Product Monograph - Gabapentin (Genpharm)

ACTION AND CLINICAL PHARMACOLOGY

Gabapentin

exhibits

anti-seizure

activity in

mice

and

rats

both i

n the

maximal

electroshock

and

the pentylenetetrazol seizure models.

Gabapentin

structu

rally related to the neurotransmitter GABA (gamma-aminobutyric acid) but

doe

s no

t interact

wit

h GABA

receptors, it i

s not

metabolized

GABA

agonists,

and

it is

not an inhibitor of GABA uptake or degradation. Gabapentin at concentrations up to 100

did

not

demonstrate

affinity

for

other

recep

tor sites

such

benzodiazepine, g

lutamate,

glycine

N-methyl-D-aspartat

e receptors

nor

does

it interact

with

neuronal

sodium

channels

L-type

calcium channels.

The

mechanism

ction

gabapentin ha

s not

yet

been

established,

howeve

unlike

that of

the commonly used anticonvulsant drugs.

itro

studies

with

radiolabele

d gabapent

in have

revealed a gabapentin binding site in rat brain

tissues i

ncluding

neocortex a

nd h

ippocamp

us. The i

dentity

and f

unction

thi

s binding

site

remain

to be elucidated. PHARMACOKINETICS

Adults:

Following

oral a

dministration

gabapentin

, peak

plasma

concentrations

are

observed

within

hours. A

bsolut

e bioavail

ability of a 300 mg dose of gabapentin capsules is approximately 59%.

doses

of 300

and

400

, g

abapentin

bioavailability

unchanged

follo

wing multiple dose

administration.

Gabapenti

n 600

mg a

800

tablets

are

bioequivalent t

o two

300

capsules

and

two

400

capsules, r

espectively

. The results of a single-dose, two-way crossover, comparative bioavailability

study

in th

e faste

d state

comparing

gabapentin

600

tablets

and

2 x

300

gabapentin

capsules

are summarized below.

TABLE 1. Summary Table of the Comparative Bioavailability Data

abapentin 600 mg tablets and gabapentin 2 x 300 mg capsules

Parameter

Gabapentin

% Ratio of

Geometric Means

600 mg tablets

2 x 300 mg capsules

Arithmetic

(CV%

)

			Geometric	Arithme (CV%)			tic	Geometric
	Mean values from measured data
AUC_T(	µg@hr/mL)	51.3 (31.8)				48.9			46.8 (28.4)		45.2	108
AUC_l(	µg@hr/mL)	52.5 (30.2)			50.4	47.7 (27.1)			46.1	109
C_max(µg/mL)		4.94 (30.9)			4.71	4.48 (25.9)			4.35	108
T_max(h)		3.2 (27.3)			-	3.5 (34.1)			-	-
T_1/2(h)		15.6 (88.2)			-	15.4 (90.5)			-	-

Gabapenti

n elimination

from

plasma is

best

described

by li

near

pharmacokinetics.

The

elimination

half-life of

gabapenti

n is

independent o

f dose

and

averages 5

hour

s in s

ubjects

with n

orma

l renal

function.

Plasma

bapent

in c

oncentrations

are

dose-proportional a

t doses

300

mg q8h, ranging

between 1

:g/mL

and

0 :

g/mL

, but ar

e less

than

dose-proportional a

bov

e the

clinical

range

(>600

q8h). T

here is

correlation

betwee

n plasma l

evels

and

efficacy.

Gabapentin

pharmacokinetics

are

not

affected

y repeated

administration,

and

steady-state

plasma

concentrations

are

predictable

from single-dose data.

Gabapentin

not

appreci

ably metabolized in humans, is eliminated solely by renal excretion as

unchanged

drug,

and

can

removed

from

plasma

hemodialysis

Gabapen

tin elimination rate

constant, plasma clearance and renal clearance are directly proportional to creatine clearance.

Gabapentin

does n

induce

inhibit

hepati

c mixed

function

oxidase

enzymes

responsible

for

drug

metabolism, does not interfere with the metabolism of commonly coadministered antiepileptic drugs, and is minimally bound to plasma proteins.

Food has no effect on the rate or extent of absorption of gabapentin.

compa

ative

bioavailability

study

capsules

was

performed.

Pharmacokinetic

and

bioavailability

data

were

measured

volunteers

the

fasting

state.

The results are

summarized

as follows in Table 2.

TABLE 2 - Summary Table of the Comparative Bioavailability Data of Gabapentin 400 mg capsules

versus

NEURONTIN 400 mg capsules

A single 400 mg (1 × 400 mg capsule) oral administration in the fasting state

Measured Data

Parameter	Geometric Mean	Ratio of Geometric Mean
Arithmetic Mean (C.V.%)
Test Reference-1
AUC

32426.2

33541.

8 97

(ng.h/mL)

33544.1(26.46

)

34319.8 (21.99)

AUC

32960.1

34051.

7 97

(ng.h/mL)

34023.1 (25.82

)

34818.4 (21.65)

max

3189.8

3284.9

(ng/mL)

3297.1 (25.13)

3357.5 (20.66

)

_ax3.42 (32.84) 3.10 ---

)

T1
	/2el

6.67 (23.11) 6.65 (23.43) ---

(h)

Neurontin

is manufactured by Parke-Davis, Division of Warner-Lambert Canada Inc. and purchased in Canada.

For T

and T

, the arithmetic mean only is presented.

max

1/2el

The

test

formulation

(Gabapentin

600

tablets,

Pharmascience

Inc.,

Montreal,

Québec,

Canada)

judged

be bioequivalent to the Canadian Reference Product (Neurontin

600

tablets,

Parke-Davis,

Division

Warner-Lamber

t Company

Canada

Inc.,

Scarborough,

Ontario,

Canada)

on the basis of the C	_xand AUC parameters.
		ma

comparative

bioavailability

study

comparing

Gabapentin

600

tablets

manuf

actured by

Pharmascience

Inc.,

with

Neurontin™

600

g tablets manufactured by Parke-Davis, Division of

Warner-Lambert Canada Inc. was conducted in healthy male adults under fasting and fed conditions.

Bioavailability data were measured and the results are summarized in tables 3A and 3B.

TABLE 3A - SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

FOR A SINGLE DOSE STUDY UNDER FASTED CONDITIONS

Gabapentin ( A single 600 mg dose - 1 X 600 mg) From measured data Geometric Mean Arithmetic Mean (CV %)
Parameter					Gabapentin	Neurontin^TMA	% Ratio of Geometric Means	90% Confidence Interval
AUC_T(ng.h/mL)					39450 40567 (25.9)	40076 41692 (27.8)	98.44	88.80-109.11
AUC_I(ng.h/mL)					41148 42243 (25.1)	41981 43589 (27.2)	98.02	88.77-108.23
CMAX (ng/mL)					4062 41.78 (24.8)	4307 4443 (22.7)	94.31	86.42-102.91
TMAX * (h)					3.30 (38.8)	3.20 (30.0)
		T½ *			6.14 (18.9)	6.05 (16.3)
		(h)
A	Neurontin		TM	is manufactured by Parke-Davis, Division of Warner-Lambert Canada Inc. and purchased in Canada.
			*expressed as arithmetic mean (CV%) only.

ABLE 3B

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

FOR A SINGLE DOSE STUDY UNDER FED CONDITIONS

Gabapentin

( A single 600 mg dose - 1 X 600 mg)

From measured data

Geometric Mean

Arithmetic Mean (CV %)

Parameter	Gabapentin	Neurontin^TMA	% Ratio of Geometric Means	90% Confidence Interval
AUC_T(ng.h/mL)	48516 50013 (23.1)	48198 49191 (20.6)	100.66	96.20-105.33
AUC_I(ng.h/mL)	50386 51828 (22.3)	50132 51098 (19.9)	100.51	96.19-105.02
CMAX (ng/mL)	4955 5091 (22.1)	5050 5137 (18.1)	98.12	93.76-102.69
TMAX * (h)	2.98 (23.9)	3.06 (23.5)
T½ * (h)	5.87 (14.2)	5.94 (19.01)

A	Neurontin	TM	is manufactured by Parke-Davis, Division of Warner-Lambert Canada Inc. and purchased in Canada.
		*expressed as arithmetic mean (CV%) only.

The

test f

ormulation (

Gabapentin

600

tablets,

Pharmascience

Inc.,

Montreal,

Québec,

Canada)

judged to be bioequivalent to the Canadian Reference Product (Neurontin

600

tablets,

Parke-Davis,

Division

Warner-Lamber

t Compan

y Canada

Inc.,

Scarborough,

Ontario,

Canada)

on the basis of the C_m

_axand AUC parameters.

Table 4 summarizes the mean steady-state pharmacokinetic parameters of gabapentin capsules.

TABLE 4 - Summary of Gabapentin Capsules

Mean Steady-State Pharmacokinetic Parameters in Adults Following Q8H Administration

Pharmacokinetic Parameter

300 mg (N = 7)

400 mg (N = 11)

C_max(:g/mL)

T_max(hr)

T½ (hr)

AUC _(o-")(:g •hr/mL) AE%¹

4.02 2.7 5.2 24.8 NA

5.50 2.1 6.1 33.3 63.6

¹Amount excreted in urine (% of dose) NA = Not Available

patients wi

th epilepsy,

gabapentin

concentrations i

n cerebrospinal

fluid

are a

pproximately

20%

of corresponding steady-state trough plasma concentrations.

Elderly:

Apparent oral

clearance (

CL/F)

gabapentin

decreased

age

increased,

from

about

225

mL/min

subjects un

der 30

yea

of a

about

125

mL/min

sub

jects over 70 years of age. Renal

clearance (CL

r) of

gaba

pentin also declined with age; however, this decrease can largely be

explained by t

he decline i

n rena

l function.

Reduction o

f gabapentin

dose

may

required

patients

who have age-related compromised renal function (see DOSAGE AND ADMINISTRATION).

Renal Impairment:

patients wi

th impaired renal function, gabapentin clearance is markedly reduced and dosage

adjustment is necessary (see Table 8 in DOSAGE AND ADMINISTRATION).

Hemodialysis:

tudy in

anuric

subjects (

n =

11),

the

apparent elimination half-life of gabapentin on non-

dialysis

days

was about 1

hours;

during

dialysis

the

apparent

half-life

gabapentin

was

reduced

3.8

hours. H

emodialysi

s thus

has

significant

effect

gabapentin

eliminatio

n in

anuric

subjects.

Dosage

adjust

ment in patients undergoing hemodialysis is necessary (see Table 8 in DOSAGE AND

ADMINISTRATION).

Pediatric:

There are no pharmacokinetic data available in children under 18 years of age.

Hepatic Impairment:

Because

gabapentin is n

ot appreciably

metabolized

humans,

study

was

performed

patients

with hepatic impairment.

LINICAL

RIALS

placebo-controlled tr

ials in patients

not

satisfactorily

controlled

with

current

antiepileptic

drugs,

gabapentin,

when adde

d to current antiepileptic therapy, was superior to placebo in reducing the

frequency

both simp

le and

omplex partial seizures and secondarily generalized tonic-clonic

seizures.

Further

analy

sis of data indicated a higher efficacy for complex partial seizures and

secondarily

generalized

tonic-clonic s

eizures

compared

all s

eizure

types.

Doses

ranged

from

900 to 1800 mg/day, with a median dose of 1200 mg/day.

Long-term, open, uncontrolled studies in drug-resistant patients for periods of up to 18 months

demonstrate

d that dose

s up to

600

mg/day

not

result

in anything unusual in the type or

frequency of adverse events.

INDICATIONS AND CLINICAL USE

Gabapentin i

s indicated

as adjunctive t

herapy

for

the

management

patients

with

epilepsy

who

are

not satisfactorily controlled by conventional therapy.

CONTRAINDICATIONS

Gabapentin i

s contraindicated in

patients wh

o have

demonstrate

d hypersensitivity to

the

dru

g or

any of the components of the formulation.

PRECAUTIONS

General:

Gabapentin i

s not

considered eff

ective

in the

treatment

absenc

e seizures

and

shou

ld therefore

used with caution in patients who have mixed seizure disorders that include absence seizures.

Tumorigenic Potential:

Gabapentin p

roduced

increase

d inci

dence of acinar cell adenomas and carcinomas in the pancreas

male

rates

, but

not

female rats

or in

mice,

in oncogenic

studie

s with

doses

200

0 mg/kg

which

resulted

in pl

asma

concentration

s 14 times hi

gher than

those

occurring

humans at

a dose o

f 2400

mg/day.

The

relevance

these

pancreatic a

cinar cell

tumors in

male

rat

s to humans is unknown,

particularly s

ince

tumors

of duct

al rather tha

n acinar

cell o

rigin a

re the

predominant

form

human

pancreatic cancer.

Drug Discontinuation:

with

oth

anticonvulsant a

gents

, abru

pt withdraw

is n

ot r

ecommended because of the

possibility o

f increased s

eizure f

requency. W

hen in

the

judgment

the

clinician the

re is

a n

eed

for

dose

reduction,

discontinuation

or substitut

ion with alternative medication, this should be done

gradually over a minimum of one week.

Occupational Hazards:

Patients

with

uncontr

olled

epile

psy should

not drive

or h

andle

potentially

dangero

machinery.

During clinical trials, the most common adverse reactions observed were somnolence, ataxia, fatigue

and

nystagmus.

Patients

should

be advised t

o refrain f

m activitie

requ

iring mental alertness or

physical coordination until they are sure that gabapentin does not affect them adversely. Drug Interactions

Antiepileptic Agents:

There

interaction

between

gabapentin

and

phenytoin

, valproic ac

id, carbamazepin

e, or

phenobarbital

. Consequently, g

abapentin m

used

combination

with

other c

ommonly

used antiepileptic drugs without concern for alteration of the plasma concentrations of gabapentin or the other antiepileptic drugs.

Gabapentin

steady-state p

harmacokineti

cs are

similar

for

healthy

subjects and patients with epilepsy

receiving antiepileptic agents.

Cytochrome P₄₅₀Enzymes:

metabolicall

y-based interaction between gabapentin and a drug whose clearance is dependent

upo

n the

major

cytochrom

e P

450 en

zymes

is unlikely

plasma

concentration

s associated

with d

oses

up to 3600 mg/day (C_max

11.6

:g/

mL), the highest recommended daily dos

Thi

s was

demonstrated th

rough i

n vitro

studie

s investigating

the

potential

of gabapenti

n to in

hibit

the

major

cytochrom

e P45

₀enzyme

s (CYP1A2,

CYP2A6,

CYP2C9,

CYP2C

19, CYP2D6

, CYP2E1,

and

CYP3A4)

that

mediate drug and xenobiotic metabolism, using isoform selective marker

substrate

s and

huma

n live

r microsomal p

reparations.

Only

the

highest co

ncentration t

ested

(171

:g/

mL; 1

mM)

was a

slig

ht degre

e of inh

ibitio

n (14%

30%)

observed wit

h isoform

CYP2A6

. No

inhibition

was o

bserved w

ith

any

of the o

ther is

oforms

tested a

t gabapentin c

oncentration

s up to

171

:g/

(

approximat

ely 15 times the C

max a

t 3600

mg/day

Gabapenti

n is

not

indic

er of

cytochrome P₄₅₀enzymes.

The

drug

interaction

data

describe

d in thi

s subsection

were

obtained

from st

udies

involving he

althy

adults and adult patients with epilepsy:

Oral Contraceptives:

Coadministrati

on of

gabapentin

with t

he or

contraceptive

Norlestrin

does

not

influenc

e the

steady-state pharmacokinetics of norethindrone or ethinyl estradiol. Antacids:

Coadministration of gabapentin with an aluminum and magnesium-based antacid reduces gabapentin

bioavailabil

ity by

up t

o 20%.

Althou

gh the

clinical

significance of

this

decrease

not

known,

co-

administration of similar antacids and gabapentin is not recommended.

Probenecid:

Renal excretion of gabapentin is unaltered by probenecid.

Cimetidine:

slight de

crease

rena

excreti

on of

gabapentin

observed w

hen

is coadministered with

cimetidine i

s not e

xpected

be of c

linical

importance.

The

effect

of gabapentin

cimetidine

has

not been evaluated.

Naproxen:

healthy a

dult v

olunteer

(N=18)

, the co-administration of single doses of naproxen sodium

capsules (25

0 mg)

and

gabapentin (

125 mg

) increased

the a

mount

of gabapentin

absorbed

12%

15%.

Gabapentin did not affect naproxen pharmacokinetic parameters in this study. These doses

are

lower th

an the

therapeutic

doses f

or both

drugs.

Therefor

e the m

agnitud

e of

interaction

steady

state and within the recommended dose ranges of either drug is not known.

Hydrocodone:

Co-administration

of s

ingl

e doses of

gabapentin

(125 m

g to 5

; N=

48)

decrease

s hydrocodone

(10 mg; N= 50) C_max

and

AUC val

ues in

a dose-dependen

t mann

er relative

administration

hydrocodone alone. The C_maxan

d AUC

value

s fo

r hydrocodone

lower,

respectively

, after

administration of

125 mg

gabapentin

and

16% an

d 22% l

ower,

respectively,

after

administrati

on of 5

mg g

abapentin

. The m

echanism f

or thi

s interaction

unknown

. Hydrocodone

increases ga

bapentin

AUC values by 14%. The magnitude of interaction with higher doses of

gabapentin is not known.

Morphine:

A l

iterature

article reported that when a 60 mg controlled release morphine capsule was administered

2 h

ours

prio

r to a

600

gabapentin ca

psule in

healthy v

olunteers (

12),

mean

gabapentin

AUC

increased by 44% compared to gabapentin administered without morphine. Morphine

pharmacokinetic

parameter

values wer

e not affecte

d by

administration

gabapentin

hours

after

morphine in

this

study.

Becaus

e this was a single dose study, the magnitude of the interaction at

steady state and at higher doses of gabapentin are not known.

Use in Pregnancy

evidenc

e of i

mpaired

fertility

or har

m to the f

etus

due

gabapentin

administration

was r

evealed

reproduction s

tudies

mic

at dose

s up to

62 ti

mes

, and

rat

d rabbits at doses up to 31

times the human dose of 2400 mg/day.

There

re, h

owever,

adequate

and w

ell-controlled studies

pregnant

women

Becaus

animal

reproductio

n studies

are

not always predictive of human response, this drug should only be used

during pregnancy if the potential benefit to the mother justifies the potential risk to the fetus.

Use in Lactation

Gabapentin

is excreted i

n human

milk.

Because the effect on the nursing infant is unknown, caution

should

be e

xercised

whe

gabapentin i

s administer

ed to

nursing mother. Gabapentin should be

used in nursing mothers only if the potential benefit outweighs the potential risks.

Use in Children

Systematic

studi

es to

establish

safety a

nd efficacy i

n children

have

not

been

performed.

Data

patients

between

the

age

s of

and 18

years include

d in

the

double-blind,

placebo-controlled

trials

showed

that

gabapentin

was

superior to

placebo

in r

educing

seizure

frequency.

Safety

data

showed

tha

t the

incidenc

e of

adverse

events in t

his grou

p of

patients

were

similar t

those

observed

older

individuals. Use in the Elderly

Systematic

studies

geriatric patients have not been conducted.

Adverse

clinical e

vents

reported

among

patients

over

the a

years

treated

with

gabapentin

did

not

diffe

r from

those

reported

for younger individuals. The small number of individuals evaluated and the limited duration of

exposure

limits

the

strength

any

conclusions

reached

about

the

influence

of a

, if

y, on the

kind and incidence of adverse events associated with the use of gabapentin.

gabapentin

liminated

primarily

renal

excretion,

dosage

adjust

ment may be required in

elderly patients because of declining renal function (See DOSAGE AND ADMINISTRATION).

Use in Renal Impairment

Gabapentin

clearance

arkedly

reduced

thi

patient

population

and

dosag

e reduction is

necessary (See Table 6 in DOSAGE AND ADMINISTRATION).

Laboratory Tests

Clinical trials data do not indicate that routine monitoring of clinical laboratory parameters is necessary for the safe use of gabapentin. Gabapentin may be used in combination with other commonly used antiepileptic drugs without concern for alteration of the blood concentrations of gabapentin or other antiepileptic drugs.

For

urinary

protein

determination

the

sulfosalicylic

acid

precipitation

procedure

recommended,

false

positive

eadings

were

report

ed with the Ames N-Multistix SG^®

dipstick

test,

when

gabapentin or placebo was added to other anticonvulsant drugs.

ADVERSE REACTIONS

Incidence in Controlled Clinical Trials

Table 5 lists treatment-emergent signs and symptoms that occurred i

n at

least 1% of patients with

partial

seizures

participatin

g in

lacebo-controlled

studies.

these s

tudies,

either

gabapentin

(at

dose

s of 6

00,

900,

120

0 or

1800

mg/day

) or

placebo

were

adde

d to

the

patient's

curren

t antiepileptic

drug therapy.

The

most

commonly o

bserved

adverse e

vents

associated

with

the

use

gabapentin i

n combination

with

othe

r antiepilepti

c drugs,

not

seen a

t an

equivalent

frequency

placebo-treated

patients,

were

somnolence, dizziness, ataxia, fatigue, nystagmus and tremor.

Among the treatment-emergent adverse events occurring in gabapentin-treated patients, somnolence

and

ataxi

a appeared t

o ex

hibit a positive dose-response relationship. Patients treated with 1800

mg/day (n

=54,

from on

e contr

olled study) experienced approximately a 2-fold increase, as compared

patient

s on

lower d

oses

600

00 m

g/da

y (

n=489,

fro

m s

evera

l controlled s

tudi

es), in the

incidence

nys

tagmus

(20.4%),

tremor

(14.8%),

rhinitis

(13%),

peripheral

dema

(7.4%),

coordination

abnorma

l , depression

and

myalgia

(al

l at

5.6%).

Adverse

events

were u

sually

mild

moderate in intensity, with a median time to resolution of 2 weeks.

Sinc

e gabapentin

was

administered

mos

t often

combination

with

other

antiepileptic

agents, i

t was

not possible to determine which agent(s) was associated with adverse events.

TABLE 5 - Treament-Emergernt Averse Event Incidence In Placebo-Controlled Add-On Trials
(Events In At Least 1% of Gabapentin Patients and Numerically More Frequent Than in the Placebo Group)

BODY AS A SYSTEM/ ADVERSE EVENT (AE)

GABAPENTIN*

N = 543

PLACEBO* N = 378

Body as a whole:

Fatigue

Weight Increase Back Pain

Peripheral Edema Cardiovascular:

Vasodilation

Digestive system:

Dyspepsia

Mouth or Throat Dry Constipation

Dental Abnormalities Increased Appetite Hematologic and lymphatic systems:

Leukopenia

11.0 2.9 1.8 1.7

1.1

2.2 1.7 1.5 1.5 1.1

1.1

5.0 1.6 0.5 0.5

0.3

0.5 0.5 0.8 0.3 0.8

0.5

Musculaskeletal system

	Myalgia
	Fracture
Nervous system:

Somnolence Dizziness Ataxia

Nystagmus Tremor

Nervousness

Dysarthr

Amnesia

Depressi

Thinking Abnormal
Twitchin

Coordination Abnormal
Respiratory syste

	Rhinitis
	Pharyng

itis

Coughin

g Skin and appendages:

	Abrasion
	Pruritus
Urogenital system

Impoten

Special senses:
	Diplopia
	Amblyo

pia

Laboratory deviations:
	WBC Decrease

2.0 1.1

19.3 17.1 12.5 8.3 6.8 2.4 2.4 2.2 1.8 1.7 1.3 1.1

4.1 2.8 1.8

1.3 1.3

1.5

5.9 4.2

1.1

1.9 0.8

8.7 6.9 5.6 4.0 3.2 1.9 0.5 0.0 1.8 1.3 0.5 0.3

3.7 1.6 1.3

0.0 0.5

1.1

1.9 1.1

0.5 ^aP

lus background antiepileptic drug therapy

Data

fro

m long-term, o

pen,

uncontrolled

studies

shows

tha

t gabapentin

treatment

does

not r

esult

any new or unusual adverse events.

Withdrawal from Treatment Due to Adverse Events:

Approximately

6.4% o

f the

543

patients

who

received

gabapentin

the

placebo-controlled

studies

withdrew

due

advers

e events.

comparison,

approximately

4.5%

the

378

placebo-controlled

participants

withdrew

due

adverse

events

during

the

se studies. The adverse events most

commonl

associated

with

withdrawal

wer

e so

mnolence

(1.2%),

ataxia

(0.8%),

fatigue,

nausea

and/or vomiting and dizziness (all at 0.6%).

Other Adverse Events Observed in All Clinical Trials:

Adverse

events

that oc

curre

d in

least

of th

e 2074

individuals

who

participated

all

clinical

trials, on

ly some o

f which w

ere plac

ebo-controlled, are described below.

During

these trials,

all

adverse e

vents wer

e recorded

by the

clinical in

vestigators

using te

rminology

of their

own choosing.

provi

de a mean

ingful esti

mate of

the

prop

ortion of individuals having adverse events, similar

types of

events w

ere groupe

d into

a smaller

numbe

r of

standa

rdized categories using modified

COSTA

RT diction

ary terminology.

Thes

e categories

are

used in

the listing

below. T

he frequencies

presente

d represen

t the proportion of

the

2074

patien

ts exposed t

o Gabapentin who

experienced

event of t

he type c

ited on at l

east one

occasion

while

receiving G

abapentin.

All repo

rted events

are

included

except th

ose alread

y listed

in Table

4, those too general to be

informative

, and those

not

reasonably associated with the use of the drug.

Events a

re further

classified

within b

ody

syste

m categories

and e

numerate

d in orde

r of decreasing

frequenc

y using th

e followin

g definition

s: fre

quent a

dverse

eve

nts are

defined as t

hose occurring

at leas

t 1/100 pa

tients; infr

equent

adverse e

vents ar

e those

occurring

in 1/

100 to 1

/1000 patients;

rare events are those occurring in fewer than 1/1000 patients.

Body as

a Whole:

Frequen

t: asthenia, malaise, facial edema;

Infrequent: allerg

y, generalized

edema, weight decrease, chill

; Rare: s

trange fe

elings, l

assitud

e, alcohol intolerance, hangover effect.

Cardiovascular S

ystem: Fr

equent:

hypertension;

Infrequent:

hypotension, an

gina p

ectoris,

peripher

al vascula

r disorder,

palpitation,

tachycardia, migraine, murmur;

Rare: atr

ial fibrillation,

heart failure, thrombophlebitis, deep thrombophlebitis, myocardial infarction, cerebrovascular accident, pulmonary thrombosis, ventricular extrasystoles, bradycardia, premature atrial contraction,

pericardi

al rub, he

art block, p

ulmona

ry embolu

s, hyperlipidemia,

hypercholesterole

mia, pericardial

effusion, pericarditis.

Digestiv

e System:

Frequent:

anorexia, flatulence, gingivitis;

Infrequent:

glossitis, gu

m hemorrhage,

thirst, s

tomatitis,

increased

salivation

, ga

stroenteritis,

hemorrhoids,

bloody

stools, fecal

incontinence, hepa

tomegaly;

Rare: d

ysphagia

, eructation,

pancreatitis,

peptic ulcer,

colitis,

blisters

mouth

, tooth di

scolour, p

erleche,

salivary

gland

enlar

ged, lip hemorrhage, esophagitis, hiatal

hernia, hematemesis, proctitis, irritable bowel syndrome, rectal hemorrhage, esophageal spasm.

Endocrine

System:

Rare:

hyperthyroid,

hypothyroid,

goiter,

hypoestrogen,

ovaria

failure,

epididymitis, swollen testicle, cushingoid apperance.

Hematologi

c and

Lymphatic

System:

Frequent:

purpura;

most

often d

escribed as

bruises

resulting

from

physic

al traum

a; In

frequent:

anemia, thrombocytopenia, lymphadenopathy;

Rare:

WBC

count

increased, lymphocytosis, non-Hodgkin’s lymphoma, bleeding time increased.

Musculoskeletal

System

: Frequent: a

rthralgia; I

nfrequent

: tendinitis,

arthritis, jo

int stiffness

, joint

swelling, positive Romberg test;

Rare

: costochondritis, osteoporosis, bursitis, contracture.

Nervous System: Frequent: vertigo, hyperkinesia, paresthesia, anxiety, hostility, decreased or absent

reflexes,

creased

reflexes

; I

nfre

quent:

CNS

tumors,

syncope

, dr

eaming

normal,

aphasia,

hypesthesia

, intracrania

l hemorrhage,

hypotonia,

dysesthesia,

paresis,

dystonia, h

emiplegia,

facial

paralysis, st

upor,

cerebellar

dysfunction, p

ositive

babinski

sign

, decreased

positio

n sense,

subdural

hematoma,

apathy, h

allucination,

decrease

los

s of

libido

, agitation,

paranoia, d

epersonalization,

euphoria, fe

eling

high,

doped-up

sensatio

n, suicidal, psychosis;

Rar

e: choreoathetosis,

orofacial

dyskinesia,

encephalopathy

nerve

palsy,

rsonality

disorder,

increased

libido,

subdued

temperamen

t, apraxia, f

ine

motor

control

disord

er, meningismus,

loc

al myoclonu

s, hyperesthesia,

hypokinesia, mania, neurosis, hysteria, antisocial reaction, suicide gesture.

Respiratory

System:

Frequent:

eumonia

; Infrequent:

epistaxis,

dyspnea,

apnea;

Rare:

mucositis,

aspiration pneumonia, hyperventilation, hiccup, laryngitis, nasal obstruction, snoring, bronchospasm, hypoventilation, lung edema.

Dermatological:

Infrequent

: alopecia

, eczema,

dry s

kin, i

ncrease

d s

weating

, urticaria, hirsutism,

seborrhea, c

yst,

herpes

simplex;

Rar

e: he

rpes z

oste

ski

n discolor,

skin

papule

s, photosensitive

reaction, leg ulcer, scalp seborrhea, psoriasis, desquamation, maceration, skin nodules, subcutaneous nodule, melanosis, skin necrosis, local swelling.

Urogenital

System

: Infreque

nt: hematuri

a, dysuria, u

rination

frequency

, cystitis

, urinary r

etention,

urinary

incontinence,

vagina

l hemorrhag

e, amenorrh

ea, dysmenorrhea,

menorrhagia, b

reas

t cancer,

unable

to climax, e

jaculation

abnormal; R

are: kidney

pain,

leukorrhea,

pruritus

genita

l, renal s

tone,

acute re

nal

failure,

anuria, gl

ycosuria, ne

phrosis, noc

turia,

pyuria

, urination

urgency,

vaginal

pain,

breast pain, testicle pain.

Special

Senses:

Frequent: ab

normal visi

on; Infreque

nt: cataract,

conjunctivitis,

eyes

dry,

eye

pain,

visual f

ield

defect,

photopho

bia, bilatera

l or unilater

al ptosis,

eye

hemorrhage, h

ordeolum

, hearing

loss, ea

rache,

tinnitus,

inner

ear infection

, otitis,

taste

loss,

unusual

taste

, eye

twitching

, ear

fullness;

Rare: e

ye itching,

abnormal

accommodat

ion, perfora

ted ea

r drum,

sensitivity

noise,

eye

focusing

problem

, watery

eyes,

reti

nopathy, gla

ucoma, irit

is, corneal disorders, lacrimal dysfunction,

degenerative

eye

changes,

blindness, r

etinal

degeneration,

miosis,

chorioretinitis

, strabismus,

eustachian tube dysfunction, labyrinthitis, otitis externa, odd smell.

Post-marketing Experience:

Sudden, unexplained deaths have been reported where a casual relationship to treatment with

gabapentin

has

t been est

ablished. Ad

ditional po

st-marketing

adverse

even

rep

orted include

acute k

idney

failure,

allerg

ic reaction

including a

naphylact

ic reaction and urticaria, alopecia,

angioedema,

blood

glucose f

luctuations i

n patients w

ith diabetes,

chest

pain,

elevated l

iver

function

tests (LFTs), erythema multiforme, hallucinations, movement disorders such as choreoathetosis,

dyskinesia,

and

dystonia, pa

lpitation, pa

ncreatitis, St

evens-Johnson

syndrome,

thrombocytopenia,

tinnitus, urinary incontinence.

Advers

e events

following th

e abrupt dis

continuatio

n of g

abapentin

have

also

been r

eported

The

most frequently reported events were anxiety, insomnia, nausea, pain and sweating.

Post-marketing adverse events that may have no causal relationship to gabapentin include acne,

angioedema,

abdominal pai

n, blood gl

ucose

fluctu

ations in patients with diabetes, confusion,

diarrhe

a, elevated

liver

func

tion tests, e

motional la

bility,

erytheme

multiform

fev

er, h

eadache,

hyponatremia, insomnia, jaundice, nausea and/or vomiting, pancreatitis, rash, Stevens-Johnson

syndrom

e, sudden u

nexplaine

d deaths

pat

ients with epilepsy, urinary incontinence, and viral

infection.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Acute, li

fe-threatenin

g toxicity

has n

bee

n observed

with

gabapenti

n overdoses

grams

ingested

at one

time.

In these c

ases,

dizziness,

double

vision,

slurred

speech,

drowsiness

, lethargy

and mild diarrhea were observed. All patients recovered with supportive care.

Gabapen

tin can

be re

moved by

hemodialysis.

Althoug

h hemodialysis

has

not

been

performed

the

few

overdose c

ases r

eported, i

t may

indicated

by t

patients

cli

nical state or in patients with

significant renal impairment.

Reduced absorption of gabapentin at higher doses may limit drug absorption at the time of overdosing and, hence, reduce toxicity from overdoses.

oral l

ethal d

ose o

f gabapentin

not

identified i

n mice

and

rats

given doses as high as 8000

mg/kg. S

igns o

f acut

e toxicity

anima

ls included ataxia, labored breathing, ptosis, hypoactivity,

or excitation.

DOSAGE AND ADMINISTRATION

Adults

clinica

l trials

, the

effective

dosag

e range

was

900 to

1800

mg p

er d

ay,

given

times

day

using

300

mg o

r 400

mg ca

psules, or

600

800

tablets.

The starting dose is 300 mg three times

day. If

neces

sary, the dose may be increased using 300 or 400 mg capsules, or 600 or 800 mg

tablets 3

times

a day

up to

180

0 mg/day

. Dosages up to 2400 mg per day have been well tolerated

long-term

open

label

clinical

studies.

Doses of 3600 mg per day have also been administered to

small

number

patients

for a

relatively

short

duration

and

have

been

well

tolerated.

Gabapentin

is given orally with or without food.

Data

from

clinical trials suggest that doses higher than 1200 mg/day may have increased efficacy

some

patients;

however,

higher

doses

may

also

increase

the

nciden

ce of adverse events. (See

ADVERSE REACTIONS).

Daily maintenance doses should be given in three equally divided doses, and the maximum time

between

doses

a three

times

daily

schedule

should

not

exceed

hours

prevent

breakthrough

convulsions.

not

necessary

monitor

gabapentin

plasma

concentrations

orde

optimize

Gabapentin

herapy.

rther, as there are no drug interactions with commonly used antiepileptic

drugs,

abapentin

may be used in

combination

with

these

drugs

without

concern

for

alteration

plasma concentrations of either gabapentin or other antiepileptic drugs.

Dosage adjustment in elderly patients due to declining renal function and in patients with renal impairment or undergoing hemodialysis is recommended as follows:

TABLE 6. Dosage of Gabapentin in Adults

Based on Reduced Renal Function

Renal Function Creatinine Clearance (mL/min)	Total Daily Dose¹(mg/day)	Dose Regimen
>60	900 1200 1800 2400 3600	Total daily dose (mg/day) should be divided by 3 and administered three times daily (TID)
>30-59	400 600 800 1000 1400	Total daily dose (mg/day) should be divided by 2 and administered twice daily (BID)
>15-29	200 300 400 500 700	Total daily dose (mg/day) should be administered once daily (QD)
15	100 125 150 200 300	Total daily dose (mg/day) should be administered once daily (QD) For patients with creatinine clearance <15 mL/min, reduce daily dose in proportion to creatinine clearance (eg. patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a creatinine clearance of 15 mL/min receive)
Post-hemodialysis Dose (mg)
Hemo-dialysis	125 150 200 250 350	Patients on hemodialysis should receive maintenance doses as indicated and an additional post-hemodialysis dose administered after each 4 hours of hemodialysis.

¹The table lists the recommended dose to be administered. When the recommended dose is unobtainable with the available dosage strengths, in these cases, dose selection should be based on available dosage strengths, clinical judgement and tolerability.

Children Over 12 Years of Age

The

dosage

used

limited

number

patients

this

age

group

was

900

1200

mg/day.

Doses

above 1200 mg/day have not been investigated.

CH₂NH₂

CH₂CO₂H PHARMACEUTICAL INFORMATION

Drug Substance

Common Name: Gabapentin

Chemical Name: 1-(aminomethyl)cyclohexaneacetic acid

Molecular formula:

C	H	NO
			9	17	2

Molecular weight: 171.24 g/mol

Molecular structure:

Description: A white to off-white crystalline solid.

Solubility: Freely soluble in water and both basic and acidic aqueous solutions.

pH and pK values:

pK_a	= 3.68; pK	= 10.70; partition coefficient at pH 7.4 = 1.25 (Log P)
			1	a2

Composition

Capsules:

Active ingredient: gabapentin

Non-medicinal

ngredients

(alphabetica

lly)

: corn starch, lactose, and talc. Capsule shells contain

gelatin,

silicon

dioxide,

sodium

lauryl

sulfate,

titanium

dioxide,

and

may

contain

red

iron

oxide

and

yellow iron oxide.

Stability and Storage Recommendations

Capsules:

Store at controlled room temperature (15

/ to 30

C).

AVAILABILITY OF DOSAGE FORMS

Gabapentin capsules are supplied as follows:

300 mg capsules:

Hard

gelat

Coni-Snap capsules with yellow opaque body and cap Printed

“Gabapentin 300 mg” on cap and “G” logo on body in blue ink.

Bottles of 100 capsules

INFORMATION TO BE PROVIDED TO THE PATIENT (CONSUMER)

BY THE DISPENSING PROFESSIONAL

LEASE READ THIS INFORMATION CAREFULLY BEFORE YOU START TO TAKE YOUR MEDECINE

, EVEN IF YOU

HAVE

TAKEN

THIS

DRUG

BEFORE.

NOT

THROW

AWAY

THIS

LEAFLET

UNTI

L YOU

HAVE FI

NISHED Y

OUR

MEDICIN

E AS

YOU

MAY

NEED

READ

AGAIN.

OR FU

RTHE

R INFORMATION OR ADVICE

, PLEASE

ASK

YOUR DOCTOR OR PHARMACIST.

What is Gabapentin?

! Gabapentin belongs to the family of medicines called antiepileptic drugs for treating epilepsy. !

Gabapentin

has

been

prescribed

for

you

your

doctor

to reduce

your

number

of s

eizures

or for

treating

other related conditions considered appropriate by your doctor.

Important Points You Must Tell Your Doctor B

efore T

akin

g Gabapentin

! Tell about all your medical conditions, especially if you have any kidney disease. ! If you are pregnant or thinking about becoming pregnant, or if you are breast-feeding. ! Any other medicines (prescription and nonprescription) you are taking.

! Inform you doctor of your usual alcohol consumption.

How To Take Gabapentin

! It is very important you take Gabapentin exactly as your doctor has instructed. ! Never increase or decrease the amount of Gabapentin you are taking unless your doctor tells you to. ! Do not stop taking it abruptly because your seizures may increase.

you

miss

a dose,

tak

e it

soo

n as

possible.

However, i

f it is

within

hours

you

r next do

se do

not

take

the

missed

dose

and r

eturn

to y

our

regular

dosing

schedule.

t a

llow

re t

han

12 h

ours

to g

between doses. If that happens, consult you doctor as soon as possible. ! Gabapentin may be taken with or without food.

When Not To Use Gabapentin

not

use

Gabapenti

n if

you

are allergic to it or any of the components in the formulation (see list of

components at the end of this leaflet).

Precautions When Taking Gabapentin

Call your doctor

immediately if

your seizures get worse

. !

Contact you doctor im

mediatel

y if you experience any severe, unusual or allergic reaction

s. !

When

you

first

begin

taking

Gabapentin

you

may ex

perience

some

side

effect

s such a

s drowsiness,

dizziness,

atigue

. Consult your doctor if you experience any of these, as the dose may have to be

adjusted. !

your

epilepsy

not

controlle

d, it

very i

mportant not

to perform

y potentially

hazardo

us tasks,

such

driving

car

operating

dangerous

machines. I

f you

r epilepsy

controlled, it

important t

o refrain

from

potentially

dangerous

tasks

until

you

are

sure

this

medication

does

not

affec

t your

mental a

lertness

or physical coordination.

! Avoid alcoholic drinks while taking Gabapentin.

What To Do In Case of Overdose

! Contact your doctor or nearest hospital emergency department, even though you may not feel sick.

How To Store Gabapentin

Store Capsules at room temperature (1

to 30

/). ! Keep out of reach of children.

What Does Gabapentin Contain?

! Gabapentin is available in:

Capsules containing 100 mg of gabapentin as the active medicinal ingredient. Non-medicinal

ingredients

include

corn

starch,

gelatin,

lactose

, talc,

titanium d

ioxide,

silicon

dioxide,

sodiu

m lauryl

sulfate, yellow iron oxide and red iron oxide.

Who Manufactures Gabapentin?

‚ Gabapentin capsules are manufactured by:

Genpharm Inc

85 Advance Road
Etobicoke, Ontario
M8Z 2S

REMINDER: This medicine has been prescribed only for you. Do not give it to anybody else. If you require any further information or advice please consult your doctor or pharmacist.

PHARMACOLOGY

In Vitro Studies - Preclinical

The

mechanis

m of the anticonvulsant action of gabapentin appears to be distinctly different from

that of other antiepileptic drugs. Although structurally similar to GABA, gabapentin at

concentrations

up to

100

0 :M

, did

not

bind

to G

ABA

receptors, it

was

not

metabolized t

o GABA

or a

GABA a

gonist,

and

it d

id not

nhibit the uptake of GABA or its degradation by GABA-

transaminase.

Therefore,

it doe

s not

appear t

o act

throug

h an

y know

n GABA

mechanism, in

contrast

to th

e benzodiazepines, b

arbiturates,

sodium

valproate

and

other si

milar

agents.

Gabapent

in (0.01-

100

:M)

did n

ot interact

with

neuronal

sodium c

hannel

s or

L-type

calcium

channels,

in c

ontrast

phenytoin, car

bamazepin

e and

sodium

valproate

which

interact wi

th these t

o promote

the

stability

of e

xcitable m

embranes.

Finall

y, gabapentin

(0.01-100

:M)

did not

interact

with

glutamate

, glycine

or N

-methyl-D-aspartate

(NMDA)

eceptors, in

contrast t

o othe

r drugs that have demonstrated

anticonvulsan

t activity

in an

imal

models following interaction with these receptors. These

neurophysiological f

indings in

dicate

that

gabapentin ha

s a m

echan

ism of

action

different f

rom

that

of commonly used antiepileptic drugs.

Studies with purified synaptic plasma membranes from rat cerebral cortex have shown that

gabapentin ha

s high

affinity f

or a

novel

peptide

bindi

ng si

te whi

ch appears to be specific to the

cent

ral n

ervou

s system.

Autoradiog

raphic studies have confirmed that there are high levels of

gabapentin binding in the outer layers of the cerebral cortex and other regions of the brain with

maj

or excitato

ry input, s

uch a

s the

hippocampus

and c

erebellum,

that are known to be associated

with seizure activity.

In Vivo Studies - Preclinical

Gabapentin ha

s bee

n shown to have anticonvulsant activity in animal models typically used to

characterize

anticonvulsant

activity.

Gabapentin p

revented s

eizure

induced by maximal

electroshock in mice and rats in a

dose-depende

nt manner (

ED₅₀,

200 mg/k

g and

9 mg/kg in mice

and

rats,

respectively). P

eak a

nticonvulsant

effec

ts wer

e see

n approximately

120-240

minutes

post

dose.

Gabapentin

prevente

d threshol

d clonic

convulsions

induced

the c

onvulsant

pentylenetetrazol

mice (ED₅₀

450

mg/kg);

the

threshold

dose

pentylenetetrazo

l needed

produce

clonic

seizures

was significantly elevated by gabapentin.

Gabapentin

treatment

prevente

d tonic

extensor

seizures

mice

from

a variety

convulsant

agents,

including bicuculline, picrotoxine, strychnine and thiosemicarbazide.

Administration of gabapentin to kindled rats significantly reduced motor seizures from electrical

stimulation

of the

brain,

but

had

relatively

little

effec

t on

the

threshold

for

electrical

after

discharges

at the site of stimulation.

Experiment

s with

genetically-s

usceptible animals showed that gabapentin prevented generalized

convulsive

seizures.

However,

results

with

othe

r g

enetic models indicated that gabapentin would

be ineffective against photosensitive myoclonic seizures and absence seizures.

The

anticonvulsant e

ffects

gabapenti

add

o t

hose

several

other

anticonvulsants

against

maximal electroshock in mice, thus suggesting gabapentin would be useful as add-on therapy.

TOXICOLOGY

Acute Toxicity

Gabapentin

exhibited

ver

y lo

der of acute toxicity in rodents and monkeys. In adult and 3-

weeks-old

mice

no d

eaths

occurred

median lethal doses (MLD’s) were not identified, being

greater than 8000, 2000, and 4000 mg/kg by the oral, intravenous, and subcutaneous routes,

respectively

. In

adult

and

-week-old

rats,

MLD’s

after

singl

e oral and intravenous doses were

greater

than

8000

and

2000

mg/kg,

respectively.

signs

toxicity

were

noted

monkeys

given

single oral doses of gabapentin up to 1250 mg/kg. Chronic Toxicity

Multid

ose oral ad

ministra

tion of gabapen

tin was well tolera

ted in all

species

tested (mi

ce, rats,

dogs,

monke

ys). Decreased bod

y weight gain

was observed in r

ats; hypoactivity

, emesis,

and salivation

were o

bserved i

n dogs; a

nd changes in

fecal consistency

were noted

in a

ll species

except mice.

Increas

ed kidney

weights

in male rats co

rrelated with the a

ccumulation

hyaline dr

oplets in

renal

proxim

al tubula

r epitheli

um. No changes were found in the kidneys of female rats. Reversible

increas

es in liver

weight w

ere observed i

n rats administered

gabapentin

at 3

000 mg/kg

for 13

weeks

or 1500

mg/kg fo

r 26 wee

ks, and in dogs

at 2000 mg/kg for

6 months.

No p

athologic

findings

were

noted in mice given up to 2000 mg/kg gabapentin for 13 weeks or in monkeys given up to 500 mg/kg for 52 weeks.

In rats,

plasma g

abapentin concentrations increased with increasing dose. The increases were not

dose pr

oportiona

l betwee

n 2000 and 300

0 mg/kg, suggestin

g saturation

of a

bsorption

at high d

oses.

Carcinogenesis and Mutagenesis

Gabape

ntin was

given in

the diet to mice

at 200, 600, and

2000 mg/kg/day

and to rat

s at 250,

1000

and 20

00 mg/kg/day for 2

years. A stati

stically significant

increase

the

incidence

of pancreatic

acinar c

ell tumor

s was fo

und only in ma

le rats at the highe

st dose, b

not i

n female r

ats or in

mice

of eithe

r sex.

Pea

k plasma

drug concentr

ations and

areas u

nder the

concentration tim

e curve i

n rats

at 2000

mg/kg ar

e 20 time

s higher than th

e therapeutic conc

entratio

n in

humans given

1200 mg/day

and are14 times higher than the therapeutic concentrations in humans given 2400 mg/day.

The pa

ncreatic a

cinar cell

tumors in mal

e rats are low gra

de malignancies

, did not a

ffect survival,

did not

metastas

ize or invade surrounding tissue, and were similar to those seen in concurrent

control

s. Furthermore, hig

her concentrat

ions of gabapentin

in pancreas

relative to plas

ma have

been

observed in rats but not monkeys, which may account for the species-specific effects.

The rel

evance of

these pa

ncreatic acinar

cell tumors in ma

le rats to

carcinogenic risk

in humans

unclear, as the biologic characteristics of the tumors in rats are unlike those observed in humans.

Ductal

carcinom

a compri

se over 90% of

all primary cance

rs of human

exocrine panc

reas, whereas

acinar ce

ll ad

enomas represent the primary pancreatic exocrine tumors in rats. In humans, pancreatic

neoplasi

a exhibit

local

and

distant

tumou

r spread

the

time

diagnosis.

Metastasis o

ccurs

67%

of c

ases,

and

survival i

s between

2 and 6

months

after d

iagnosis.

contrast,

pancreatic

acinar

cell

tumors in male rats given gabapentin did not metastasize, exhibit aggressive behaviour or affect survival.

Gabapentin has no genotoxic potential. It was not mutagenic in the Ames bacterial plate incorporation assay or at the HGPRT locus in mammalian cells in the presence or absence of

metabol

ic activation. G

abapentin

did no

t induce

structural

chromosome

aberrations i

n mammalian

cell

s in v

itro

vivo

, and

did no

t induc

e micronucleus

formation

in t

bone

marrow

hamsters.

Reproduction Studies

In a

fert

ility and general reproduction study in rats with dietary doses of gabapentin up to 2000

mg/kg, (

i.e.

times t

human d

ose of

2400

mg/day),

adverse

fects were noted on fertility,

precoital interval, pregnancy rate, gestation length, parturition, nesting/nursing behaviour, or lactation.

teratogenicity

was

observed i

n mice

given

doses

gabapentin

3000

mg/kg,

rats

and

rabbits

give

doses

f gabapent

up t

o 1500

mg/kg

. These

doses

e 62 times and 31 times,

respectively, the human dose of 2400 mg/day.

REFERENCES

Schmidt B.

Potential

antiepileptic d

rugs:

Gabapentin.

In:

Lev

y R,

Mattson

Meldrum

al Eds. Antiepileptic Drugs. Raven Press Ltd, 3

^rdedition. 1989;925-35

Chadwick

D. Gabapentin:

Profile of

a new

antiepilepti

c drug. I

n: McLean

Ed.

Antiepileptic

drug

resear

ch: the se

cond fifty years. Proc Symp, Jerusalem, September 6, 1987. Princeton,

Excerpta Medica 1988: 24-28.

Bartoszyk

G, Meyers

on N,

Reimann

W. et

al.

Gabapentin.

In:

Meldrum

Porter

Eds.

New

anticonvulsant drugs. John Libbey & Co., 1986:147-163

4. UK Gabapentin Study Group. Gabapentin in partial epilepsy. Lancet 1990;335:1114-1117.

Bauer	G, B	echinger	D, Castell	M, et	al. Gabapentin	in t	he	treatment	of	drug-resistant	epileptic
patients. Advances in Epileptology 1989;17:219-221.

Crawford P

, Ghadial

i E,

Lane

R, et

al. Gabapentin

as an antiepileptic drug in man. J Neuro

Neurosurg Psychiatry 1987;50:682-686.

Vollmer K	, Anhut H, Thomann P, et al. Pharmacokinetic model and absolute biovailability
of the new anticonvulsant gabapentin. Advances in Epileptology 1989;17:209-211

Kond

o T,

Fromm G

, Schmidt

Comparison

gabapenti

n wit

h o

ther

anti

epileptic and

GABAergic drugs. Epilepsy Res 1991;8:226-231.

Reimann W

. Inhibiti

on by

gaba, ba

clofe

and

gabapentin of

dopamine

releas

from r

abbit

caudate nu

cleus: Are

there

common

or different

site

s of

action?

Eur

J Pharmacol

1983;94:341-

344.

10.

Schlicker

E, Reima

nn W,

thert M. Gabapentin decreases monoamine release without

affecting acetylcholine release in the brain. Arzeim.-Forsch/Drug Res 1985;35:1347-1349.

11.

New

trends in epilepsy management: The role of gabapentin, edited by D.

Chadwick,

1993;

Royal

Soci

ety of Me

dicine

Services

International

Congress a

nd Symposium

Series

. 198,

published by Royal Society of Medicine Services Limited, London, New York

12.

The US Gabapentin Study Group No. 5. Gabapentin as add-on therapy is refractory partial
epilep	sy: A double-blind, place-controlled, parallel-group study. Neurology 1993;2292-2298.

13. Chadwick, D. Drug Profile: Gabapentin. Lancet 1994;343:89-91.

14.

Bruni	J. Ou	tcome eva	luaion	of	gabapentin	as	add-o	n therapy fo	r partial	seizures.	Can J Neurol
Sci 1998; 25: 134-14

0. 15.

McLean	MJ, Morrell MH, Willmore LJ et al. Safety and tolerability of babapentin as
adjunctiv therapy in a large, multicenter study. Eiplepsia 1999; 40(7): 965-972.

16. Product Monograph - NEURONTIN, Pfizer Canada Inc., Revision October 29, 2003.
17. Product Monograph- pms-GABAPENTIN, Pharmascience, Inc., Revision July 23, 2004

18.

Comparative Bioavailability Study of pms-GABAPENTIN 400 mg Capsules.
Data on file at Pharmascience, Inc. (Vol 4/ Part IV, Pgs. 69-72).

19.

Comparative Bioavailability Study of pms-GABAPENTIN 800 Tablets.
Data on file at Pharmascience, Inc.

Rx or OTC	Prescription (Rx)?
DIN	02273853
Schedule(s)	PRESCRIPTION
Active ingredient(s)	Gabapentin 300 MG
Dosage form(s)	Capsule
Route(s) of administration	Oral
Drug class (WHO ATC)	N Nervous system drugs N02 Analgesics N02B Other analgesics and antipyretics N02BF01 Gabapentin
Company	GENPHARM ULC
Current status	Cancelled Post Market
Current status date	February 17, 2009

Gabapentin (Genpharm) Product Monograph

Product Monograph - Gabapentin (Genpharm)

ACTION AND CLINICAL PHARMACOLOGY

INDICATIONS AND CLINICAL USE

CONTRAINDICATIONS

PRECAUTIONS

ADVERSE REACTIONS

SYMPTOMS AND TREATMENT OF OVERDOSAGE

DOSAGE AND ADMINISTRATION

TOXICOLOGY

REFERENCES

About this document

Drug information for Gabapentin (Genpharm)