Free Redacted Document - District Court of Delaware - Delaware

Case 1:04-cv-00171-GMS

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWAR

GLAXO GROUP LIMITED )

v. )

Plaintiff, )
)
)

Civil Action No. 04-171-KAJ
)

TEV A PHACEUTICALS USA, INe. and )

TEV A PHACEUTICAL INUSTRIS )

LIMITED )) Defendants.
)

CONFIDENTIAL FILED UNDER SEAL

APPENDIX SUPPORTING TEV A'S BRIEF IN OPPOSITION TO GLAXO'S MOTION FOR SUMMARY JUDGMENT DISMISSING TEV A'S AFFIRMTIVE DEFENSES AND CORRSPONDING COUNTERCLAIM ALLEGING INEQUITABLE CONDUCT DURNG THE PROSECUTION OF U.S. PATENT NO. 5,068,249
YOUNG CONAWAY ST ARGATT & T AYLOR, LLP Josy Ingersoll (# 1088) Adam W. Poff (#3990) Karen E. Keller (#4489) The Brandywine Building 1 000 West Street, 17th Floor P.O. Box 391
Wilmngton, DE 19899-0391

(302) 571-6600

kkeller~ycst.com
Mark D. Schuman (Pro Hac Vice) Ronald A. Daignault (Pro Hac Vice) Jeffer Ali (Pro Hac Vice) Jeffrey C. Brown (Pro Hac Vice)

MERCHAT & GOULD P.C.
3200 IDS Center 80 South 8th Street Minneapolis, MN 55402
Attorneys for Defendants Teva Pharmaceuticals USA, Inc.

and Teva Pharmaceutical Industries, Ltd.

DBO 1:157825.1

058956.1011

Case 1:04-cv-00171-GMS

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TABLE OF CONTENTS

Exhibit Number
A
B

Appendix

Description

Number
B001B002 B003B004 B005B009
BO 1 0Excerpts from deposition of

Dr. Hempenstall taken February 28,

1997 in Glaxo v. Pharmadyne (G028575)
Excerpts from deposition of

Dr. Long taken Februar 6, 1997 in Glaxo v. Pharmadyne (G030051)

C

Excerpts from deposition of

Dr. Anderson taken June 8, 2006

D
E

Physicians' Desk Reference, 1985, pp. 1974-1975

B012

B013B015

Physicians' Desk Reference, 1988, pp. 2031-2032

DB01:2157825.1

058956.1011

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EXHIBIT A
Fully

Redacted

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EXHIBIT B
Fully

Redacted

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EXHIBIT C

Fully

Redacted

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EXHIBIT D

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P D R(I

I
PHYSICIANSI DESK REFERENCE~
Publisher. EDWARD R. BARNHART
Director of Production

JEROME M. LEVINE
Managing Editor

Circulation Director THOMAS S. KRAEMER
Fulfillment Manager

BARBARA B. HUFF
Medical Consultant

JAMES SCIURBA
Research DIrector

IRVING M. LEVITAS, M.D.
Manager of Production Services

CHARLOTIE E. SIBLEY
National Sales Manager

ELIZABETH H. CARUSO
Index Editor

GARY J. GYSS
Account Managers SALLY H. BERRIMAN DAVID M. MJOLSNESS PETER J. MURPHY
Design DIrector

ADELE L. DOWO
EditorIal Assistants

F. EDYTHE PATERNITI YVONNE HARLEY
AssocIate Editor

WILLIAM J. KNIPPING
DIrector of PrInting

JöHN NEWCOMB
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. WILLIAM KUHN

.. the conlenl 01 Ihis publicalion may be reproduced. slored in a relrreval sysiem. or Iransmilled in any lorm or by any means

!! Copyright \S 1985 and published by Medical Economics Company Inc. al OradelL. N.J. 07649. All righls reserved. None 01

(electronic. mechanicaL. pholocopying. recording. or olher\'~sel wiihoul the prior virillen permissiOn 01 the publisher.
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1974
Uqutd: Each 5 ml. (1 teponful) coi:ta, .in

Product liiformation
as follows:

Always consult Supple
studies hava report that the rate ohOC;i
slightly higer for patients healed on 'Tagaií:. than for patients healed on other rorin orthsr.
apy; however, the 'Tagamel'-treate paUSht...

for possible revisions
are not known. Short-term treatment of Deii,,1 Hie ulcer. There is no ¡nforma
ing userulnes or treatmenl

aqueous solution, dmetldlne hydroJùonde equivalent to cimetidle, 300 mg.; alcohol, 2.8%.

acid aeretion stiulate by betele (an isomer race once therapy was disntinued 'was ofhisina), pentaastr, caleine and inulin

Vials: Each 2 m!. contans in aqueous solution, cietidine hydrohloride equivalent to cimeti- Stimulant

Stlmulanl
Dose 1.5mg/kg
(ee)
'Tagamet' \llnhibltlon

dine,30 mg.; phenol, 10 mg. !JWnI
droJùoride equivalent to cimetidme. 300 mg.;

generaly had more severe diseas.

Multlple-osa Vlats: 8 ml. (300 mg.l~ ml:): .Each 2 e mi. contans, in aqueus solubon, i;etidine hy. Penta.
phenol, 10 mg. Singte-ose Prefilled Disposabl~ Syrli:ges:. .Each 2 phenol, 10 mg.

Caeine

gasin

m!. conta, in aqueous solution, cimetidine hy- Insulin droJùoride equivalent to cimetidine, 30 mg.;

6mog/kg/ l00mg/hr 60% at 1 (iv) hour hr (iv) 300g 100% at 1 5mg/kgl (po) hour hr (iv) 0.03 units/ l00mg/hr 82% at 1
kg/hr (iv)

300g 85% at 2'1 (po) hours

ment with a reduced dose of'Tagamet has ben.
shown to decreas the recurrence or duodenal

ulcer, ...
400 mg, h.s,

Reeurrent Dulienal Ulcer. Extnde. lrt..

longer than 8 weeks. 141 The treatment of pathologice tory condillon. Ii.e., Zollinger drome. systemic mastoyto:: endocrine ndenomasi.
Contrndications: There are nO k

In double-lind multicenter studies, 40 mg. or.c. betime, resulte in asignü. 'Tegamel', taen at
icantly lower incidence of duodenal ulcer rec.

indications to the use of 'TagamE cietidine¡. However, the physician 10the Precauilonssection regarding l

(iv) hour

rence in patients trete for up lø one yea. .
PERCENT RECURRING tN EACH QUARTER':" Double-Blind Studies Conducted in the U,5,

l!t, nursing. or pediatric patients.
Prutions: 'Tagamet ibrand 01

Clca Plicology: 'Tegel' (brand of

cimetidine) competitively inhiits the action of hitamine at the histamine Hz recplørs of the

When foo and betale were use. to stiulate
seretion inbition

of hydrgen ion concentra.

paeW cell. and thus reprents a new clas of phascolog agents the histain Hi-recep.
tor antaonists 'Tagamet' is not an anticholinergc agent. Studies have shown that'Tagamel' inhibits both daytime
iud nocurnal bas gastrc acid secretion. 'Taga-

tion usually raged from 45-75% and the inhi. bition of volume raged from 3O5%.

Quarter 'Tagsmel Pte..bo"
II
IV
I 1I

wdemonstrate a weak antiandrog. !!imal studies this was maniresie

¡rtale and seminal vesicle weigh
lhre was no impairment or mating
do or 'Tagamet', as compared wiih
orfertility, nor any harm to the retui

7% (3/46)
7% (2128)

22% (1l/49) .
46% (13/28) 10% (1/10).' 33% (1/3)

2) Pel'ln: Oral 'Tagamet' 30 mg. reu~d
løta pepsin output as a reult.or the decreas In
volume of gastrc juice.
3) tnuln.ic Factor. Intric factor seretion

6% (1/1m
- (0/4)

mi at doses 9 10 56 times the rul
(: or gynecomastia seen in pntien
on' monih or longer may be relate. i

met' al inhibits gastric acid seretion stimulate
by foo, hiine, pentaastrn, caffeine and

was studied with beWnle as a stimulant. Ora

Total 13% (6/46) 53% (26149)

insulin. Aniisecreiory Activity

'Teget' 30 mg. inhibite the ri in intrinsic ractr concentration produce by beWnle, but
some intriic ractr was serete at al times.

b human siudles. 'Tagamet has b.
t.Yi! no effect on spermatogenesis.

Quarter 'Tagamat Placebo .
400 mg. h...
I

Double-Blind Studies Conducied In EuroP'.

motilty. morpholog or in "Uro rerl
~y.

1) Acid Seereilon: &s Ora 'Tageiet 30 mg. inhibite ba gastric acid seretion by
two hours and by 100% for at leat the 4 hour study in fasting throughout ulce patients.

at leas 00%

Oiher l.ower Esophageal Sphincter Pressure and Gastric Emptying
'Tegel' has no efec on lower esphaeal

II
IV

II

duodenal

The gasc pH in all subjects was increaed to 5.0 or greater for at lea 2'1, hours

aphictr (L) preur or the rate of gastric emptyg.
Pharmacokinetics
'Teget is rapidly absrb af ora admin.
isration and pe levels oor in 45-00 min-

5% (8/179) 10% (14/143) 5% (4/78) 5% (2/44)

32% (108/3Sl
24% (45/184) 21% (17182)
20% (10149).

In a 24.month to.icity siudy conduci

do levels or iso, 378 and 950 mg.
~..ximately 9 to 56 times the racor

ToW 169' (28/179) 54% (180/33)
Activa Benign Gastric Uteer . .

ma dose), there was a small ini:re~ p.nce of benign Leydig cell tumors

Nocturnl: Nigbttie bas seetion in fas

'Tagnmet' has ben shown lø be effective ii Ui

ing duodenal ulear patients was inhibite by a
300 mg. dos of 'Teget' by 100% for at least one hour and by a mea of 89% over a seven

ut. The half-lie of'Tagamet is approximately

short-term treatment of active benign gasri
ulcer. .

I'Jp: when the combined drug.tN ï:i ",ntrol groups were compared, reched statistical significance. In , !L,'lonth study, there were no di

2 hours Both ora and paenteal (IV or 1M)
admintrtion provide compable period or
therpeuticaly efecve bloo levels; bloo con. centrations rei:n abve that reuire to pro

to the rats receiving 150 mg./kg.
nitre.ted controls. However. a statis

In a multicenter, double-blind U.S. study.. pa
tients with endosopically confirme. oo.íj

hour period. Gasric pH was incred to 5.0 or grter in lUos or the patients for three to rour hours
'Tegel' 300 mg. reure non-stimulate acid

Ì3nt increae in benign Leydig cel

gasc ulcer were treate ':th 'Taget .si
mg. rour times a day or with plecebo for 1IX
weeks Patients were limite to thos with.u1.

~nce was seen in the rats that rec
is mg.lkg.lday. These lumors weri ""trol groups as well as treated gn

vide 80% inhibition of bas gac ecid sere

concentrtion by 70-100% and the non-smulate volume of gastric seCetion by 20%. Foo Stimuùite During the first hour aftr a stada expmenW mee, oral 'Tagamel' 300
mg. inhibite gastrc acd setion in duodenal 50%. Dunng the aubs.. . ulcer patients by at leat

tion for 4- hour followig a dos of 30 mg.

The pnncipal roi:te of excretion of 'T"1me~' is
the ure. Following parentera adminlStration.

cers ranging from 0,5-2.5 cm. in siz Enaos& caly confirmed healing at si. weeks wos se m

most of the dru is excrete ll the parent compound; followig ora adm~Lition, the di:g

significatly' more 'Tagaet-trete patents

is more extensively metaliz, the sulfoiode
being the major metalite Followi a single

beow: ..

than in patients receiving placebo, as shOW

æir,rence became apparent onty In Ba Instances of cardiac arrhyihmi Wton have b""n reported followi, "iiinistration of'Tagamel' HCI IbrE

æn. hydrochloridei Injeiion by
Siiptomalic response to 'Tagamet'

Quant two hours 'Tegamel' inhibite gastrc

acid seetion by at leat 75%.

ora dos 48% ofthe drug is recvere from the
urine wr 24 hours as the parent compound.

total at week 6 43/65 (66%)' 30/67' (45%)

The effec or a 300 mg, breas dos of'Tagmet' continued ror at least four hours and there

Followig IV or 1M administration, approxi'
mately 75% of the drg is revered from the

'p .:0.05 . . '_'
with 'Tagaiet' than with placebo. .

'Tagamet Placebo" wee 2 14/63 (22%1 7/63 (1%)

!oios.

no preclude the presence or a gastric

11.", have ben rare report or tran
ilgastric ulcers despite subsequent!)

was pa suppren of the ri in gasl'c
acid seretion rollowing the luncheon meal in

Similarly, in worldwide double-lii:d clink,;'
studies, endospically evaluate benigng~biC
ulcer healing rate were consistently .~igbeT

duodena ulcer patients. This suppreion or
gastric acid output was ennced and could be ' maitained by another 300 mg. dose of Tag amet' given with lunch. In another study, 'Teget' 300 mg. given with the mee increas gastrc pH as compare with

Clea Trls

unne wr 24 hours as the perent compound.
Duodenal Ulcer

taignancy.

i.mible conrusional slates Isee A
i;1 hove been observed on aecasi

'Tagamet' (brad of eimetidlneJ has ben shown
to be effeCve in the treatment of active duod.. nal ulcer and, at reduced dose, In the preven-

PaiholOjical Hypersecretory Condltio~ (sèh

Ulily, bui not exclusively, in severel

as Zollinger.Ellisn Syndrome) ."d
'Tegamet' signifcatly inhiite gast!'c ac

Adncing age 150 or more yearsl an

li;r and/or renal diseas appear to

tion or reurnt ulce.

seretion and reuce ocrrnce of di~e:

It fadors. In some paiients th..
"'\O have been mild and heve not ~_a.tinuation. of 'Taga!"et therapy. Ii
~nlinuation was Judged necesi

placbo.
Mean Gastric pH

1 2 3 4

hour 3.5' hours 3.1 hours 3.8 hours 6.1

'Tagamai' Placebo

2.6 1.6 1.9 2.2

Active Duodenal ULCe In worldwide doubl.. blind clinical atudies, endospicaly evaluate duodena ulcer heeing rate 'with 'Tagamet were consistently higher than thos of the pia.

anorexia and peìn in patients with ~logÐt . hypfSretion asociate withZollln~et- i:
son Syndrome, sytemic mastoytis an n;~~ pie endocrine adenoma. Use of 'Teg,t .

:: Usually cleared within 3-4 days
u'''al.

ce controls In many of the studies, th dif.
ference were mtisticaly signifcat.

The ellect. or ora 'Tagamel' 300 mg. and pro
pantheline hromide on foo.stimulate gasric

Speificaly, in various definitive, controlled 'Tagamet' (brand of cimetidine) is ii:dica ein~.t (11 Short.term !reatment of active ~u . '6etudies conducte worldwide with deìly doses or ulcer. Since most patients heal With~ a. 'Tagat' ranging from 80 mg. (40 mg, b.i.d.)
to 1200 mg. (30 mg, q.i.d.), huling rate raged from 36% to 00% at two weeks; 57% to 100% at

Indlcations: . ta..

also followed by healing of intrctable ulcer,

Org Interactions: 'Tagamet',
IIrough an effec on certain micros

r,ms, has boen reported to reduc.
"'labolism of warfarin.type an

weeks there is rarely reBSn to use.ag

acid setion were compare in 7 duodenal

met' ~t rull d~e for longet; period~~
comilant antecidsshould be given asn. us

ilinytoin, propranolol, chlordiazp :ii: lidooaine and theophyllne, the.

ulcer patients. Propentheline bromide was ti.
trate to maxmally tolerate dosegesthe

four weeks; and 58% to 100% at six weeks in
duodenal ulcer outpatients. The corresponding
heaing rate for placbo groupe were 8% to

, "'mation and increusing bloo Ie
inigs.

.for relief of pain. However, simul~% is
administration of'Tagnmet and antaCl be not reommended, since antacids haYti n of

averege dos was 45 mg. 'Tagamet 300 mg. reo
dure gatric acid output by 67% vs. 27%
; ;1

50% at two weeks: 14% to 78% at four wee;
and 23% lø 67% at six weeks
In thes atudies, 'Tagamel'.treate patients report a general reduction in both daytime

(p" 0,05) ror propatheline bromide. 24-Hour Mea H + Actiuity: The 24-hour acid
suppresion provide. by 'Tagamet' with the 400 mg. b.i.d. and 30 mg. q.i.d, regimens is similar

report to interfere with the absl' 0
(2) Prophylectlc use In duodenal ulcerpll¡eur.

'Tagemel'. ìe,iis

Q.inically signifcant effects have b I\lh the warfarin anticoagulants: th t)riiloring or prothrombin time is n

~ adjustment or the anticoagulant

l¡~ry when 'Tagamet' is admii
erse c1inicnl effects.

and nocturnal pain. and they al consumed les

(54% an 69%, repetively). Howaver, the 30
\ l 1 ,J
1

mg, q.i.d. remen produce greater daytime
acid suppreon, while the 400 mg. b.i.d. re-

antacid than did placebotrte patients. In tral comparng q.Ld. and b.Ld. remens, tbere
was a nonsigficepttrend løward lower anlacid us in the q.i.d. group.

at reduced dosage, 10 prevent uicer ic1 rence In patients likely to need sur~ hi!
irealmenl, a.g" as demonsuated bY and in

~milantiy. Interaction with phenyti

phylline hns also been rep
. r the drugs mentioned abo'

lory of reurrence or complications. ~
pailenu wlih concomilSnl 11nes, In m.n.
surgery would consiiiue a gre~iepoii&-

~llarlY metaboliied drugs, particul

men resulta in grter suppreon of nocurn
acid secetion. The exact degee and duration of

acid suppreion neee. for healin ulcers are
not known.

:\
:I .)

CJmuxlly StiulaW: Oral 'Tagamet (brand or cimetidine) significatly Inhibite gastrc

Whe shortterm trtment with 'Tegimel' (brand of cimetidine) ca result in complete healing of the duodenal ulcer, acute thrapy will not prevent ulcer reurrence aftr 'Tagmet' has ben disntiued. Some follow.up

usuat risk, Limitaticn or us to th; ",ii tion is remmended beus. e be¡!d
quances of very 10ng.term us, i.~, th,rWY
one year. or continuous 'Taget . 't~: '

h' therapeutic raiio or in petient ../or hepatic impeirment, may re
.~~ when storling or siopping c'
~inislered 'Tagsmet to mointa

"'"poutic bloo levels.

Case 1:04-cv-00171-GMS

Document 141

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pplement

~r possible revisions

Product Information
Additional clinica experience may revea other
drug afec by the concomitat administration

1975
aline and some incr in ,"rum train

'ofr~ nued w..
ns of ther.
d patients

"r"lt'

are not known. (31 Short.term treatment 01 active benign gaatrio ulcer, There is no informallon concern.
ing usfulnes' of treatment pariod of

have ben report. Thes did not proges with
continued therapy and disppered at the end of therapy. Rae ca of fever, interstitial nephritis and pan. creatitis, which cleare on withdrawal of the drg,
have ben report. Adverse hepatic effects have ben report rarely. Thes were reversible and

of 'Tagmet.

Dereed white bloo cell. counts, including
agnulocis, have ben report in 'Tegamet'-

tonger than 8 weeks

ded tr",~

(41 The treatment 01 pathotoglcal hype"ecr.. a (i.e., Zollnger.Ellison Syn.
tory condition

treate patients who al reeived antimeta
lite, alkylating egenta or other drugs andlor
tretment known to produce neutropenia.
ence to date with the us of 'Tegamet' in pregnant

t'ha be.

drome, systemic mastoytsis, multiple
endocrine adenomas).
Clotrdications: There are no known contra-

f dUodenal
400 mg. of

USlge In Prenancy There has ben no experi-

choleslaûc Or mixed cholestatic-hepatollular in
nature. Beus of the predominance of chole-

inasigiif.
deer rer.

¡,dicitions ti the use of 'Tamet' ibrand of

ne yea.
JARTER
n the U.S.

slatic features, ,"vera parenchymal injury is con. strte that 'Tagamet' croses the placental bar. sidere highly unlikely. diietidine). However, the physician should refer rier. Teratology studies (1()950 mg.lkg./day) There ha ben report e single ca of biopsy. IDthe Precutions setion rearding use in preg- have shown no effects attributale to 'Tagmet' On proven periport hepatic firois in a patient re øs~ nursing, or peiatric patients. litter parameters or early development of the ceiving 'Tagamet.

paUents. However, animal studies hava demon.

lrution.: 'Tegamet' (brand of cimetidine)

i.demonstrate a wea antiandroenic effect. In

Placebo

iial studies this was manifeste as reduced ¡ite and seminal vesicle weights. However,

, (1/49)
, (13/28) , (1/10)

young. 'Tegamet' should not be us in preant patients or women of childbering potanUal unles in the judgment of the physician, the anticipaie ben.. iler was no impairment of maUng peormance irrtity, nor any harm to the fetus in thes ani. fitS outweigh the potetial riks.

Dosage and Admtration:
Duodenal Ulcer

Acilve Ourxenal Ulcer The remmended
adult oral dosage regen or 'Teget. for the

routie tretment of duodenal ulcer is 300 mg.
four times a day, with mea and at betúe, the

; (1/3)
; (2$/49) in Eurot) Placebo
~ (108133)
~ (4511Sli
~ (171821

Nursing Mother: Cimetidine is serete in hu.,' at dos 9 to 56 times the full therapeutic ~of'Teget', as compared with controls. The man milk and, as a general ruie, nursing should ~ of gynecmastia sen in patients treate ror not be undertn while a patient is on a drug.
tÖ month or lònger may be relate to this effect.

Pedlatrrc Use Clinical experience in children is

dose regmen with which U.s. phYSicia have the most experience, Europe clinica tral have studied smer daily doses 20
mg. three times a day with meals and 400 mg. at betime, as well as 400 mg. twice a day, in the morning and at betime. Although the advataes of one regmen over another for a parcu-

in human studies, 'Tagmet' has ben shown to
hi.e no effect on sprmatogenesis, sperm coun~

limite. Therefore, 'Tagemet therapy cannot be
reommended for children under 16, unles, in the

iiity, morphològ or in vilro fertilzing capac. judgment of the physician, anticipate benefits outweigh the potential risks. In very limite ex ~à 24-month toxicity study conducte in rats, at 'rience, dos of 200 mg.lkg. per day ha~e ben
ò5 levels of 150, 378 and 950 mg.lkg./day (ap~ately 9 to 56 times the recommended hu.

us.

lar patient population have yet to be demon.
strate, the 400 mg. twice-a-dy regimen may be

Advers Reactions! ì\l1d and transient diar.
rhea. diznes, somnolence and rash have ben

partcularly appropriate for thos patients in
whom dosing çonvenience is importt.

¡, (10/49)

i5 dose), there was a small incre in the incialce of benig Leydig cell tumors in each dos
'l& control groups were compared, this increae
wuP; when the combined drug.treate groups

report in a small numbe of patients, e.g., approximately 1 in 100, during tretment with

iç (180133)

Concomitant antacids should be given as neeed for relief of pain. However, simulteeous admin.

'Tagamet (brand of cimetidine). A few ca of
heaache. ranging from mild to severe have ben

istrtion of'Tegamet' and antacids is not reom.
mended, since antscids have ben report to interfere with the absrption of 'Tagamet

:recve in th

"nigi ga.ot
.S. study, pa

rGed statistical significance In a subsuent
ÌÍlrte controls. However, a statistically signif-

the dru. report; thes cleare on withdrawal of U;onth study, there were no diferences be There have ben rare report ofreversible arthra, l..n the rats receiving 150 mg.lkg.lday and the

(brand of cimeûdine).

.rmed beni
Tagamet' 30

gia and myalgia; exacerbation of joint symptoms lit increae in benign Leydig cell tumor ind- in patients with preisting arritis has also ben al was sen in the rats that received 378.and report Such sypwms have usually ben allevi-

While healing v.ith 'Tegamet oftn ocurs dur-

ing the rtr week Or two, treatment should be
continued for 4- weeks unles healing ha be
demonstrate by endospic exintion.

lacobo for m :hos with ul

:u.Endos¡i
ks was se in
iate patiel~

i: in.lkg.lday. Thl! tumors were common in ate by a reduction in 'Tagamet (brand of dmetiæftrl groups as well as treated grups and the dine) dosae. A few ca ofpolymyositis have ben
Míerence beme apparent only in aged rats. il insnces of cardiac arrhytmias and hypo 'Tag idinistration of

Prophylaxis of necurreni Ourxenel Ulcer In
th patients in whom prophylactic us is indio

report, but no caus relationship ha ben es
tablished.

cate, One 40 mg. tablet or two 20 mg. tablets

ibo, as sh_
Placebo

7163 (1%)
30161145%)

sion, agitation,' pschosis depresion, anxiety, disrientation, have ben report á¡ hydrohloride) Injection by intravenous hållucinations, but nol exclusively, in ,"verely il predominantly, fi\uS Sjiptimatic respoo."" to 'Tagamet' therapy doe patients. They have ' usually develope within 2arneI' HCI thrand or dmeti.

Iion have be report rollowing the rapid Reversble confusional states, e.g., mental confu.

at betime is remmended. Prophylactc trat.
Active Benign Go:tnc Ulcer

ment with higher or more freuent dos doe not improve effecvenes.
The recmmended adult oral dose for short.
term treatment of active benign gasric ulcer is 300 mg. four times a day with meals and at be.

.blind cliniC!

benign gas itently hiher
.o.

t¥prelude the presenceofa gasric malignancy. Tire have ben rare report of transient healing Rtatnc ulcers despite subsuently documente ancy.

days or initiation Tag of

arneI' therapy and have

cleare within 3- days of discontinuation of the
drug.
Mild gynecomastia has ben reporte in patients

time. Controlled clinica studies were limite to
six weeks of treatment lse Clinica TralsL.

ndition. isucl

:- of diarrhe .
Zollnger.ElI. .
¡.is and mUIU"lagameC was

d gasc ac

sible confusional states I,"e Advers Reoc- treated for one month or longer. In patients being have been obsrved on occaion, predomi. treate for pathological hyprsretory states. this not exclusively, in severely il patients. ocrred in about 4 pereent of ca while in all ""cing age (50 or more years) and preexisting others thé inddence was 0.3% ti 1% in various
1lr andlor

Si-iptomatic respoii to 'Tagamet doe not
preclude the presnce of a gastric maligcy. It is importnt to follow gastric ulcer patients ti
asure rapid progr to complete healing,

renal disase appear to be contrihut.

studies. No evidenceoflnduced endocrine dysfunc-

Pathotoglcal Hypersecretory Conditions (such as
Zollnger-Ellisn Syndrome)

. factrs. In soma patients thes confusional
have been mild and have not reuire dis

tion was found, and the condition remained un-

th patholog .
Lelble ul","indicate in:

'nuation or 'Tagamet therapy. In ca where
nustion was judged necry, the condi.

changed or returned toward nonnal with continuing 'Tagamet treatment.
Reversible impotence has ben reported in pa'

Remmended adult oral dose: 30 mg. four
times a day wiih meal and at betie. In some
patients it may be necry to administer

ally cleare within 34 days or drug with. tients with pathologcal hypersetory disorders, e.g., Zollnger.Ellisn Syndrome, receiving 'Taga.

clive duod..
ieal with &$

Interactions: ITagamet. apparently mel" partcularly in high dos, for at least 12 an effec on ceNin micromal enzye month (range 12-79 months, mea 38 months!. h"" been report to reuce the hepatic However, in large-le surveilance studies at
of warfarin.typ anticoagulants,

'Tegamet' 300 mg. dos more freuently. Do should be adjuste to individual patient nee, but should not usually exce 2400 mg. per day
and should continue as long as clinicaly indio

cate

reglar dos, the incidence ha not exceed

P8renteral Administration
In some hospitalize patients with pathological
hyprsretory conditions or intrctable ulcers,

n to us "l*

!l periods. Co
given as ne¡eJ
. simultsn£:US ~nd antocídsis

acids have ii
,e absorption or

propranolol, chlordiazpoxide, dia that commonly report in the general population. ine and theophyllne, thereby delaying Furthennore, in controlled long-term studies in ion and incre""ing bloo levels of thes patients reivig a single daily betime dos, the incidence of reversible impotence did not differ y significant effects have been reported sigificantly between the 'Tagamet' and placebo warrarin anticoagulants; therefore, clos groups. . ng or prothrombin time is recmmended, Reversible alopecia has ben report very rarely. ment of the anticoagulant dos may be Dereas white bloo cell counts in 'Tagamet-

or in patients who are unable to tae ora medi.

cation, 'Tagamet may be administered parenterally accrding to the following reommenda.
tions:

ii ulcer patients

ent ulcer ,.ur.
i nee SuI11U1

trated by a h~ ,ications, eod in
ilnes Inwh..

when 'Tagamet is administered con. treate paUents (approximately I per 100,00 paInteraction with phenytin, lidocine tients), including aganulocyt (approximately ine has also ben report to pro- 3 per milion patients), have been report, including a few report of recurrence on rechallenge. linical effects.

intramusoular rnjectlon: 30 mg. q 6 hours ino dilution necary). Transient pain at the site or injection has ben report. Intermrttent r"travenoui Inlusion: 30 mg. q 6
hours. Dilute 'Tegamet HCI Injection, 30 mg.. in 100 m!. of Dextros Injetion 15%\ or other compatible i.v. solution (se Stailty of 'Taga. met' HCl Injection) and infus over 15-20 mi. nute. In some patients it may be necary to increa dose. When this is necesry the in.
craas should be made by more frequent ad-

a grea ter thin. e to this popult

metabolize drugs, particularly those of mnes ànd reived drugs andlor treatment apeutic raUo or in patients with renal known to produce neutropenia. Thrombo
hepatic impairment, may require edjust. penia (approximately 3 per milion patientsl and a
when sterlng or atopping concomitantly

f the drugs mentioned abve and other These patients generally had serious concomitant

¡us the "':d

few caes of aplastic anemia have als ben re

u.s, i.e., be, . \garnet' thenPJ.

í.ied 'Tagamet to maintain optimum

port.

ministration of a 30 mg. dos, but should not

pautic bloo levels.

Reglarly observed small increa In plasma ere

Continued on nexr psge

8012

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Case 1:04-cv-00171-GMS

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PDR~

~

1988

PHYSC ANSi
DESK REFERENCE'
Publisher. EDWARD R. BARNHART

Director of Production
MARY TRELEWICZ

Director of Manufacturing
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Managing Editor
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Medical Consultant
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Marketing and Circulation Director
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Manager of Production Services
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~ Copyriht (;1988 and published by Medical Economics Company Ine., at Oradell, N.J. 07649. All oghls resrved. None of Ihe conlent 01

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Olfiors 01 Medical Ecoomics Company Inc.: President and Chief Execlive Offcer, Thomas J. McGill: Senior Vice Presdenls: Jack e. Angel. Howard C. elullerbuck:
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8013

ISBN 0.87489.844.7

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Document 141

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~
)f.posslbie revisions tl of the follOwi advers rectons have ben obsrved ~ ev phenothie derivative, hut they have ben
~ vtth one or more and should be borne in mind when

-

Product Information
Only in very exceptional ca sÌould intnuusar dose .
. exce 10 mg. witlùn 24liours.lnjetions6houJd not be given

20.31
TAGAMET~
(to 'ah.mat L Ibrand of clmetldlne tebtels clmettdine hydrOChtoride liquid and clmeildtne hydrochloride tn¡""tlonl

R

at interla1 ofles tha 4 hours bewi of a poible cunuJative effecL

.: of~ cla are adin~~: exrapyi~al syp~ (opisotonos, oculogc cnsls, hyprreflexia, dyi
.iiia dy¡kiesia pakinlm) some or whih

Note: Stelazne (tnuoperaze HCI. SK&F) Injecon ha
ben usually well tolerate and ihere is little, if any, pa
injection. at and irritation the site of

";losvtth previous'brainyearparcularly in elderly i. to month and even dame; grd mal and pem
~o'liOns, particularly in patients with EEG abnoriiti or hisry or such disrders altere cereropinal

PRODUct OVEVI
KE FACT
its both dayte and hocturnal bas gastrc acid setion.
'Tagament al inlùbitB gastrc acid seretion stimulate by

The Injecion should be prote from IighL Expour may caus diloration. Slight yellowih disloration wil not alter potency or efcacy. Ifnikedy disolore, the solution

'Tagamet' is a hisine H2 reptor antaonist which inhib-

i: pitein cerebra edema; intensifcation and prolongaØl althe action or centr nervous sy¡tem deprents (opi¡iiiaJescs, antiisines baiturate, alcohoi), atT
ø;(diyes of

should be died. .

DOSAGE AN ADMIRATION-PSYCHOTIC
CHILDREN

jr'; li orgophosphoru congestion, headache,llus mouth, nas incides; autonomic ret:

¡ipation, obspation, adynamic ileus, ejacatory elr-

iiiipotence, priapia, atonic ",Ion, uriary retention, .

Doe should be adjus to the weight of the clùld and se verity of the syptoms Thes dooes aÌ for childrn: ages.

foo, histaine, pentaasrin, caeine and insulin. MAJOR USES 'Tamet' is .lndicate in the short.term tretment of active

di:odenal ulcer, and promote heaing in most patients
witlùn 4 weaks. The 80 mg. h.s. dosing regen Is the regi.
men of choice for mosL patients as it provides a lùgh heaing
rate maxmal pai relief, a dec potenti for dru interactons and IIal patient convenience. Afr heain

¡' lld mydris): reivation or pschotic pro ,iDÌc.like stte; hyptension (sometiO$ fata: caiac ~ bloø dyiraias (pacypeni thmbopenic
~rl, leukopeia, agulocis, eoinophia, heme-

6 to 12, who are hospitaiz or under close supervion.
Oral: The sterting dooe ia1 mg: administere once a day

or b.i.d. Dose may be incre grdualy until syptoms
are controlled or unti side effects beome troublesme.

¡tllei aplatic anema) liver damage (jaundice. bil-

While it is usually not ne= to exce dos of 15 mg.
daily, BOrne older children vtth Be,'ere sypwms may re

of acve ulcer; patients have ben maitaed on continued
trtment with 'Tagamet 400 mg. at betime for period of

ø"glyai lacttion, galctrrhea, gyecllti

ii¡j): endixe di~bance (hyprglycemia, hypg!y-

~ irrties fa poitive preancy te): skn

quire hIgher dos.
Intrmuscular. There ha ben litle exprience with the us of Stelaze (truoperazne HCl, SK&Fllnjection in
chdrn. However, if it is necry to aclùave rapid control of severe syptoms, 1 mg. ('f mI.) of

~ (photnnsitivity. itchi, eryhema, urtcaa,
Ø! up to exolitive dermatitis); other alergc retins
~ lagea edein angioneurtic edema, anphylac-

up to five yea, 'Tagamet 30 mg. q.i.d. has proven effecive in the treatment of active beni garic ulcer and pathologca hyprs1'tory conditions (i.e., Zollngsr-E1lisn Syndrome).
In hositaiz patients with patholOgica hyprs1'tory

i:Wions); penphera edema: revers epinephre ef-

the dr may be ad-

",nditions or intrable ulcers, or in patients who ar un.
able to tae ora mediction. 'Tagamet may be admre

~;byrpyrxia mild. fever afr lare LM. dos; in-

isre intrusularly once or twce a day.

~ appetite; increas weight; a sytemic lupus ery.

panteraly.

~li sydrome; pigentery retiopathy: with

~ adintration of sutial do, ski pigen.
¡, epithelial keratopathy, an lentìcular and cornea

;IchesicularlY nonspeifIC usually reversble
Qii T wave ditortonsve ben obsrved in some pa.

OVEDOSAGE (Se al under Advers Reons.) Symptoii&-Pnmary involvement of the expyrada mecha proucig some of the dy¡tonic rections descri abve. Symptoms of central nerVous sym depre
sion to the point of somnolence or coma. Agtetion and re

SAF INRMTION

There ar no lmo"1i C1ntraidications to the us of'Tag a-

melt. ' R TAGAI'ET0
PRESCRIBING INORMTION
(to 'oh.met J
(brand of clmetìdlne tablets

l! ravi phenothiie trquilizrs Although phe-

~es caus neither pschc nor phys dependence,
~, tremulouses.

leses may al occur. Oter poible maestions include convulsons, EKG chages and caac arrhytas,

~. dintiuace in long-term psclùatric patients

raøus tempora syptoms. e.g., naus and vomitig,
/i'oorrce of neurleptic maigit syndrome (NMSl

rever, and autonomic rections such as hyptension, dr

mouth and ileus. .

clmetidlne hydrochloride liquid end cimetdine hydrochloride InJ""tlonl

Ii ben 1'port in patients revig neuroleptic dru.
i;6Ydrome is compri.of the symptom complex of hy-

Treatment-It is importent to detenne other medcations
taen by the patient sice multiple dos theray is common

("agamet' is a prouc of SK&F La Co., Cidra, P.R. 0039,
Phiadelplua, Pa.)

Subsidi of Smithine Bekman Corpration,

~ia altere. conso.uses :nuslar ridity and
idc dysunction and 15 potetialy fata. ~. There have ben lXional1'port or sudden death

in overdose situations. Trtment is esntily symptomatic and supportve. Ealy gatrc lavage is helpful, Keep

DESON

patit under obsrvation and maintan an open airwey,

¡(~ts recivig phenothes. In soma ca, the

since in~olvement of the exapyridal mecha may
prouce dyshaga and reiratory diffculty in severa overdose. 00 not attempt to induce emesis beuse a dystonic reection of the head or n""k maydevelop ihet coutd ~utt In

'Tagamet' (brad of cimetidine) is a hiiaine H2 reptor antaonisL Clemiy it is N ".cano-ji.methyl-N r_¡z.((5methyl.lH-imidal-4yl) methyll thiol-ethyll-gnidinc.
The empmca formula for cimetidie is ClllHisNsS and ror
cietidie hydrhloride, CioHisNsSHCl; thes represt
molecular weights or 252.34 and 28,80, restively.

~. appe to be cac arest or ashyxa due to rail~ the cough reflex.

IlGE AN ADMITION-ADULTS
~ahould be adjus to

the nee of the individuaL. The

aspiration of vomitus. Exnpyramidal sympwni may be
trete with anti-parkinsnlm dru barbitutæ, or Bene-

Cimetidie C1nta an imidale rig, and is chemicaly

~efec~e dose should alwey¡ be us Doe should
~i: mora grdualy in debiltate or emaciate pa.

relate to hisne.
the hydroclùoride.)

drylU, Se prebing inrormation for thes prouct Care

('he liquid and injectìon dooe forms con.tBin cimetidine as
Cictidie ha a bittr tate and chactriic odor.

fsWhen maxmum respons is ecleved, dose may be
~ giadualiy to a maitenance level Beus of the
~t long acton of the dr. patients may be controlled

depreion, If should be taen to avoid increng repiratory adminisration of a stiult is desirable, amphetaine,

dextroaphetaine, or caeine vtth soum benzate is
remmended Stimulants that may caus convulsons (e.g..

Tabtei: Each liht grn, fim-cate talet conta

Ilti,,,nient b.id. adminration: some patients may be
titsed on onceaody adminiation.
il'Stelaze (trifluoperae HCl, SK&Flis adminisred Ii:it:usular injecion, equivalent oral dooe may be ..llte once symptoms have ben contrlled.

cimetidie as follows: 20 mg.-round, imprite with the

picrotoi: or pentylenetetrazl) 6hould be avoided. If hyptension ocurs, the stada measure ror maagng
if circuiawry 6hock should be initiate.it is desirable to adminisr a vasnsctor, Levophed' and Neoynephriet
ar most suiteble. Oter presr agents, includig epineph.

prouct name TAGAM. SKF and 20; 300 mg.-round, imprite with the prouct iie TAGAM, SKF and 30:

TAGAM. SKF and 40; 80 mg,-oval Titsb~ tebletB,
imprite with the prouct name TAGA.'U;:r, SKF and 80.

400 mg.-cpse-hape, imprinte with the prouct name

~.'AJthongh there is little lioo of contat dermatiIito the dru, petSns with know senstivity to pheno-

~e dru should avoid dire contect
~ Patients In general, doses in the lower range ar

rie, are not remmended beus phenothe derivatives may 1'vers the usua elevatìng actn af thes agenlÆ

Inactve inentB consis of cellulos, D& Yellow No. 10, FD&C Blue No.2, FD Yellow No.6, hydroxropyt meth.
ylcellulos, irn ondes, magesium sterate, povidone, pro

~ent for mos elderly pstients. Since they appe to be
~'SUptile to hypteon and neuromusular rec.

and caus a further loweri of bloo preur.

pylene glycol, soium lauryl sulfete, soum stliglycolate,
stah, titaui dioxide and trac amounts of other inactive

tí.-such patients should be obsrved closly, Doe
~ more grdually in elderly patients,
~Chotic Anxiety

Liite experience indicate tht phenothies ar not dialy:le.

ïnedentB,

~ be talore to the individua, repons cafully moni:'~ and dose adjus acciiingly, Do should' be

HOW SUPLI
Tablets, 1 mg. and 2 mg., in bottles of 100 and 100; in aingle

Uquld: Each 5 mi..(one teponfi) or clear, light ors.ge, mint-pe flayored liqui contans cimetidine hydrlùoride equivalent to cietidie, 30 mg.: alcohol, 2.8%. Inac.
tive ingrentB cons ofFDC Yellow No.6, flvor¡, meth. ylpaaben, polyoxyethylene polyoxyropylene glycol, propylene glycol, propylparabn, saccha soum, soium chloride, soum' phosphate, sorbitol and water. Viels: Each 2 rol. contans, in aqueous solution, cimetìdine
hydrohlorida equivalent to cimetidine, 300 mg.; phenol, 10
mg,

Unit Packaes of 100 (intended ror intitutional us only).
For psyclùatric patients who ar hospitaliz or under clos aupervlson: Tablets, 5 mg. and 10 mg., in bottles of 100 and 100: in Sin-

Uõ'doo is 1 ór 2 mg, twce daily, Do not adminislÆr at
~Ló'rmore than 6 mg, perdey or for longer then 12 weeks
'lfOtiC Otaordani

~; Usua staing dooe is 2 mg.-to 5 mg. b.i.d. (Small or
~te patients should alway¡ be st on the lower
"¥'ptients wi show optimum reponse on 15 mg. or 20

~..) .

only). oflOO (intended forinitutìonal us gle Unit Packaes Muilipleose Vials,10 mL. (2 mg./ml.,ln boxO$ of 1 and 20, 10 mg./ml., in 2 fl: oz bottles nnd in cartns of Concentrate,

lily, although a few mey reqnir 40 mg. a day or more.

12 bottles. Each botte is packaged with a gruate dropper.
The Concentrte rorm is ligh~nsitive. For th reni it

Multlplo-ose Vtats: 8 ml. (80 mg.l2 mI.): Each 2 ml. conta, in aqueous solution, cimetidie hydroclùoride equlva.

lent to cimetidie, 30 mg.: phenol, 10 mg.
Singte-oae Preflled OI,posable Syringes: Each 2 ml. con.

. therapeutic dooe levels 6hould be reched

e Concentrate dooe form is to be us it should be .L,. 60 ml. (2 11. cr.l or more of diluent juit prir to ad.
~!rtÚln to insure paatabilty and stility. Vehicles
lés for dilution ar: tomato or frwt juice, milk, simple

two or three weeks. .

sliould be pro~te from light and dispens in am\ir bot-

tles. Refrration is not reuire .
, N01'pinephrine bitartrate. Winthrop-Bren Laratories.
hydrhloride. Winthrop-Bren Laborato t Phenylephrine.

. tein, in aqueous solution, clmetidine hydrochloride equivalent to cimetidine. 30 mg.: phenol, 10 mg. Singte-oie Premixed Ptaatlc Contatneni: Each 60 rol. con. tans cimatidine liydrolùoride equivalent to 30 mg. cimeti. die and 0,45 giam soum chloride.
No presrlatìve ha ben added.

i",¡ i: orange syp, canate beverages, coffee, te, or

ries.

l/r¡8emislid foo (soup, puddings, etc.) may also be

""ular (for prompt contr of UV1rs symptom.):

necar,
""

e ial mg. to 2 mg, ('1Tl mI.) by deep intramusuh, p,r.n. More tha 6 mg. within 24 hours ia

i Phenytin, ParkeDavi. § Metride, Winthrop-Br""n LaratoriO$. II Diphenhydrine hydroloride, Parke-Davi.
SZ:L6 Shown in Pruct IdetifICtion SedÚln, pa 431

The platic contaner ia fabricate rrom speially formulate polyvyl chloride. The amount or water that ca permeate

from inide the contaer into the overwrap is inuffcient to

8014

Conflnued on nexf page

Case 1:04-cv-00171-GMS

Document 141

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REDACTED VERSION ­ PUBLICLY FILED

8015
2032
affect the solution sigficatly. Solutions in contact with

Product Information

Always consult SUPPletneli ti poi

Smith Kline & French-Cont,

Phirmacoklnatlca .

the plastic contaner ca leach out cert of its chemica components in vet) am amounta withn the expiration
period, e.g., di 2-thylhexyl phthalate (DEH), up to 5 part per milion. However, the safety or the plastic has ~n i:nfirmed in tets in anmals according to the USP biological
ADD.Vantage~ . Vlela: Each 2 mi. conta, in aqueous

'Tagaial' is rapidly Bbrbe afr oral admintrtion and pek levela ocr ìn 4ó9( minute. The haf,life of
'Tagamet' is approximately 2 hours Both ora and pare.
tera (I or lM administration provide comparale pe

riod of therapeuticaly effective bloo levels; bloo con,
centratioii reman above that reuired Ui provide 80%

'p":O.05 "l
tota at wee 6 43/65 (66%)' 30/67 (4,%1 í'''''
Zollnger-Ellisn Syndrme, eystemic mll an . or

in plac, as shown below: ;; 'Tegarr!' Plsct.. ileo wek 2 14/63 (22%) 7/63 !1%) ~ l

tets for plastic contanern as well as by tiie culture toxic. ity studie;.
solution, cimetidine hydrohloride equivalent to cimetidine, 300 mg.; phenol, 10 mg.

inhibition ofbe.l gastrc acid setion for 4- hourn fol.
lowig a dos of 80 mg.
The principa route of excrtion of'Tsgeiet' is.the uri

Followig parenteal administration, mos of tha dru is

cebo. it
son to us 'Tagemet' at full dose for loiÍ Ui db th

Simllarly, in worldwide double-lind clinica atud ~ ~3C
dosopically evaluate benig gastric ulcer heeling rakt f)fS!
were consistently higher with 'Tagemet' tha wi\b Jl :Ø-f

ger-Ellisn Syndrome) . . . ~ re

Pathotoglcal Hypersarotory Conditions (such as 2014 ~ D.

CLCAL PHARMCOLOGY

. ADD..ant.e~ is e trademark or Abbott Laboratories.

excrete as the parent compound; followig ora admij¡ traion, the dru ia more extensvely metaliz, the sulf.
oxide beg the major metabolite. Following a aingle ora

'Teiel' signifcatly inhiite gastrc acd 5Otk ~1 re and reuce ocumnca of diarrhea anorexia en pa ii ~ ( patiente with pathologca hyprsretion llla wilb ~ii

'Tagamel' (bni or cimetidine) competitively inhibits the
acton of histaine at the histaine Hi repto", ofthe peri-

dos 48% or the dr is recvered from the urine afr 24 hourn as the parent compound. Followng IV or 1M admin.

etal cells and thus is a hitaine H2'reptor antaonist.
'Tageiel' is not en anticholinerg agent. Studies hava

istration, approi:átely 75% of the dru is recvere
from the urne afr 24 hours as the pant compound.

shown thet 'Tageiet inhibits both dayte end nocurn
bas gastrc aci seretion. 'Teget al inits gastric
acid seretion stmulate by roi, histae, pentaastrin, caeine and insin,

CLICAL TR
Duodenal Ulcer
'Teget' (bran of cimetidle) haa ben shown to be effec.

INICATIONS ~ bl
'Tageiet (brand of cimetidine) is indicate in; ilon

multiple endocne adenomas. Use of 'Tagemet' was'¡ ::rei

followed by healing of intrctale ulce",. ¡s e(

i 1) . Short,term treatment of activ dUodenl1 u!c:~ j, b¡
patients heai with 4 weeke and ther in rsy rn ~ In

Antisecretory Activity

I) Acid Secreon: Nocturnl: 'Tagemet' 80 mg. at be.
tie reuce mean hourly H+ activity by grtar than

tive in the trtment of active duodena ulcr and, at reduce dose, in maintenace therapy rollowig heag
of active ulcern. .

S- weeke (se Doe. end. Adiinis~ ¡i i
Duodenal Ulcer). Concomitat antacids sboulre it pIt

85% over an eight-our periòd in duodenal ulcer patients, with no effec on daytme ecid setion. 'Tagemet 160 mg. h.s. prouce 100% inhibition of.mea hourly H+ ac.

Active Duodenel Ulcer. 'Tegmet' acclerate the rate of duodenal ulcer heeling, Heeng rate report in U.S. an~

given as neeed for relief of pain. However, siuli. rg./ neons administration of 'Tageiet' and antads li iiOlI
not remmended, sinOl antacids have ben repo f¡e

foreign controlled tral with 'Tageiel' er summari
below, begining with the regimen providing the lowes
nocturnal dos.

to interfer with the abrption of'Taget!. . ihdb
(2) Maintenance therapy for duodenal ulcer patlnti.i Øi tl
reduce dosaga after healing of active ulcer.Paooti blng have ben mantained on continued tretmeitwitb fÁ as
'Tegmel' 400 mg. h... for period of up to five ya i! a

tivity over an eight-hour period in duodenal ulcer pe.
tients but alSl reduce H + activity by 85% for en eddi. tionsl five hours into the following morning. .'Tagamet' 400 mg. b.i.d. end 80 mg. q.id, decrea nocturnal acid
seretion in a dorelate menner, i.e., 47%-83% over a

Duodonal Ull;r Haallng Rates with Various 'Tagamet Dosage Regimens'
300 mg.

(3) Short.term trestmeni of active benign gearic u!c. hdirl,
There is no information concerning usul cl I'Ol

six- to eigt-hour period and 54% over e nine-hour period,
experimental meal, oral 'Tagamet' 300 mg. inhibite gas.

respetively. Foo Stimulate During the first hour aftr a stndard
tric acid seretion in duodenal ulcer patients by at least 50%. During the subsequent two hours 'Tageiet' inhibite gastric acid seretion by at least 75%.
The effed of a 300 mg, breakfast dos of 'Tp.gmet contino

400 mg.

. Regimen
week 4 week 6 week 8

q.i,d,

b.i.d.

SOD mg. . h.s.

1600 mg.

h.$.

68% 80%

73% 80% 92%

80% 89% 94%

86%

toytis, multiple endocne adenomas). CONTICATIONS us of 'l .. VEB There are no known contraindications Ui the
met' (brad of cimetidine). However, the physicieSl
nursng, or peiatric patients. ......

(4) The trat""nt of pathotoglcel hypersecreto ço Elpa tions(i.e., Zollnger-Elln Syndrome,systinii Íl'i,

tretment period of longer then 8 weelu !1lrn

ued for.at leat four hours and ther wa partial suppre
sion of the ri in gastric acid seretion following the

. Averaes from controlled c1inicel trial.
study demonstrate tht all once-eily at betime lh.s.)
'Tagamet' regiens were superior

refer to the Prutions seon i-arding us in pre~

luncheon meal in duodenal ulce patients. Th suppres sion of gastric acid output was enhace and could be
inntaned by another 300 mg. dos of 'Tagemet' ghen

A U.S., double-blind, placelxntrolled, dosragig
to placebo in ulcer hee. ing and tlut 'Tagamet' 80 mg, h.s hcaed 75% ofpatiente

PREAUTONS
'Tagamel' (brad of cimetidlne) has demonsrate'fli
anti androenic effec In animal stdies this was nies as reduce prote 'and seminal vesicle weights. ir~, there was no impairment of mating performance or.f~, . nor any harm w the fetus in thes anim at dos'9'¡n 50

with lunch. . In another study, 'Tagamel' 300 mg. given with the meal

increased gac pH as compared with place.
Mean Gastric pH

at four weeke. The heeing rate witli 80 mg, h.s was si_ nificatly superior to 400 mg. h.s. (66%) and not sigif.
catly diferent from 160 mg. h.s. (81 %).

ties the full therapeutic dos of 'Tagamet', as í:m¡m

1 2 3 4
ology.

hour hours hourn hours

3,5 2.6 3.1 1.6
3.8 1.9 6.1 2.2

'Tagame!' Placebo

In the U.S. dosraging tral, over 80% of patients reiv. ing 'Tagamet' 80 mg. h.s experience norna pan
relief aftr one day, Relief from dayte pa was report in approximately 70% of patients afr two days As with
ulcer healing, the 80 mg. h.s, dos superior was

with controls. The ca of gyecmaatia se in"!itiails trete for one month or longer may be rellte to tlèleC
In human etudies, 'Tagemel' has ben shown to luNgPeI.

URour Mean H + Activity: 'Tagamet' 80 mg. h.s., 400
mg. b.i.d. and 300 mg. q.i,d. all provide a similar, moderate Oes than 60%) level or 24hour acid suppreion. However, the 80 mg. h.s. regmen exert its entire effect on nocturnal acid, and doe not affec daytme gasric phys. Chmiclly Stimulate Or 'Tagamet' (brand of cimeti.

Whle short-enn tretment with 'Temat' (brand of
cimetidine) ca reult in complete heeling ofduodenal the

h.s. end not different from 160 mg. h:s In foreig, double-blind studies with 'Tegamet' 80 mg. h.s., 7S-% of patients were heeled at four wee.

to 40 mg.

or in vitr fertlizng capacity. ,'4'-' .
of 150, 378

fee on spenrtonesis, spenn count, motilty, m~log
In a 24month toxicity study conducte in rats, at dci.~-e and 950 mg./kg./day (approi:ately9 to5!wnts

the remmended human dos), there was a sma 'Í\~ in the incidence of benig Leydi cell tumors in .

ulcer, acute therapy will not prevent ulcer reurrncè

.gups were compaed, lh increas reached s

grup; when the combined drg-trete grups

dine) significatly inhibite gastric acid seretion stimulate by betale (an isomer "f histamine), pentaastrin,

afr 'Tagamel' has ben disontinued, Some follow.up studies have report that the rate of recurrnce once

diffarence between the rata reeivig 150 mg.!~1\f~
the untreate controle However, a sttisicaly ~::

nicace. In a subsuent 24month study, theier: - _. 1l

therapy was discontinued was slightly hier for patientS

caeine and insulin as follows

healed on 'Tagenet' than for patients heeed on other
form of therapy; however, the 'Tagamet'.treate generlly lud more severe disas. % Inhibition 85% at 21/2

increa in benig Leydi cell tumor incidence wll~.in

Stimulant

patients

the rats that reived 378 and 950 mg./kg.lday. '!~'~
mora were common in control grups as 'well es~. groups and the difference bee apperentonl . Rare instace of cadiac arrhythmiaS and h
ben report following the rapid edministi ..

Betale
Caffeine

Stlmutant

Dose 1.5mg/kg
(50)

'Tagamel
300mg

Penta. gestrin
Insulin

6mcg/kgl

5mg/kgl hr(lv) 0.03 unitsl
kg/hr (Iv)

!i(lv)

l00g/hr
80mg
l00mg/hr
(iv)
(po)

(po)
(iv)

100 at 1
hour 82% at 1 hour

hours 60% et 1 hour

Maintenance Therpy In Duodenal Ulcer. Treatment with a reduce dos of'Tageiet' has ben proven effecive
as maintenance therapy rollowig healing of active duode-

nal ulcera.
In numerous placelxntrlled studies conduct world.

met' HCI (brand of cimetidine hydrohloride) In) : . ~

wida, the perent of patients with obsrved ulcer at the end of one yeats therapy with 'Tegmsl' 400 mg. h.s was

intravenous. Symptomaiic respons to 'Tageiet.' therapy doe.~W';Pro

bolus. ..t:?.~:

ciude the prence of a gastric maligancy. There ~~

signifcatly lower (10%-4%) then in petients reciving
placebo (440/.-70%). Thus, from 55% to 9(% of patients
were maintaned free or observed U10lrs at the end of one

subsuently documente maligancy. . ::'10 f" ~
Revernibie confusional stte (se Advers RectO~~~. ben obsrved on ocon; preominantly, but n. .". óie
iively, in severely. patients Advancig age (50.O~ to il

rare report of tranient healing of gasric ulce~k!rl

When foo and beta1e were us w stimulate Slretion, inhibition or hydroen ion concentratin usually ranged
from 45-75% and the inhibition of volume ranged from

yea with 'Tagamet 400 mg. h.s .

21 Pepsin; Oral 'Tagamat 300 mg. reuced total pepsin
juice.

30-%.

. Facto", such as smoking, duration and severity of dis, gender, and genetic traita may contribute to varitions in
actual percntsges.

yearn) end prexiing liver and/o~ renal diseas ~~~cQii
be contrbuti factn; In some patients thes co,,i¡.

output as a reult of the dec in volume of garic
3) Intrinsic Factor. lntrinsic factr setion was studied
with betale as a stimulant. Oral 'Tagamet' 300 mg, in.

Trial of other anti.ulcer therapy, whether placelxntrlled, poitive-ntrolled or open, have demonstrate a
range' of reults similar to that sen with. 'Tagamet'. Activa Sentgn Gasulc Ulcer

stte have ben mild and hava not reui .

or 'Tagamet' therapy, In ca wher disn judged n~ry, the condition usually clea days or dru withdrwal.

hibite the ri in intrinsic factor concentration produced by betale, but Slme intrinsic factor was serete ot all
times. Other
Lower Esophageal Sphincter Pressure and Gastric Empty. Ing

'Tagamet' ha ben shown Ui be effecve in the short-trm
trtment or active benign gastrc ulcer,

on cert micromal enzye systems, ha be
reuce the hepetic metebolim of warfar-typ. lants phenytin, propranolol, chlordazpoxide,.

Druglnteractlons: 'Tagamet', apParently thr

In a multicenter, double-blind U.S. study, patiente with

endosopicaly confirmed benign gastric ulcer were

treate v.ith 'Tsgenel' 80 mg. four times a day or wi.th placebo for si weeks. Patients were limite to thos with

lidocine, theophylline and metronidazle, thereb elimination end incrasing bloo levela of theo
Clinicaly sigificant effec have ben rePO. warfarin anticolants; therefore; clos monito f thrombin tie is reommended, and adjustment 0

'Tagamet has no effect on lower esphageal sphincter

ulcers raging from 0.5-2.5 em. in siz Endospicaly
confinned heeing at six weeke was sen in significatly'

(LES) presure or the rate of gatric emptyig.

more 'Tageiet-treate patients thi in patients reciv.

coalat dos may be nec when 'Tagamet is.

Case 1:04-cv-00171-GMS

Document 141

Filed 08/04/2006

Page 14 of 14