננכתמתא

הליחתץעוויהלילבמלופיטהתאיקיספתלא.ךכלעץילמהךלשאפורה

.ךלש אפורה םע

.םא בלחל רובעל םילוכי טלבורט לש םיביכרה םא עודי אל

תאלוקשיאפורה.הקנהןמזבטלבורטתליטנלעךלשאפורהםעיחחוש

.ךקוניתל והשלכ ןוכיס לומ ךרובע תלעותה

תונוכמב שומישו הגיהנ

הלופכהייארלםורגלוםונמנואתרוחרחסשיגרהלךלםורגלהלולעטלבורט

טלבורטךיאעדתשדעתונוכמבשמתשתואגהנתלא.תשטשוטמוא

.ךילע העיפשמ

הגיהנלעךלשהיספליפאהתעפשהלעךלשאפורהםעחחושלךילע

.תונוכמב שומישו

?הפורתב שמתשת דציכ.3

חקורהואאפורהםעקודבלךילע.אפורהתוארוהיפלשמתשהלשידימת

.חוטב ךניא םא

.דבלב אפורה ידי לע ועבקי לופיטה ןפואו ןונימה

:אוה לבוקמה ןונימה

הליטנב,ג"מ100איהטלבורטלשתלבוקמהתיברימהתיתלחתהההנמה

הגרדהבםיאתהללוכיאפורה.)םוילג"מ300לכהךס(םויבםימעפשולש

הטילשבויהיךלשםיפקתההשךכתועובשרפסמךשמבךלשהנמהתא

ג"מ400איהתיברימההנמה.תוילמינימויהייאוולהתועפותורתויהבוט

.)םויב ג"מ1,200לכה ךס( םויב םימעפ שולש הליטנב

תתחפומהנמךלתתליושעךלשאפורה,דבכואהילכתויעבךלשיםא

.טלבורט לש

תועובשרפסמוחקיוןכתיי.אפורהךלץילמהשהממטלבורטרתויחקיתלא

.ךרובע טלבורט לש הנוכנה הנמה תאיצמל

לופיט תלחתה תזיראב שמתשהל דציכ

םעךלשלופיטהתאליחתהלתנמלע"לופיטתלחתהתזירא“תלביקוןכתיי

ךשמבתחקלךרטצתשטלבורטתוילבטלכתאהליכמוזהזירא.טלבורט

םינמוסמ,םישגמינשבתואצמנתוילבטה.לופיטהלשםינושארהםייעובשה

,)7דע1םימי(ךלשלופיטהלשןושארהעובשהךשמב.2עובשו1עובש

עובשהךשמב.םויבםימעפשולשג"מ100לשתחאהילבטתחקלךילע

ג"מ100לשתחאהילבטתחקלךילע,)14דע8םימי(לופיטהלשינשה

.םויב םימעפ שולש ,דחיב ג"מ50לש תחא הילבטו

תחקל ךיא

.הילבטהתאתוצחלואקסרל,סועללןיא.התומלשבהילבטהתאעולבלשי

.לכוא ילב וא םע טלבורט לוטיל לוכי התא

רתוי הובג ןונימ תועטב תלטנ םא

הובגיוכיסךלהיהישןכתיי,טלבורטלשתוילבטידמרתויחקולהתאםא

:תואבה תועפותהמ תחאל וא יאוול תועפותל רתוי

בלבצקלעתועפשה

ואאפורלדימהנפ,הפורתהןמדליעלבתועטבםאוארתיתנמתלטנםא

.ךתיא הפורתה תזירא אבהו םילוח תיב לש ןוימ רדחל

הפורתה תא לוטיל תחכש םא

רחאל.תרכזנשעגרבתחאהנמחקטושפ,תונמהמתחאתחקלתחכשםא

.ךלש האבה הנמה ינפל תועש3תוחפל ןתמה ןכמ

ךניאםא.וחכשנשתונמלעתוצפלידכםעפלכבתחאהנממרתויחקתלא

.ךלש חקורה וא אפורה תא לאש ,תושעל המ חוטב

ץועיי אלל הפורתה תא תחקל קיספהל ןיא

ןכםאאלאקיספתלא.אפורהידילעץלמוהשיפכלופיטבדימתהלשי

.ךל הרוה ךלש אפורה

ךלשםיסוכרפה,תוימואתפבהפורתהתליטנתאקיספמהתאםא

אפורהתארוהבאלאךלשהנמהתאתיחפתלא.רימחהלוארוזחלםילולע

ךשמב,הגרדהבתחפותהנמהשבושח,טלבורטתחקלקיספהלידכ.ךלש

.תועובש3תוחפל

יאוול תועפות.4

קלחביאוולתועפותלםורגללולעטלבורטבשומישה,הפורתלכבומכ

לובסתאלוןכתיי.יאוולהתועפותתמישרארקמללהביתלא.םישמתשמהמ

.ןהמ תחא ףאמ

:תואבה תועפותב שח ךנה םא אפורל דימ תונפל שי

ןתש ןתמב תויעב

תתלתלוכירסוחלאיבהלתולוכיו,טלבורטםילטונהםישנאבתוצופנהלא

םינושארהםישדוחהךשמבהרקיהזשךכלרתויהובגיוכיסםייק.ללכבןתש

:תוללוכ תועפותה .טלבורט םע לופיטה לש

ןתשןתמןמזבבאכ

ןתשןתמבליחתהלישוק

ןתשתתלתלוכירסוח

:תואבה תועפותב שח ךנה םא ירשפאה םדקהב אפורל תונפל שי

תוישפנ תויעב

הרקיהזשךכלרתויהובגיוכיסםייק.טלבורטםילטונהםישנאבתוצופנהלא

:תוללוכ תועפותה .טלבורט םע לופיטה לש םינושארה םישדוחה ךשמב

לובלב

)תורומחתוישפנתויעב(תויטוכיספתוערפה

)םימייק םניאש םירבד לש העימש וא הייאר(תויזה

.ךל םיאתמ וניא טלבורטש טילחהל יושע ךלש אפורה

תופסונ יאוול תועפות

תובורק םיתיעל תועיפומ

תרוחרחס

םונמנ

היגרנארסוח

גירחעבצבןתש;ןתשבםד

הדרח;לובלבתשוחת

ןורכיזתויעב

תנבהבישוקוא,ןווכתמהתאשהמרמולואהביתכ,האירקבישוק

םילימ

זוכירתויעב

תויעב;לקשמיווישבתויעב;) וגיטרו(רורחסתשוחת;היצנידרואוקרסוח

הכילהב

םירירשהלשהדחתינוצריתלבהעונת;תודיער

םיילגרבואםיידיבהשוחתרסוחואץוצקע

הלופכואתשטשוטמהייאר

הפבשבוי;לוכיעבתויעב;הליחב;תוריצע

רבגומןובאית;לקשמבהיילע

םיילגרהתופכבוםיילגרהלשןותחתהקלחבתוחיפנ

הבוטאלתיללכהשוחתואהשלוחתשוחת

תוקוחר םיתיעל תועיפומ

תתחפומואתיטיאםירירשתעונת

העילבבישוק

רועבהחירפ

תרבגומהעזה

תוילכבםינבא

יאוולתעפותמלבוסהתארשאכוא,הרימחמיאוולהתועפותמתחאםא

.אפורה םע ץעייתהל ךילע ,ןולעב הרכזוה אלש

?הפורתה תא ןסחאל ךיא.5

ץוחמרוגסםוקמברומשלשיתרחאהפורתלכווזהפורת!הלערהענמ

.הלערהענמתךכידילעותוקוניתוםידלילשםדיגשיהלוםתייארהדשל

.אפורמ תשרופמ הארוה אלל האקהל םורגת לא

לטונךנהשםעפלכבהנמהותיוותהקודב!ךשוחבתופורתלוטילןיא

.םהל קוקז ךנה םא םייפקשמ בכרה .הפורת

יבגלעעיפומה) exp . date (הגופתהךיראתירחאהפורתבשמתשהלןיא

.שדוח ותוא לש ןורחאה םויל סחייתמ הגופתה ךיראת .הזיראה

לעמןסחאלןיא

ףסונ עדימ.6

:םג הליכמ הפורתה ליעפה רמוחהלעףסונ

Croscarmellosesodium,hypromellose,magnesiumstearate,

microcrystallinecellulose,polyvinylalcohol,titaniumdioxide(E171),

talc (E553b), lecithin (SOY) and xanthan gum .

:ףסונב תוליכמ ג"מ400טלבורטו ג"מ50טלבורט

Indigo carmine aluminium lake (E132) and carmine (E120).

:ףסונב תוליכמ ג"מ300טלבורטו ג"מ100טלבורט

Indigo carmine aluminium lake (E132) and iron oxide yellow (E172).

:ףסונב הליכמ ג"מ200טלבורט

Iron oxide yellow (E172).

הזיראהןכותהמוהפורתהתיארנדציכ

דצב" RTG50 “-בתונמוסמותולוגס,תולוגעתוילבט-ג"מ50טלבורט

.דחא

דצב" RTG100 “-בתונמוסמותוקורי,תולוגעתוילבט-ג"מ100טלבורט

.דחא

" RTG200 “-בתונמוסמותובוהצ,תוכרואמתוילבט-ג"מ200טלבורט

.דחא דצב

" RTG300 “-בתונמוסמותוקורי,תוכרואמתוילבט-ג"מ300טלבורט

.דחא דצב

" RTG400 “-בתונמוסמותולוגס,תוכרואמתוילבט-ג"מ400טלבורט

.דחא דצב

.םישגמינשהליכמלופיטתלחתהתזירא-ג"מ100טלבורטג"מ50טלבורט

לופיטהלששגמה.ג"מ100 X תוילבט21ליכמלופיטהלשןושארהעובשלשגמה

.ג"מ100 X תוילבט21-ו ג"מ50 X תוילבט21ליכמ ינשה עובשב

.הוקתחתפ,25לזב'חר,מ"עב)לארשי(ןיילקתימסוסקלג:םושירהלעב

2012רבמצד:ךיראתבתואירבהדרשמידילערשואוקדבנהזןולע

:תואירבה דרשמב יתכלממה תופורתה סקנפב הפורתהםושיררפסמ

148-83-33615:ג"מ100טלבורט ג"מ50טלבורט

148-82-33614:ג"מ50טלבורט

148-84-33616:ג"מ100טלבורט

148-85-33617:ג"מ200טלבורט

148-86-33618:ג"מ300טלבורט

148-87-33619:ג"מ400טלבורט

,תאזףאלע.רכזןושלבחסונהזןולע,האירקהתלקהלותוטשפהםשל

.םינימה ינש ינבל תדעוימ הפורתה

1250

1250

Patient leaflet in accordance with

the Pharmacists' Regulations (Preparations) - 1986

The medicine is dispensed according to

a physician’s prescription only

Trobalt

TM 50 mg contains Retigabine 50 mg

Trobalt

TM 100 mg contains Retigabine 100 mg

Trobalt TM 200 mg contains Retigabine 200 mg

Trobalt TM 300 mg contains Retigabine 300 mg

Trobalt

TM 400 mg contains Retigabine 400 mg

Trobalt TM 50 mg Trobalt TM 100 mg

Treatment initiation pack

contains Retigabine 50 mg and Retigabine 100 mg

Film coated tablets

List of the additional ingredients detailed in section 6.

Readtheentireleafletcarefullybeforeusingthemedicine.This

leafletcontainsconciseinformationaboutthemedicine.Ifyouhaveany

other questions, refer to the physician or the pharmacist.

Thismedicinehasbeenprescribedforthetreatmentofyourillness.

Donotpassitontoothers.Itmayharmthemevenifitseemstoyou

that their illness is similar.

1.What is themedicine intended for?

Trobaltisoneofagroupofmedicinescalledantiepileptics.Itworks

bypreventingthebrainoveractivitythatcausesepilepticseizures(also

called fits).

Themedicineisusedwithothermedicinestopreventepilepticseizures

in adults 18 to 65 years of age who suffer from epilepsy.

2.Before using the medicine

Donotusethemedicineifyouaresensitive(allergic)totheactive

ingredientortoanyoftheotheringredientscontainedinthemedicine

(detailed in section 6).

Special warnings regarding the use of the medicine

Before starting the treatment with the medicine your physician needs

to know if you have kidney or liver problems.

In this case the physician may decide to give you a reduced dose.

The medicine is not recommended for children aged under 18 and

adults over 65.

Heart conditions

Trobalt can affect heart rhythm. Especially in the following cases:

if you are taking other medicines

if you have a heart problem

if you have low potassium (hypokalaemia) or low magnesium

(hypomagnesaemia) in the blood

Tellthephysicianifanyoftheseapplytoyou,orifyounoticeany

unusualchangesinyourheartbeat(suchasbeatingtoofastortoo

slow).Youmayneedextracheck-ups(includinganelectrocardiogram

[ECG]) while you are taking Trobalt.

Thoughts of harming yourself or suicide

Asmallnumberofpeoplebeingtreatedwithantiepilepticssuchas

Trobalthavehadthoughtsofharmingorkillingthemselves.Ifatanytime

If you need a blood or urine test

Trobaltcanaffecttheresultsofsometests.Ifyouneedabloodorurine

test: tell the person who orders the test that you are taking Trobalt.

Other medicines and Trobalt

Ifyouaretakingorhaverecentlytakenothermedicinesincluding

non-prescriptionmedicinesandfoodsupplements,tellthe

physicianorthepharmacist.Especiallyinformthephysicianorthe

pharmacist if you are taking:

Digoxin-Trobaltmayincreasethelevelofdigoxinintheblood(used

to treat heart problems).

Anaesthetics-Trobaltmayaffectsomeanaesthetics(forexample

thiopentalsodium).Ifyouaregoingtohaveanoperationundera

generalanaesthetictellthephysicianthatyouaretakingTrobalt,well

in advance.

Using the medicine and alcohol

Drinking alcohol with Trobalt can make your vision blurred. Take extra

care until you know how Trobalt and alcohol affect you.

Pregnancy and breast-feeding

YoumusttakeTrobaltduringpregnancyaccordingtothephysician’s

instructiononly.ThereisnoinformationaboutthesafetyofTrobaltin

pregnantwomen.Youmustuseareliablemethodofcontraceptionto

avoid becoming pregnant while you are being treated with Trobalt.

Talktoyourphysicianifyouarepregnant,thinkyoucouldbepregnant,

orifyouplantobecomepregnant.YoushoulduseTrobaltwhileyou

arepregnantonlyifyourphysicianhasadvisedtodoso.Donotstop

treatment without first discussing it with your physician.

ItisnotknownwhethertheingredientsofTrobaltcanpassintobreast

milk.

TalktoyourphysicianabouttakingTrobaltwhileyouarebreast-feeding.

Thephysicianwillweighupthebenefittoyouagainstanyrisktoyour

baby.

Driving and using machines

Trobaltcanmakeyoufeeldizzyordrowsyandcausedoubleorblurred

vision.

Don’t drive or use machines until you know how Trobalt affects you.

Youshouldtalktoyourphysicianabouttheeffectofyourepilepsyon

driving and using machines.

3.How should you use the medicine?

Alwaysuseaccordingtothephysician’sinstructions.Youshouldcheck

with the physician or the pharmacist if you are unsure.

Thedosageandtreatmentwillbedeterminedbythephysician

only.

The recommended dosage is:

TheusualmaximumstartingdoseofTrobaltis100mg,takenthreetimes

aday(atotalof300mgaday).Thephysicianmaygraduallyadjustyour

doseoverafewweekssothatyourseizuresarebettercontrolled,and

sideeffectsarekepttoaminimum.Themaximumdoseis400mgtaken

three times a day (a total of 1,200mg a day).

Ifyouhavekidneyorliverproblems,yourphysicianmaygiveyoua

reduced dose of Trobalt.

Don’ttakeanymoreTrobaltthanthephysicianhasrecommended.It

may take a few weeks to find the right dose of Trobalt for you.

How to use a Treatment initiation pack

Youmayhavebeengivena“Treatmentinitiationpack”tostartyour

treatmentwithTrobalt.ThispackcontainsalltheTrobalttabletsyouwill

needtotakeduringyourfirsttwoweeksoftreatment.Thetabletsare

contained in two blister wallets, marked week 1 and week 2.

Duringyourfirstweekoftreatment(days1to7),youshouldtakeone

100mgtabletthreetimesaday.Duringthesecondweekoftreatment

(days8to14),youshouldtakeone100mgtabletandone50mgtablet

together, three times a day.

How to take

Swallowthetabletwhole.Don’tchew,crushorsplitthetablet.Youcan

If you have accidently taken a higher dosage

IfyoutaketoomanytabletsofTrobalt,youmaybemorelikelytohave

side effects, or any of these symptoms:

feeling agitated, aggressive or irritable

effects on heart rhythm

Ifyouhavetakenanoverdoseorifachildhasaccidentallyswallowedthe

medicine,referimmediatelytoaphysicianortoahospitalemergency

room and bring the package of the medicine with you.

If you forgot to take the medicine

Ifyouforgottotakeoneofthedoses,justtakeonedoseassoonasyou

remember. Then wait for at least 3hours before your next dose.

Don’ttakemorethanonedoseatatimetomakeupfortheforgotten

doses.Ifyouarenotsurewhattodo,askthephysicianorthe

pharmacist.

Don’t stop taking the medicine without advice

Persistwiththetreatmentasrecommendedbythephysician.Don’t

stop unless your physician advises you to.

Ifyousuddenlystoptakingthemedicine,yourseizuresmaycome

backorgetworse.Donotreduceyourdoseunlessyourphysiciantells

youto.TostoptakingTrobalt,itisimportantthatthedoseisreduced

gradually, over at least 3weeks.

4.Side effects

Aswithanymedicine,useofTrobaltmaycausesideeffectsinsome

oftheusers.Donotbealarmedbyreadingthelistofsideeffects.You

may not experience any of them.

Referimmediatelytothephysicianifyouexperiencethefollowing

symptoms:

Problems passing urine

ThesearecommoninpeopletakingTrobalt,andcanleadtonotbeing

abletopassurineatall.Thisismostlikelytohappenduringthefirst

few months of treatment with Trobalt. Symptoms include:

pain when passing urine (dysuria)

difficulty in starting to urinate (urinary hesitation)

not being able to pass urine (urinary retention)

Refertothephysicianassoonaspossibleifyouexperiencethe

following symptoms:

Mental health problems

ThesearecommoninpeopletakingTrobalt,andaremostlikelyto

happen during the first few months of treatment. Symptoms include:

confusion

psychotic disorders (severe mental health problems)

hallucinations (seeing or hearing things that are not there)

Your physician may decide that Trobalt is not suitable for you.

Additional side effects

Frequently occur

dizziness

drowsiness

lack of energy

blood in the urine; abnormally coloured urine

feeling disorientated; anxiety

memory problems (amnesia)

difficulty in reading, writing or saying what you mean, or difficulty in

understanding words

attention problems

lack of co‑ordination; spinning sensation (vertigo) ; balance problems;

problems walking

tremors; sudden jerking of muscles (myoclonus)

tingling or numbness of the hands or feet

double or blurred vision

constipation; feeling sick (nausea); indigestion; dry mouth

weight gain; increased appetite

feeling weak or generally unwell

changes in liver function, which will show up in blood tests

Uncommonly occur

slow or reduced muscle movement

difficulty in swallowing

skin rash

excessive sweating

kidney stones

Ifanyofthesideeffectsgetsworse,orwhenyousufferfromasideeffect

not mentioned in the leaflet, you should consult the physician.

5.How to store the medicine?

Avoid poisoning! This medicine and any other medicine should be

keptinaclosedplaceoutofthesightandreachofchildrenand

infantsinordertoavoidpoisoning.Donotinducevomitingwithout

an explicit instruction from the physician.

Do not take medicines in the dark! Check the label and the dose

each timeyou take a medicine. Wear glasses if you need them.

Do not use the medicine after the expiry date (exp. date) appearing on

the package. The expiry date refers to the last day of that month.

Do not store above 25°C.

6.Additional information

In addition to the active ingredient the medicine also contains:

Croscarmellosesodium,hypromellose,magnesiumstearate,

microcrystallinecellulose,polyvinylalcohol,titaniumdioxide(E171),

talc (E553b), lecithin (SOY) and xanthan gum.

Trobalt 50 mg and Trobalt 400 mg also contain:

Indigo carmine aluminium lake (E132) and carmine (E120).

Trobalt 100 mg and Trobalt 300 mg also contain:

Indigo carmine aluminium lake (E132) and iron oxide yellow (E172).

Trobalt 200 mg also contains:

Iron oxide yellow (E172).

What does the medicine look like and what is the content of the

package

Trobalt50mg–round,purpletabletsandmarked“RTG50”onone

side.

Trobalt100mg–round,greentabletsandmarked“RTG100”onone

side.

Trobalt200mg–oblong,yellowtabletsandmarked“RTG200”on

one side.

Trobalt300mg–oblong,greentabletsandmarked“RTG300”on

one side.

Trobalt400mg–oblong,purpletabletsandmarked“RTG400”on

one side.

Trobalt50mgTrobalt100mg–Treatmentinitiationpackcontains

2blisters.Theblisterforweek1oftreatmentcontains21tablets

x100mg.Theblisterforweek2contains21tabletsx50mgand

21tablets x100mg.

License Holder: GlaxoSmithKline (Israel) Ltd., 25 Basel St., Petach

Tikva

This leaflet was checked and approved by the Ministry of Health in:

December 2012

Registration number of the medicine in the National Drug Registry

of the Ministry of Health

Trobalt 50 mg Trobalt 100 mg: 148-83-33615

Trobalt 50 mg:148-82-33614

Trobalt 100 mg:148-84-33616

Trobalt 200 mg:148-85-33617

Trobalt 300 mg:148-86-33618

1250

1250

Theformat of thisleaflet wasdeterminedbytheMinistryofHealth and itscontentwaschecked and approved in

December2012

Trobalt™

1. NAMEOFTHEMEDICINALPRODUCT

Trobalt50mg

Trobalt 100mg

Trobalt 200mg

Trobalt 300mg

Trobalt400mg

Trobalt 50mg,Trobalt100mg(Initiation pack)

2. QUALITATIVEAND QUANTITATIVECOMPOSITION

Each film-coated tabletcontains50mg, 100 mg, 200 mg, 300 mg, 400 mgofretigabine.

For a fulllistof excipients, see section6.1.

3. PHARMACEUTICALFORM

Film-coated tablet(tablet).

50mgtablets:

Purple, round, film-coated tablets, markedwith“RTG50”on oneside.

100mgtablets:

Green, round, film-coated tablets, marked with “RTG100”on oneside.

200mgtablets:

Yellow, oblong, film-coated tablets, marked with “RTG-200”on oneside.

300mgtablets:

Green, oblong, film-coated tablets, marked with “RTG-300”on oneside.

400mgtablets:

Purple, oblong, film-coated tablets, marked with “RTG-400”on oneside.

4. CLINICALPARTICULARS

4.1 Therapeuticindications

Trobaltis indicated as adjunctivetreatmentofpartialonsetseizureswith orwithoutsecondary

generalisationin adults aged 18-65yearswithepilepsy.

4.2 Posology andmethodofadministration

Posology

Trobaltmust betitrated,accordingto individualpatientresponse, in orderto optimisethebalance

between efficacyand tolerability.

Themaximumtotaldailystartingdoseis300mg(100mgthree times daily). Thereafter, thetotal

dailydose is increased byamaximumof150mg every week,accordingto theindividualpatient

response and tolerability. An effective maintenance dose is expected to bebetween 600mg/dayand

1,200mg/day.

Themaximumtotalmaintenance dose is1,200mg/day. Thesafetyand efficacyof doses higherthan

1,200mg/dayhavenotbeen established.

Ifpatientsmissonedoseormore, itis recommended thattheytakea single doseas soon as they

remember.

Aftertakinga missed dose,atleast3hoursshould beallowedbeforethenextdoseand then the

normaldosingscheduleshould beresumed.

When withdrawingTrobalt, thedosemustbegraduallyreduced (seesection4.4).

Renalimpairment

Retigabineand its metabolites are eliminatedprincipallybyrenalexcretion.

No doseadjustmentisrequired in patientswith mildrenalimpairment(creatinineclearance50to

80ml/min;see section5.2).

A50%reduction in theinitialand maintenancedoseofTrobaltis recommendedinpatientswith

moderateorsevererenalimpairment(creatinineclearance<50ml/min;seesection5.2).Thetotal

dailystartingdose is150mg, and itisrecommended thatduringthetitration period, thetotaldaily

dose is increased by50mgeveryweek, to amaximumtotaldoseof600mg/day.

Theeffectof haemodialysis on retigabineclearance has notbeen adequatelyevaluated.

Hepatic impairment

No dosereduction isrequired in patientswith mild hepaticimpairment(Child-Pugh score5to6;see

section5.2).

A50%reduction in theinitialand maintenancedoseofTrobaltis recommendedinpatientswith

moderateorsevere hepatic impairment(Child-Pugh score ≥7;seesection5.2). Thetotaldailystarting

dose is150mg, and itisrecommended thatduringthetitration period, thetotaldailydoseisincreased

by50mgeveryweek, to amaximumtotaldoseof600mg/day.

Paediatricpopulation

Thesafetyand efficacyofretigabinein children below18years of age have notbeen establishedyet.

No data are available.

Elderly(65years of age and above)

Thereareonlylimited dataon thesafetyand efficacyofretigabinein patientsaged 65years and

above.

Method ofadministration

Trobaltmustbetaken orallyin threedivided doseseach day. Itmaybetaken with orwithoutfood

(seesection5.2). Thetabletsshould beswallowed whole, and notchewed, crushed ordivided.

4.3 Contraindications

Hypersensitivityto theactive substance or to anyof theexcipients.

4.4 Specialwarningsand precautionsforuse

Urinaryretention

Urinaryretention, dysuriaand urinaryhesitation werereported in controlled clinicalstudieswith

retigabine, generallywithin thefirst8weeks of treatment(see section4.8).Trobaltmustbeused with

caution in patientsatriskofurinaryretention, and itisrecommended thatpatientsareadvised about

theriskof these possible effects.

QTinterval

Astudyofcardiacconductionin healthysubjectshasdemonstrated thatretigabinetitrated to 1,200

mg/dayproduced aQT-prolongingeffect.Amean increase in IndividualCorrected QTInterval

(QTcI)ofup to 6.7 ms(upperbound of95%one-sided CI12.6 ms)wasobserved within 3hoursof

dosing.Caution should betakenwhenTrobaltis prescribed with medicinalproductsknown to

increase QTinterval and in patientswithknown prolonged QTinterval, congestive cardiac failure,

ventricularhypertrophy, hypokalaemiaorhypomagnesaemia

In these patients itis recommended thatan electrocardiogram(ECG)is recorded before initiation of

treatmentwith Trobaltand in thosewith acorrected QTinterval>440msatbaseline, an ECGshould

berecorded on reachingthemaintenance dose.

Psychiatric disorders

Confusionalstate, psychoticdisordersand hallucinationswerereported in controlled clinicalstudies

with retigabine(see section4.8). These effects generallyoccurred within thefirst8weeks of

treatment, andfrequentlyled to treatmentwithdrawalinaffectedpatients. Itis recommended that

patients are advised abouttheriskof these possible effects.

Suiciderisk

Suicidalideation and behaviourhavebeen reported in patientstreated withantiepilepticagentsin

severalindications. Ameta-analysis of randomised placebo-controlled trialsofantiepilepticdrugshas

also shown asmallincreased riskofsuicidalideation and behaviour. Themechanismofthisriskis

notknown and theavailable data do notexcludethepossibilityof an increased riskforTrobalt.

Thereforepatientsshould bemonitored forsignsofsuicidalideation and behavioursand appropriate

treatmentshould beconsidered. Patients (and caregivers of patients)should beadvised to seek

medicaladviceifsignsofsuicidalideationorbehaviouremerge.

Elderly(65 years of age and above)

Elderlypatients maybeatincreased riskof centralnervoussystemevents, urinaryretention andatrial

fibrillation.

Withdrawalseizures

Aswith otherantiepilepticdrugs,Trobaltmustbewithdrawn graduallyto minimisethepotential for

rebound seizures. Itisrecommended thattheTrobaltdoseisreduced overaperiod ofatleast

3weeks, unless safetyconcernsrequire an abruptwithdrawal.

4.5 Interactionwithothermedicinalproductsand other forms ofinteraction

Interaction studies haveonlybeen performed in adults.

Otherantiepilepticdrugs

In vitrodataindicated alowpotentialforinteraction with otherantiepilepticdrugs(seesection 5.2).

Thedruginteraction potentialwasthereforeevaluated based on apooled analysis across clinical

studiesand whilstnotconsidered asrobustas stand-aloneclinical interaction studies,theresults

supportthein vitrodata.

Based onthesepooled data, retigabinedid notcauseclinicallysignificanteffects on theplasma trough

concentrationsofthefollowingantiepilepticdrugs:

- carbamazepine, clobazam, clonazepam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine,

phenobarbital, phenytoin, pregabalin, topiramate, valproate, zonisamide.

Further, basedon pooled data, there were no clinicallysignificanteffects of thefollowing

antiepilepticdrugson retigabinepharmacokinetics:

- lamotrigine, levetiracetam, oxcarbazepine, topiramate, valproate.

Thisanalysisalso showed noclinicallysignificanteffectoftheinducers(phenytoin, carbamazepine

and phenobarbital)on retigabineclearance.

However,steady-state data froma limitednumberof patientsinsmallerphase IIstudiesindicated

that:

- phenytoin can reduceretigabinesystemicexposureby35%

- carbamazepinecan reduce retigabinesystemic exposure by33%

Interaction with digoxin

Data fromanin vitrostudyshowed thattheN-acetyl metaboliteofretigabine(NAMR)inhibited

P-glycoprotein-mediated transportofdigoxin in aconcentration-dependentmanner, indicatingthat

NAMRmayinhibitrenalclearanceofdigoxin. Administration ofTrobaltattherapeutic doses may

increasedigoxin serumconcentrations.

Interaction withanaesthetics

Trobaltmayincrease theduration ofanesthesia induced bysome anaesthetics (forexamplethiopental

sodium;see section5.1).

Interaction withalcohol

Co-administration ofethanol(1.0g/kg)with retigabine(200mg)resulted in anincrease in visual

blurringin healthyvolunteers. Itisrecommended thatpatients are advised aboutthepossible effects

on vision iftheytakeTrobaltwith alcohol.

Laboratorytests

Retigabinehasbeen shown to interferewith clinicallaboratoryassaysofboth serumand urine

bilirubin, whichcan resultin falselyelevated readings.

Oralcontraceptives

Atretigabinedosesofup to 750 mg/daytherewasno clinicallysignificanteffectofretigabineon the

pharmacokinetics of theestrogen(ethinylestradiol)orprogestogen(norethindrone)componentsof

theoralcontraceptivepill. In addition, therewasno clinicallysignificanteffect ofthelowdose

combination oralcontraceptive pillon thepharmacokinetics of retigabine.

4.6 Fertility, pregnancy andlactation

Pregnancy

Risk related toantiepilepticdrugsin general

Specialistadviceshould begiven to women who areofchildbearingpotential. Theneed fortreatment

withantiepilepticdrugsshould bereviewed when awoman isplanningto becomepregnant. In women

beingtreated forepilepsy, sudden discontinuation ofantiepilepticdrugtherapyshould beavoided as

thismaylead to breakthrough seizuresthatcould haveseriousconsequencesforthewoman and the

unborn child.

Theriskofcongenitalmalformationsisincreased byafactorof2 to 3 in theoffspringofmothers

treated withantiepilepticdrugscompared with theexpected incidencein thegeneralpopulation of

approximately3%. Themostfrequentlyreported defects are cleftlip, cardiovascularmalformations

and neuraltubedefects. Therapywith multipleantiepilepticdrugs is associated with ahigherriskof

congenitalmalformationsthan monotherapyand thereforemonotherapyshould beused whenever

possible.

Riskrelated to Trobalt

There areno adequatedatafromtheuseofretigabinein pregnantwomen.Animalstudiesare

insufficientwith respect to reproductivetoxicitybecausetheplasma levelsachieved inthese studies

wereless thanthosereachedin humansatrecommendeddoses(see section5.3).In adevelopmental

studyin rats whose mothers were treated with retigabineduringpregnancy, therewasadelayin

auditorystartleresponsedevelopmentoftheoffspring(see section5.3). Theclinicalsignificance of

thisfindingisnotknown.

Trobaltisnotrecommendedduringpregnancyand in women ofchildbearingage,notusing

contraception.

Breastfeeding

Itisunknown whetherretigabineisexcreted in human breastmilk. Animalstudieshaveshown

excretion ofretagabineand/oritsmetabolitesin breastmilk. Adecision on whetherto

continue/discontinuebreast-feedingorto continue/discontinuetherapywithTrobaltshould bemade

takinginto accountthebenefitofbreast-feedingto thechild and thebenefitofTrobalttherapyto the

woman.

Fertility

There were no treatment-related effects of retigabineon fertilityin animal studies. However, the

plasma levelsachieved inthese studieswereless thanthosereachedin humansatrecommendeddoses

(see section5.3).

Theeffectof retigabineon human fertilityhas notbeen established.

4.7 Effectsonability todriveand usemachines

Adverse reactionssuch asdizziness, somnolence,diplopiaand blurred vision werereported in

controlled clinicalstudies, particularlyduringtitration(see section4.8). Itisrecommended that

patients are advised abouttheriskof such adverse reactionsattreatmentinitiation and followingeach

titration step, and thattheyareadvised notto driveoroperatemachineryuntiltheyhaveestablished

howTrobaltaffects them.

Asthereisindividual variation in responseto allantiepilepticdrugtherapy, itisrecommended that

prescribers discuss with patients thespecific issues ofepilepsyanddriving.

4.8 Undesirable effects

Inpooled safetydata fromthreemulticentre,randomised, double-blind, placebo-controlled studies,

adversereactionswere generallymild to moderate in intensity, and weremostcommonlyreported in

thefirst 8weeks of treatment. There was an apparentdose-relationshipfordizziness, somnolence,

confusionalstate,aphasia,coordination abnormal,tremor, balancedisorder,memoryimpairment,gait

disturbance,blurredvisionand constipation.

Adverse reactionsthatweremostfrequentlyreportedtolead to discontinuation weredizziness,

somnolence, fatigueand confusionalstate.

Thefollowingconvention hasbeenused for theclassification ofadverse reactions:

Verycommon: ≥1/10

Common: ≥1/100 to <1/10

Uncommon: ≥1/1,000 to <1/100

Rare: ≥1/10,000 to <1/1,000

Veryrare: <1/10,000.

Within each frequencygrouping,adverse reactionsare presented in orderofdecreasingseriousness.

SystemOrganClass

Very common Common Uncommon

Metabolismand

nutritiondisorders

Weightincreased

Increased appetite

Psychiatric disorders

Confusionalstate

Psychoticdisorders

Hallucinations

Disorientation

Anxiety

Nervoussystem

disorders

Dizziness

Somnolence 1

Amnesia 1

Aphasia

Coordination

abnormal 1

Vertigo 1

Paraesthesia

Tremor 1

Balance disorder 1

Memoryimpairment 1

Dysphasia

Dysarthria

Disturbancein

attention

Gaitdisturbance 1

Myoclonus

Hypokinesia

Eyedisorders

Diplopia

Blurred vision

Gastrointestinal

disorders Nausea

Constipation

Dyspepsia

Drymouth Dysphagia

SystemOrganClass

Very common Common Uncommon

Hepatobiliary

disorders Increased liver

function tests

Skin and

subcutaneous

disorders

Skin rash

Hyperhidrosis

Renaland urinary

disorders

Dysuria

Urinaryhesitation

Haematuria

Chromaturia

Urinaryretention

Nephrolithiasis

Generaldisorders and

administrativesite

conditions Fatigue Asthenia

Malaise

Peripheraloedema

1 Datafromelderlypatients indicates thatthey may be more likely to experience certaincentral

nervous systemevents.

Description ofselected adverse reactions

Adversereactionsrelated to voidingdysfunction, includingurinaryretention, werereportedin5%of

retigabine-treated patientsin thepooled safetydataset(see section4.4). Themajorityofevents

occurred in thefirst8weeks of treatment, and there was no apparentdose-relationship.

Inretigabine-treated patients inthepooled dataset, confusionalstatewasreported in 9%ofpatients,

hallucinationsin2%ofpatientsand psychoticdisordersin1%ofpatients(see section4.4).The

majorityofadverse reactionsoccurred in thefirst8weeks of treatment, and there was an apparent

dose-relationship forconfusionalstateonly.

4.9 Overdose

Symptomsand signs

Thereislimited experience of overdose with retigabine.

Retigabineoverdoses in excess of 2,500mg/daywerereported duringclinicalstudies. In addition to

adverse reactionsseen attherapeutic doses, symptoms of retigabineoverdose included agitation,

aggressive behaviourandirritability.There were no reportedsequelae.

In astudyin volunteers, cardiacarrhythmia(cardiac arrest/asystole or ventriculartachycardia)

occurred in twosubjectswithin 3hoursofreceivingasingle900mgretigabinedose. Thearrhythmias

spontaneouslyresolved,andboth volunteersrecovered withoutsequelae.

Treatment

In theeventofoverdose, itisrecommended thatthepatientisgiven appropriatesupportivetherapyas

clinicallyindicated, includingelectrocardiogram(ECG)monitoring. Furthermanagementshould beas

recommended bythenationalpoisonscentre, where available.

5. PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeuticgroup:antiepileptics,otherantiepileptics, ATCcode:N03AX21.

Mechanismof action

Potassiumchannels are oneof thevoltage-gated ion channelsfound in neuronalcellsand are

importantdeterminantsofneuronalactivity.In vitrostudies indicate thatretigabineacts primarily

through openingneuronalpotassiumchannels(KCNQ2[Kv7.2]and KCNQ3[Kv7.3]). Thisstabilises

therestingmembranepotentialand controlsthesub-threshold electricalexcitabilityin neurons, thus

preventingtheinitiation ofepileptiformaction potential bursts.Mutationsin theKCNQchannels

underlie severalhuman inheritable disorders,includingepilepsy(KCNQ2 and 3).Themechanismof

action ofretigabineon potassiumchannelshasbeen welldocumented,howeverothermechanisms by

which retigabinemayassertan antiepileptic effecthave yettobefullyelucidated.

In arangeofseizuremodels, retigabineincreased thethreshold forseizureinduction produced by

maximalelectroshock, pentylenetetrazol, picrotoxin and N-methyl-D-aspartate(NMDA).Retigabine

also displayed inhibitorypropertiesinmultiplekindlingmodels,forexample,in thefullykindled state

and in some casesduringthekindlingdevelopment.In addition, retigabinewaseffectivein preventing

statusepilepticusseizures in rodents with cobalt-induced epileptogeniclesions, andinhibitingtonic

extensor seizures in geneticallysusceptible mice.Therelevance of these models to human epilepsy,

however, isnotknown.

Pharmacodynamic effects

In rats, retigabineincreased thesleep timeinduced bythiopentalsodiumfromapproximately 4minto

53min, and thepropofol-induced sleep timefromapproximately8minto 12min. There was no effect

on sleep timeinduced byhalothaneormethohexitalsodium.Trobaltmayincrease theduration of

anesthesia induced bysome anaesthetics (forexamplethiopentalsodium).

Clinicalefficacyof adjunctive retigabinetherapyin partialonsetseizures

Threemulticentre, randomized, double-blind, placebo-controlled studiesin atotalof1239adult

patients have been conducted to assess theefficacyof retigabineas adjunctive therapyof partialonset

seizures, with orwithoutsecondarygeneralisation. All patientsenrolled were to havehad seizures

thatwerenotadequatelycontrolled with 1to3concomitantantiepilepticdrugs, and morethan 75%of

allpatients were taking ≥2concurrentantiepilepticdrugs.Across allstudies, patientshad amean

duration ofepilepsyof22years and amedian baselineseizure frequencyrangingfrom8to12 per

28days.Patientswererandomized to placebo orretigabineat600, 900or1,200mg/day(see Table1).

Duringan 8-weekbaselineperiod, patients had to experience ≥4partialonsetseizuresper28days.

Patientscould notbeseizure-freefor ≥21days.Theduration ofthemaintenance phase was8 or

12weeks.

Theprimaryefficacyendpoints were:

- percentage change in the28-daytotalpartialseizure frequencyfrombaselineto the

double-blind phase(titration and maintenance phasescombined)in all threestudies

- responderrate (defined as thepercentage of patients with a ≥50%reduction in 28-daytotal

partialseizure frequency)frombaselineto themaintenance phase(Studies301 and 302 only).

Retigabinewas effective in adjunctive treatmentof adults with partialonsetseizures in threeclinical

studies (Table1). Retigabinewas statisticallysignificantlysuperior to placebo at600mg/day

(onestudy), 900mg/day (twostudies)and 1,200mg/day (twostudies).

Thestudieswerenotdesigned to evaluatespecificcombinationsofantiepilepticdrugs. Consequently,

theefficacyand safetyof retigabinewhen taken concomitantlywith antiepileptic drugs thatwere less

commonlyused as background treatmentin theclinicalstudies, includinglevetiracetam, has notbeen

definitelyshown.

Table1. Summaryofpercentagechangesin 28-daytotalpartialseizurefrequencyand responder

rates

Study

(n=population in double-blind phase;

n=population in maintenancephase)

Placebo Retigabine

600

mg/day 900

mg/day 1,200

mg/day

Study205(n=396;n=303)

Totalpartialseizure frequency(median) %change -13% -23% -29%* -35%*

Responderrate(secondaryendpoint)

26% 28% 41% 41%*

Study301(n=305;n=256)

Totalpartialseizure frequency(median) %change -18% ~ ~ -44%*

Responderrate

23% ~ ~ 56%*

Study302(n=538;n=471)

Total partialseizure frequency(median) %change -16% -28%* -40%* ~

Responderrate

19% 39%* 47%* ~

* Statisticallysignificant, p ≤0.05

~ Dosenotstudied

In open-labelextensionsofthethree placebo-controlled studies, persistence of efficacywas

maintained overan evaluation period ofatleast12months(365patients).

Paediatricpopulation

TheEuropean Medicines Agencyhas waived theobligation to submittheresultsofstudieswith

retigabinein paediatric patients aged 0 tobelow2yearswith Lennox GastautSyndrome.

TheEuropean MedicinesAgencyhasdeferred theobligation to submittheresultsofstudieswith

retigabineinpaediatric patients aged 2 tobelow18yearswith Lennox GastautSyndrome, and in

paediatric patients aged 0 tobelow18years with partialonsetseizures.

5.2 Pharmacokinetic properties

Absorption

Afterboth singleand multipleoraldoses, retigabineisrapidlyabsorbed with mediant

max values

generallybetween0.5and 2hours. Absoluteoral bioavailabilityofretigabinerelativeto an

intravenousdoseisapproximately60%.

Administration ofretigabinewith ahigh fatmealresulted in no changein theoverallextentof

retigabineabsorption, butfood reduced thebetween-subject variabilityin C

(23%)compared to the

fasted state (41%),and led to an increase in C

(38%). Theeffectoffood on C

underusual

clinical conditionsisnotexpected tobeclinicallyrelevant. ThereforeTrobaltmaybetaken with or

withoutfood.

Distribution

Retigabineisapproximately80%bound to plasmaprotein overtheconcentration rangeof0.1 to

2µg/ml. Thesteadystatevolumeofdistribution ofretigabineis2to 3l/kgfollowingintravenous

dosing.

Biotransformation

Retigabineis extensivelymetabolisedin humans. Asubstantialfraction oftheretigabinedoseis

converted to inactive N-glucuronides. Retigabineisalso metabolised to an N-acetylmetabolite

(NAMR)thatisalso subsequentlyglucuronidated.NAMRhasantiepilepticactivity, butislesspotent

than retigabinein animalseizure models.

Thereisno evidenceforhepaticoxidativemetabolismofretigabineorNAMRbycytochromeP450

enzymes. Therefore co-administration with inhibitorsorinducersofcytochromeP450 enzymesis

unlikelyto affectthepharmacokinetics of retigabineor NAMR.

In vitrostudiesusinghuman livermicrosomesshowed littleorno potentialforretigabineto inhibit

themajorcytochromeP450 isoenzymes(includingCYP1A2, CYP2A6, CYP2C8, CYP2C9,

CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5). In addition, retigabineand NAMRdid notinduce

CYP1A2 orCYP3A4/5 in human primaryhepatocytes. Thereforeretigabineisunlikelyto affectthe

pharmacokinetics of substrates of themajor cytochromeP450 isoenzymesthrough inhibition or

induction mechanisms.

Elimination

Elimination ofretigabineoccursviaacombination ofhepaticmetabolismand renalexcretion.Atotal

ofapproximately84%ofthedoseisrecovered in theurine, includingtheN-acetylmetabolite (18%),

N-glucuronidesoftheparentactive substanceand oftheN-acetylmetabolite (24%), orparentactive

substance(36%). Only14%of retigabineis excreted in thefaeces. Retigabinehas a plasma half-life

ofapproximately6to10hours. Thetotalclearanceofretigabinefromplasmafollowingintravenous

dosingistypically0.4to0.6l/h/kg.

Linearity

Retigabinepharmacokinetics are essentiallylinearoverthesingle dose range of 25to600mg in

healthyvolunteersand up to 1,200mgdailyin patientswith epilepsy, with no unexpected

accumulation followingrepeated administration.

Specialpatientpopulations

Renalimpairment

In asingle dose study, retigabineAUCwas increased byapproximately30%in volunteerswith mild

renalimpairment(creatinineclearance50to80ml/min)and byapproximately100%in volunteers

with moderateto severerenalimpairment(creatinineclearance<50ml/min), relativeto healthy

volunteers. AdjustmentoftheTrobaltdose is recommended in patients with moderateto severerenal

impairmentbutno adjustmentoftheTrobaltdose is recommendedin patientswith mild renal

impairment(see section4.2).

In asingle dose studyin volunteers with end stage renaldisease, theretigabineAUCwas increased by

approximately100%relativeto healthyvolunteers. However,theeffectof haemodialysis on

retigabineclearancewasnotadequatelyevaluated.

Hepaticimpairment

In asingledosestudy, there were no clinicallysignificanteffects onretigabineAUCin volunteers

withmild hepaticimpairment(Child-Pugh score5to6). TheretigabineAUCwas increased by

approximately50%in volunteerswith moderatehepaticimpairment(Child-Pugh score7to9)and by

approximately100%in volunteers with severe hepatic impairment(Child-Pugh score>9), relativeto

healthyvolunteers.AdjustmentoftheTrobaltdoseisrecommended in patientswithmoderateor

severe hepatic impairment(see section4.2).

Bodyweight

In apopulationpharmacokineticanalysis,retigabineclearanceincreasedwith increasingbodysurface

area. However, this increase is notconsidered to beclinicallymeaningful, and since retigabineis

titrated accordingto individualpatientresponseand tolerability,dose-adjustmentsarenotrequired on

thebasisofbodyweight.

Elderly (65yearsofageand above)

In asingle-dose study, retigabinewas eliminated more slowlybyhealthyelderlyvolunteers

(66to82years of age)relative to healthyyoungadultvolunteers, resultinginahigherAUC

(approximately40to50%)and longerterminalhalf-life(30%)(see section4.2).

Gender

Theresultsofasingledosestudyshowed thatin youngadultvolunteers, retigabineC

was

approximately65%higherin females than in males,and in elderlyvolunteers(66 to 82years of age),

retigabineC

was approximately75%higherin females compared with males.WhenC

was

normalized forweight, thevalueswereapproximately30%higherin youngfemalesthan in malesand

40%higherin elderlyfemales compared with males.However, there was noapparentgender

difference in weight-normalizedclearance,and sinceretigabineistitrated accordingto individual

patientresponseand tolerability, dose-adjustments are notrequired on thebasisofgender.

Race

Apost-hocanalysis across multiple healthyvolunteerstudies demonstrated a20%reduction in

retigabineclearance in healthyblackvolunteers relative to healthyCaucasian volunteers. However,

this effectis notconsidered clinicallysignificant, thereforeno adjustmentoftheTrobaltdose is

recommended.

Paediatricpopulation

Thepharmacokinetics of retigabinein children and adolescents have notbeen investigated.

5.3 Preclinicalsafety data

Maximumdosesin repeatdosetoxicitystudieswerelimited bytheexaggerated pharmacologic effects

ofretigabine(includingataxia, hypokinesiaandtremor).Atno observed effectlevels, animal

exposurein these studies was generallyless than thatreachedin humansatrecommendedclinical

doses.

Distension ofthegallbladderwasseen in studieswith dogs,butthere was no evidence of cholestasis

orothersignsofgallbladderdysfunction,and bileejection volumewasunchanged. Thegallbladder

distension in thedogresulted infocalcompressionoftheliver. No signsofgallbladderdysfunction

were seen clinically.

Preclinicaldata revealno specialhazard for humansbased on studies of genotoxicityorcarcinogenic

potential.

Reproductivetoxicology

Retigabinehad no effect on fertilityorgeneralreproductive performance.

In rats,retigabineand/or its metabolites crossed theplacenta resultingintissueconcentrationsthat

were similarindamsand foetuses.

Therewasno evidenceofteratogenicityfollowingadministration ofretigabinetopregnantanimals

duringtheperiod oforganogenesis.In astudyofperi-and post-nataldevelopmentin rats, retigabine

wasassociated with increased perinatalmortalityfollowingadministration duringpregnancy. In

addition,there was a delayin auditorystartle response development.These findings wereapparentat

exposure levels lowerthan those obtained with clinicallyrecommended doses and were accompanied

bymaternal toxicities(includingataxia, hypokinesia, tremorand reduced bodyweightgain).The

maternaltoxicitiesinterfered with higherdosingofthedamsand hencededuction ofsafetymargins

with regard to human therapy.

6. PHARMACEUTICALPARTICULARS

6.1 Listofexcipients

Tabletcore

Croscarmellose sodium

Hypromellose

Magnesiumstearate

Microcrystallinecellulose

Film-coating

Polyvinylalcohol

Titaniumdioxide(E171)

Talc(E553b)

Lecithin (SOY)

Xanthan gum

The50mgand 400mgtablets also contain indigo carminealuminiumlake(E132)and carmine

(E120).

The100mgand 300mgtablets also contain indigo carminealuminiumlake(E132)and iron oxide

yellow(E172).

The200mgtablets also contain iron oxideyellow(E172).

6.2 Incompatibilities

Notapplicable.

6.3 Shelflife

Theexpirydateoftheproductisindicated on thelabelandpackaging.

6.4 Specialprecautions forstorage

Do notstoreabove25ºC.

6.5 Natureand contentsofcontainer

50mg, 100mgtablets(maintenance packs):

OpaquePVC-PVDC-aluminiumfoil blisters.Packscontaining21,84or168film-coated tablets.

200mg,300mg, 400mgtablets:

OpaquePVC-PVDC-aluminiumfoil blisters.Packcontaining84film-coated tablets; multi-pack

comprising168 (2x84)film-coated tablets.

Treatmentinitiation pack

OpaquePVC-PVDC-aluminiumfoil blisterssealed into secondaryheat-sealed card packaging.Pack

containing63film-coated tablets (21x50mgfilm-coated tablets and 42x100mgfilm-coated

tablets), presented as:

- oneblisterof21x100mgfilm-coated tablets

- oneblisterof21x100mgfilm-coated tablets and 21x50mgfilm-coated tablets.

Notallpacksizes maybemarketed.

6.6 Specialprecautions fordisposal

No specialrequirements.

7. MANUFACTURER

GlaxoWellcomeS.A, Burgos, Spain

CatalentUKPackagingLimited, Corby, UK

8. LICENSEHOLDER AND IMPORTER

GlaxoSmithKline(Israel)Ltd., 25 BaselSt., Petach Tikva

9. LICENSENUMBER

Trobalt 50mg 148-82-33614

Trobalt 100mg 148-84-33616

Trobalt 200mg 148-85-33617

Trobalt 300mg 148-86-33618

Trobalt 400mg 148-87-33619

Trobalt 50mg,Trobalt100mg 148-83-33615

Tro DR v2

Document Outline