Supplementation with Folic Acid during Methotrexate
`Therapy for Rheumatoid Arthritis
`
`A Double-Blind, Placebo-controlled Trial
`
`Sarah 1.. Morgan, MD, RDg J~ph E- Baggolt, PhD: William H. Vaughn, BS: Janet S. Austin, MA:
`Tonya A. Ve[tch, BS; Jeannette Y. Leer PhD; William J. Koopman, MD:
`Carlos L. Krumdi~k, MD, PhD; and Graciela S- AlarcA, n, MD, MPH
`
`¯ Objective: To determine the effect of two different
`we~kly do~es of folic acid on the toxicity and effic~etcy of
`low-dose methotrexate therapy for rheumatoid arthrit~.
`¯ Design: Rancromized, double-blind, placebo-
`controlled study.
`¯ Patients: 78 persons between 19 ~ 78 years of
`age who fulfilled lt~ Ame~’¢aurt Rheumatie~rn Assoeiat-
`tion’s c~eria for rheumatoid arth~is.
`¯ Intervention: Parficlpant~ were t’andomly assigrw~d
`to visually identieaJ placebo or ~o 5 mg or 27.5 rng of
`folio acid each week.
`¯ ~[s: Duration, intensity, and ~tr~.~d se-
`verity of ~oxic events; all~Atey findices ot Dint tender=
`nezs and swelling ~ grip strength); plasma and eryth-
`roeTte f~lete levels; and other iabor~to~ variable~.
`¯ Resulted- Folio acid supplementation at either dose
`did not alfect the elEcacy of mothotrexate theml~r as
`judged by joint indices and patient and physician as-
`easements of disease. Patients given re!it cola supple-
`rnents had I~wer toxicity scores than t~id p~cUciparas
`given placebo (P -< 0.0(D). Low blood relate levels and
`increased mean corp~soulm" volumes were a~i~tt~d
`w~ substantial methotrexate toxicity, where~s daily
`dietary intakes el more than 900 nmol D00 big) of relic
`acid were associated with little rnetholrexate toxi~.~ty.
`¯ Conc3usions; Folio acid, an inexpe~siw vitamin, i~
`safe in a I:woad range of doses and protects patients
`wi~ rtteumatoid arthritis who atr~ ta~r~g melhotrexate
`from toxicity while preserving the efficacy of methotrex-
`
`The folio acid antagonist methotre~te (N.10.methyl.ami-
`nopterin) is useful in Low do~s (2.5 to ~ m~k) for
`t~afi~ chronic inflammato~ di~ 0-7). Many t~ials
`have ~stab]ish~ th¢ ~ of melho~ate in rheuma-
`~old affhfitis (7=~3). ~m~cd with olher
`~ing d~, methottexate h~ the highest pmbabili~
`~rug ~n~inuat~n at 10 ~, ~se ~rela~ed
`t~c eff~s have ~en re~ in ~% m ~ of
`tients ~ven methot~e (13). To~¢ effe~ ine[u~
`t~inl~linzl ia~olemn~, hematolo~(cid:128) abno~alities, ale-
`xia. hepatotoxi~Ly, and puLmona~ tofici~
`Some ~ effec~ of mcthotre~te administrztion, such
`~ gastrointestinal imolemn~, mim~ complicated
`deficien~ (23), Folat¢ deficien~ ~u~ flequently in
`fients with rheumatoid aahfitis; [urther, refute stores are
`decreed in ~tien~s with rheumatoid a~hfitis who ~ake
`methot~xatc, su~est~g that impaired ~]ate status
`~laled to ~ici~ (24-26).
`Folio acid su~l~mentation has ~en ~n~ anodes-
`ally to ]~n to~ci~ in patients ~i~ng me~hotr~te
`~reatment (27, ~), [n a 6-month, double,blind, place~
`~nt~ll~ tfiu]. 7 mg of ~[ic aci0 ~kly (1 m~d or 2265
`nmoffd) decreed methotr~ate mfici~ ~thou~ aff~ting
`e~ (~), ~is was ~afirmea by S~aa and col-
`I¢~ (~) in a retroactive chaO Jeview.
`Folin~ aci0 0e~n, eitr~m [~or) is a one-
`ca~n~ubslituted, fully ~du~d refute that h~ al~ been
`aamiaistered cluing mcthot~xat¢ thera~ (31-36),
`doses of the vitamin (1 to 7 m~k) ha~ ~a~d
`methotr~tc t~city (35, 36). H~her ~s ne~te e~-
`ca~ and Le~n t~ (31, 32), ~us. the fol~nic acid
`do~ may ~t[~[ly affect the e~¢a~ of methoue~te ther-
`
`~e iafiuence of the ~]ie acid d~ on
`tofiei~ ~d (cid:128)~ ~mains cont~v¢~i~, and the
`of different ~ of fol~ ~id a~ ~! ~ (37, ~).
`Some i~tiga~o~ argue ~hat if t~c eff~s ~r, the
`most rational app~ch is to ~edu~ the do~ of metho-
`tre~te rather than to pr~de folio acid supplements (37).
`Wc desired a la~er ~d longer stu@ ~ ~aluate differ-
`ent doses of folio a~d, ~ming that t~¢i~ ~uld
`~edu~d without changng the c[~ of met~tre~t¢.
`
`Ann Intern Mcd. 1~;121:833-841.
`
`Sandoz Inc.
`Exhibit 1010-0001
`
`Teva – Fresenius
`Exhibit 1010-00001
`
`

`
`daily llvin$ asscs~(cid:128)~l and a~;r.~Fd at b~.~Jin¢ and at
`using !~ ~Lhed HeaLl]~ A~mem Ou~[lonnai~’
`
`~ [all~,up visit a~ ~ 3 w~e&~ ~ ~e[ephoa~ intc~w
`(aoae ~ SLM).
`
`Laboratory A &r,~-£~’n ¢ n is
`
`At IL’~ initial viii!, torrid.late blc~cl ~li ~llln!, W~i¢~rcn
`~h~t¢ ~dim~nta~i~n rate, ~r (cid:128)n~(cid:128) (a~rtate amino
`
`~ph¢lom~, and ~ru~ creatininc ~’alucs ~’r= {~b~ain~, ~#
`
`morc fr~q~ni[y than s~i~l~lcd [n rh= ?~tK~, ~he~ were
`
`Ol~ fer plasma and e~ihr~’l= [olalq l~’¢~, m~in~ u melh.
`
`drawn a! ell ~i~li~ (4Jj. At ba~lJn¢. #lt~ wa~ a~a for
`~t~mLn pane[ [pl~a ~nd ~h~l~ ff~la[~, ~ita~in~ Bi:> ~
`and ~. (cid:128)~rolcn¢. fi~a~’m, ihlam]~, pyridoxmcl 1~-~!). If
`tients had ~bnn~al ~!~ for a~y of i~ vitamins, (cid:128)~h~r than
`fulfil, t~e abno~ality wa~ lrca~a ~i[h ~in~e v[lsmin
`
`Figure I sho~ the trial de-sign. To maintain the double.b-]]~d
`
`~,~(cid:128) and a ~d vj~[ number rcpr~nlcd the t~tmcnt ~ign.
`
`Ra6iog~phic Asscssment
`
`trcalmc~t a~ignmcnt pr~ d~igncd to ~lan~ the
`
`t~i~i.~ vl!~min ~, ~hcum~oJd factor s~t~. and pr~n~n~
`
`Hand and wrist r-~’,dinBraphs taken within ~~ monlh~ {~f cn~:rin~
`!~ iT~al ~re a~’~d ~ one ~f qh~ rh~matologJs~s (GSA)
`~tchout knowled~ =ff study xlaluS. Joinl ¢rosio~ ~ sp~.
`n~r~ing ~ delermJn~ ~" lh¢ mndilld m~th~ o[ Sharp
`
`Frequency and Severity
`
`To~Jc (cid:128)ff(cid:128)¢!~ and dk~.-oniinuation of therapy, with slut.{}" medi-
`cation~ du~ tO ~exicity ~ ~nsidcr~d p~ma~ outcome, We
`de[~rmine~ a t~[¢ity ~o~’, mt~difiCd from Ihe off(cid:128) prcvit~
`u~. lot (cid:128)~ ~!~nt a~ each visit or ~nlil m~!~!~xa[L" Ih~t~
`
`Effica~
`
`We determined p~licn! rcs~.mxe IO treatment ~sing
`cation of the criteria u.~e~ in o~r p[¢vio~ folic ~,~1 ~uppl~men.
`tado~ trial an~ by olhcr~ (~. 29, -~31. We d~ned marked irn-
`pr~w~ment Jn Ih~: .moire=
`and pa[~ [n~x as a net decr~,a~(cid:128) of 5IIe~4 ur mo~ in value at any
`
`cc~ ~ ~ ~g ~ folic ~id g~oup> or 27.~ mg foI[(cid:128) acid
`
`in Ihc I~ an~ high~ ~1~ ~i6 grou~ ~s~cl[~ly.
`
`of 16.5 pmul {7.5 ~) ~r week a~ [~e~d in 5,5-~ol
`~) inc~menls a= t~ r~em=tologi~l’~ d~r~t~n,
`
`12 hou~ for thr~ ~s), ~e methot~te ~ing regime~
`
`were g[v¢~ 5 ~ ~i ~k when m~thotr~!¢ ~ ~L
`Compliance ~th Ih¢ ~(cid:128)~ was ~in~[ea ~s~ a ~[~tai f¢-
`
`pa~icip~nts and im’¢sti@(ors ~re bLL@d to viiamin ~psule
`
`~inica! Assessment
`
`ti=ti=m a! ~ mc~n of t3, ~, 39. and
`
`Twu r~a~h ~ista~[~ (J~ or WHV) did t~ j~nt evaluati~s.
`
`(P = 9.fi [or tcn~e~; P = ~,9 for s~]l~g).
`
`~ Bl~d C/
`
`3) ~inl ~elE[ng and ~e~e~ in6~s, e~d as a sum. ~th
`
`~le)> or 3 {~re)~ 4) mean ~? st~gth
`for bo!5 han~ ~r¢~d ia mm H$’. 51 duration ~ marnL~
`
`m¢~i~lio~ and d~s’, 8) = I~aT di=au r~ll =ing the Min-
`
`Fiiu~ l, Sludy design for th~ ~ul~-I~nd. i~ceho~untmlied’
`
`~qu~nt~! t~tment ~gn~t p~¢m in whi=h the
`~ t~nspa~ni ~nd a ~ed vial n~m~r ~s u~d as u~ t~at-
`
`834 i l~ml:ter if~4 ¯ Annet.~ o.f" [~zwaf M~l=’~ne ¯ V~]umel2l * Numbcr]!
`
`Sandoz Inc.
`Exhibit 1010-0002
`
`Teva – Fresenius
`Exhibit 1010-00002
`
`

`
`Coml~rri_s~wt o[ ToMcit~ Scores
`
`’Wc u~d Ihe Fi-~her ex~-ct !¢~t to
`=~ic effeels in Ihe lo]Jc acid and pla~ groups-
`
`data UnL[L the ~dy w~ comp]em or the panJd~nl withd~, To
`evaL~te the e~ec~ of time, t~a!~nl ~vp, and theh in~-
`
`~ of I~e t~x~i~ ~ores. W~ did ~’o.~y ~na~
`{or ~ Ihe ~an~ for ~la ~b~l were ~n-~g~ ~L~l~B~led) t~
`
`_~mlts
`
`Patients
`
`We enrolled 94 patients (age range, t9 to 78 years) into
`the trial, Sulr, cquently, wc withdrew 15 ~lienls
`of noncompliance (numbe~ ~ equally distributed
`among the ~tuay ~u~), Out results are f~m 7g
`who ~mpteled the trial: ~S in the l~-d~ logic
`group, 26 in the high-d~ folic acid ~oup, and ~
`place~ group, ~c dcm~aphic and ~lecled
`feature~ ~f Ihe patients in the thr~ study groups
`fimilar ~Tab]¢ I). No ~lients were raking ~ulfasal~ine
`heroin enrollment, Wc Found no stalistica]
`among Ibe ~ou~ in previous u~¢ of goJd ~ft~ (P ~ 0.92).
`Four patients in the pla~ g~up (~%), 4 tn the [~-
`d~e folio acid ~oup (14.3%), a~d 6 in the high~ose
`~d ~oup (23%) p~viously had t~cra~ ~th melhot~x-
`ale di~omin~ea beca~ of tox~ effect~ (P = &76).
`fients who pr~iousty d~onliaued metho!~t¢ thera~
`beca~ of tox[c ¢ffe~s were randomly dlsttlbul~d in the
`lhm¢ grou~. Other inilial ~ariahlcs such as hemoglobin
`I~!, hemat~t, Icuk~te ~unt. mean corpu~u~ar
`~, ¢te~ti~iDg ]~¢1, aspa~atc aminolransfcra~ v~uc,
`
`Compm~gn of Data mrto~rg Gtr.mp.~
`
`We ICstcd the ba~line values of all ~ulta~m¢
`normzGq~ ,,xiag lh¢ Shcpin-Wilk statistic. For ~o~trmll), di~trib-
`ul~d dala, ~e u~d tilt-square: analyx¢~ ttr t~mj~r¢ proportions
`
`Table l÷ I~nmgr~phic and Seleoted Clinica! ~.’hp~eri~llcs o[’ 79 PMlents wkh Rheumatoid Arthritis’
`
`(’haracteristies
`
`Me-an ag~.),
`S~. % rm~-n~n
`
`Placebo
`
`Low.D~a.~ ~o[[~ P~iO H~-~ Folio Acid
`
`52.2 z L3,0
`82
`
`54,4 - 1431
`
`53.2 _~ 14,3
`
`Mean d~a~ durat~n,},
`
`8~ = 8,2
`
`7A
`
`I~ rheumat~d faczoc ~ilivity (>.~ ILJ~L or L: I~ !iteO. %
`C~a~ ~ of aspirin or no~ste~idal ami-inflammat{~
`d~ %
`C~cu~¢m prcdni~ use, 7~
`C~cu~nl h~hlor~uinc u~’. ff
`Patients ~iously ~ivin~ ~ld ~lis..
`Patients p~i~u~l~ ~’in~ mclhot~te, n
`P~io~s d~a~-m~J~ing an=irheumafi¢ drag v~. %
`Mean joint ¢~n ~re
`Mean joint ~p~ ~in~
`
`71
`
`~
`~
`I
`16
`4
`~
`9.2 = 9.5
`20,2 s 20,1
`
`17
`
`t5 = 16.7
`
`i I,8 = 9,5
`
`85
`
`4
`17
`4
`77
`17.7,+. 17,8
`36.3 _+ 3L1
`
`] 1_3o:¢mlrer Ir~4 , Am:ot~ o! lne~rnaf Medf;im" ¯ Volume t21 ¯ hruml~r I 1 ~
`
`Sandoz Inc.
`Exhibit 1010-0003
`
`Teva – Fresenius
`Exhibit 1010-00003
`
`

`
`10
`
`g
`
`I
`
`alkaline phosphatas~ level and ~ryihr~-~2~ sedimentation
`
`joint spa~ narrowing ~ores ~ere similar at baseline
`
`Melhotrexate Do~; Folate and t~z~ Intake
`
`mczhotmxat¢ do~ among the three ~ou~ ~(cid:128) mean
`
`ce~, i~-do~ folio adR, znd high~ [olic acid ~ou~
`w~re 2~ rag, 217~ 113 m~ ~d ~
`
`do~ was 8.~ ~ ].~ rag, 9A ~ 2.4 mg, ~d 9.6
`the ~la~, ]~-d~ [oli¢ acid, and h~gh~ folic acid
`
`~e mean ~cla~ [ola~e and ~min B,~ intak~ ~o~
`the [~ps ~re never stalist~l~ di~emm. M~ian
`~ta~ foible inl~kes were ~ p~d in the pl~
`19S ~d in the ~-~ f~]ic ~¢[d gkoup, and
`~he high-d~ fo!~ a~d ~oup {P = 0.37 for all ~mp~r-
`~m], The m~ian daily Jntake~ in aft study ~ did
`not su~tantially differ [~ thu ~e~ian values of
`~0 ~d ~tted ~n the ~(cid:128)ond Nation~ Heath and
`Nu~tion ~inaficn ~fies
`
`Primary Outcome: Toxic Effects
`
`Fifty-four p~tieats (68%) experienced some form of
`(oxieiw: 25 (~9%) ~n the p[a~ ~p, 12 (48%) ~
`
`~bo), and 17 (~%) in the hi~ [o1~ ~d ~oop,
`
`gmu~ (0,685, 0.0~6. und 0.~1 in the pla~, ]~.d~
`folio acid, a~ h[gh~ folio ~id Uou~,
`~e [~icity ~ for the pla~ ~oup ~ grcatez ~
`lh~ fo~ lhe ~ folio aci~i~menled ~u~ (P
`0.~1 for ~th ~mpafi~ fo~ 1~ fo[~ acid
`hi~.~ folio aci~ ~mpa~ with pl~; P ~ 0.71
`!~o~ folio ~id ~m~d with h~h~ ~]ic add).
`~c m~t fr~uent~ re~ed z~citi~ ~m aau~a and
`in~igesz]on (31 patterns), diarrhea (11 palien~), stomatifis
`pad~nls), and zash (9 patients), ~hen the palien~
`r~ei~ h~z~hlot~o~ne were omitted ~m ~(cid:128) anal.
`~es, the r~ui~ ~ idcnb~l,
`
`lag and P = 0,17 [o~ erosions: Table I),
`
`As noted in Table :2, the p~rccnzag~s o[ p~liots who
`
`Table 2,Jolnt S~tllng and Ten~l~ss ~t 6 and 12 M~nths Je the ~hre~ Treatment GrOUl~
`
`Oul~e
`
`,’~
`29
`
`29
`
`33
`55
`
`fl
`$
`
`61
`39
`
`26
`
`9
`3O
`
`4
`4
`
`68
`53
`
`t6
`
`II
`21
`
`5
`~0
`
`7~
`~3
`
`13
`
`$
`35
`
`4
`9
`
`78
`61
`
`$
`
`I7
`17
`
`0
`6
`
`’ P .--. O.S (¢hi.~,q~!~} I~r ~,mpad~om smo~ ~’oul~ at 6 r~m~ end 12 nmmth~.
`
`:g36
`
`I Det-ember 1~4 ¯ Annab of Interaa¢ Medicin~ ¯ Volume 121 * Number
`
`Sandoz Inc.
`Exhibit 1010-0004
`
`Teva – Fresenius
`Exhibit 1010-00004
`
`

`
`J,~nt i~li~:~, ~r lenOc~ess?
`
`J~z i~s for ~lling~
`
`~fi~nn ~meat of di~
`~
`
`~i~n ~cn~ o~ d~
`
`Grip ~n~h in ~t ~nd.
`
`Orip sl~n~th in ~ ha~d,
`mm H~
`
`~.7
`
`5~.7
`
`~7
`
`34
`(~ ~)
`45
`~6. ~)
`
`21
`{0, hi)
`~
`(3, 5I)
`
`18
`(4,62)
`12
`(O, 51)
`
`32
`(& 112}
`51
`(t4. ~)
`
`3
`
`2
`
`2
`
`2.O
`~, 99)
`28
`(2. ~
`
`2
`
`26 14
`3,t
`2.1
`(0, 66) (2, 41)
`(2, ~05)
`~o; ~)
`20
`43
`14
`(~ ~) 08. to~) (~, 62)
`
`(~, 58)
`
`2
`
`3
`
`2
`
`2
`
`3
`~2, 4)
`
`2
`C£ 3)
`
`~-
`4
`(2, 5) (2, 5)
`
`2
`(2, 4)
`
`482
`127) (1&3, 133) {5. 132) (5, IS0} (8-g 118)
`
`34.2
`(5, 115}
`
`483
`(10, 152)
`
`4~.3
`30
`3Z5
`(I.g 183) (6.7, 190) ($0, 157)
`
`Q~t~nn~ir¢
`
`1.8
`O. 3,4}
`
`!.~
`U, 2,8)
`
`2
`O, 3.8)
`
`t_2
`(1, ~,8)
`
`2
`[i,i, 3.4)
`
`1.2
`($,
`
`volume of lO0 FL or more at one or more follow-up visits
`compared with onbi one and none in the low-dose o:
`high-r2o~(cid:128) folio acid gmu~ r~ctiv¢fy (P ~ 0-~).
`Mean ~[ine pl~a [o~te levels we~ 15, 10, and
`13.5 nmo~L (P > 0,1), and me~ b~eline e~hr~le
`relate ~els ~re ~2, 591, ann 624 amol (P> 0.1) in the
`pianO, I~-d~ ~!~ a~ and high~ foli¢ acid
`g~u~, ~s~y. ~ter I year. mean pi~m folate
`revels in the pla~ ~up d~d to 4~ amo~mL
`(P< ~,01) and m~n plasma Eolat¢ levels i~a~d f~
`to ~(cid:128) tim~ from b~lin¢ valu~ in the folio acid ~ou~
`(P< ~.~1). In onl~t, mean e~hr~e folate levels in
`~ I~dosc and hi~-d~ folio acid grou~ ~ litl~e
`eha~ged (~ 5%) from b~line ~u~ ~tet I year.
`whereas l~ls in the pla~ g~u9 ~e~ea ~ a~p~x.
`imat~ 50% (M9 nmo~mL; P < 0.~1 for ~li~ values
`~mpatea with ~lues at 1 year). Twelve (43%), 5 (20%),
`and 4 (15%) ~ticnts in the pla~, ~ folio acid,
`
`II1:
`
`el
`
`had marked improvemem, moderate improvement, no
`procemenl, or worsening were simitar among the
`gmu~ (P> 0.5). We o~ed marked ~mp~ement in
`~he ~[n and !(cid:128)~m¢~ index after 12 month~ in 53%,
`43%, and 61% of ~tien~ r~iag place~, 1~ do~
`~]ie acid, a~d hi~ doses of folio acid, res~i~ly.
`louad marked impr~ement in the ~lli~ ind~ in ~%,
`78%, and 78% of patien~ r~ing place~, t~ ~ of
`Iolie acid, and high d~s of folio acid,
`
`Patient ~thdrawal and Dropout
`
`Wc withdrew 13 patients I~e, cause of noneocnpliance.
`One patient was withclrawn for taking additional relate
`supplements and one ~use dia~is w~
`~ven ~tients in the place~ group, 2 in the
`folio aci~ group, and 2 in the high.dose fofic acid group
`di~nt~aued mc~hotr~te treatment ~ca~ of t~ ef-
`~cts. Mo~ d~uts ~ur~d ga the pla~
`(~%) than in the relic acid g~u~ (8%) (P ~
`
`Other lndic~
`
`As noted, in Table 3, patient and physician assessment,
`joint indk:es for swelling and tendernes,_’~ and grip
`strength improvec~ with time. We found xi~ifi~nt time
`(cid:128)ff~s with respe~ to join! tcndetn~ indi~ (P=
`0.025), joint ~¢Lling indi~ (P = 0,0~), physician ~.
`meat og di~ (P = 0.011), ~ient a~mem ofd~
`(P = 0.~), ri~t-ha~ ~ip strength {P = 0.032). and
`lea-hand ~ip strength (P = 0,~7). We o~wed no sg.
`n~at time-t~lment inter~tions.
`At the foli~-up ~isits, changes in the median or mean
`values for the fo]l~ing variables ~r¢ not stads~lly
`diff¢~nt among ~he g~u~: m~ified Heailh ~¢nt
`~e~nnai~, e~lhr~l¢ ~imentaUon rate, hem~l~
`bin level hema~t, 2cuk~te ~unt, mean ~u~u~ar
`volome, ~eatinine ~ncentration, and astraL(cid:128) ami~
`tmnsEera~ or alkaline phosp~la~ Icveg. H~er, s~ ~
`the ~lients in the pl~ group had a mean ~rpa~at~r
`
`l Decem~n,er 1994
`
`¯ Amrag~oylntc~ttalMe~licLqe . Volumcl21 ¯ Numberll g~7
`
`Sandoz Inc.
`Exhibit 1010-0005
`
`Teva – Fresenius
`Exhibit 1010-00005
`
`

`
`m[ncO in ~$i~t~ in whom mc~holrcxalu will ~
`
`c~(cid:128)~. ~md ~ticm~ may have d~mo~hic anemia (i~ plus
`H~z ~r folaw ~.ficicncy). yielding u norm mean CO~S-
`culaT volu~¢, w¢ I!lJllk vitamin levels a~c u~[uL
`no ~’ontraindication to starting folio acid at a d~e of ~ to
`7 m~iwk dud~ me~hotre~te the~a~ initiation. Supple-
`mcntation whh higher do~ may ~ indicated
`cr¢~s~ng mean corpuscular volume [~ o~ed
`
`;cvc~ ~lh of lhe-~ clinical findings. Serial cvalaat[on o[
`the m~an corpuseuLaT ~lume ha~ ~¢n ~u~t~ as an
`incxpc~siy¢ means !o monito~ mciplent toxici~
`~ow~vcr, olh~r i~v~s!;gat~r~ have found that Ihu
`~rpu~ular volume d~s no1 ~redi~t to~¢[~ in
`given G~Lic acid {30). Our data ~u~t Ihal a hi~ mean
`~rpu~ulur volume a~d a t~ b]~od [olui~ ]~! a~ often
`a~iatcd w jib methotrc~l~ toxicity.
`The m~=’hanlsm or mechanisms ~ which [o]~tc
`~uces the c[inicat (cid:128)ff¢cls on !~i¢ity am not clear. Folinic
`acid. ~=h~rmyi.=~ffahydro[o]ic acid. a[~ has been
`
`~c[d and folimc acid t~wuct a Slate of folale defic[e~, or
`~’rha~ fofinic acid. by ckcumvcnting dihyd~fola[e re-
`dudasc inhibition, ccJievcS zoxicity, However, ehc~
`mechanisms are not mulually cxcius[~.
`The v~umin ~’orm and ;arid of folat~ to
`a;e important [~c=~r~ in d¢!¢Tmining whelh~r effica%’ ~ll
`be to~ with combination vhumin and antMlam~n
`~cca~c 1dilate ~¢id i~ a fully reducL’d ~nd onc-cat~n-
`~ubslitutcd [o[at~. ~[ ~-an ~pa~ fola=~-metabolizing
`IIl~l reduce Ihc pl¢;idmc moiety and ;=dd a one-carOm
`fragmcm- Table 4 sh~s the ratios of rotate !o metho-
`Ir~’xal~ a~ cfinical o~l~a~mes in previous sludics.
`
`mutholrexal¢ thc’raW fi~r rheumatoid arihrJlis (3!), Our
`prcviou~ trkLI u~d a folio acid-to-mcthot~c~l¢ ~dl[O Of
`
`efficacy 12~}. Similar results a~c now rc~dcd with a ratio
`as high as 2,85 to !, The participants who ~c~ivcd 27=5
`
`~’ll]~acy wa~ negalcd. A study ~ Duhfa (61} using 35 mg
`o[ h~l~¢ acid ~r week dudng mclhut~=~lc lh~m~ for
`
`margin of mfcly for fol~(cid:128) acid. Although fotinic ~id can
`Ic~=ll ~t¢l]t~d~xate u~icity, the do~= level is atom cfilical
`than IhtL! fi~r ~ulic acid,
`
`~latiun to m~lhotr~xate is m~t khan. The half-life
`(lvaJ= ~ntmmu~cular, and inlF~v~nous I~.dosc mcthotmx-
`
`l~m~o~ of lh¢ folatc to mc~hv~r~xalc ~n p~viously pub-
`[i~hed r¢~r[~. Ia file ~ludie~ ~ Joyc~" and a~[a!¢s (31).
`li~hlcr a~d coworkc~ (32), and Bucklcy a~d colleagues
`(34L Eflinic ;~id was given within the fi~t half-life of the
`m~’lhol~xat¢ ~, lh~ nttk~ of folat¢ to
`used ~ these three invcstiga[o~ was 2.3, 0.95, and 0.5.
`respectively, with the I~cst ratio causing no flare
`
`Discussion
`
`This controlled trial shov,.’s that folio acid supplem¢|th=-
`tion of 11 327 nmo] {5 rag) or r,2 302 ~mo! (27.~ m~
`
`ici~. ThLs finding s~$sts that the int~k~ ~[ one multiple-
`vitamin pill ~onl~imng 9~ nmol o[ foEc ~’id (~
`
`other m~onutriem dcficicn~i~ (SYl.
`We d~sign~d th~ lr[al using ¢ompletc~ anaL~is. Onv
`
`h~ oblalncd co~l¢le data o~ the p~Tticip;mt~ who
`
`~ out sludy with other m¢lhoE~xatc cEimeM trials lhul
`u~d completc~ anai~es and thu~ eh{~e m, tt= analyze
`th~ data ~ intent to treat. The overall resuh~ of ~hu study
`~re not ~catly ~nflucn¢cd by ~h~ ~[udy d~x~n. By u~ing
`
`degree of d~fferenee for e~’. but ~~" ~’ould ha,’~
`~ed the ~mc toxic e~ccl,~ and [tS~][[~
`o[ d~g
`
`~¢ent r~mmcndation~ f~om lhe American ~ollcge
`Rhcumatoto~ for monitoring hepal=c ¢=mdhio~s in ~-
`tients ~th rheumatoid arthrlt[s ~h~ ~r~ ~c~¢-ivia~
`oirexate, but ihis di~ no= chan~ Ihc fox[oily ~ [~).
`We prc~ously sh~ed that t~w ba~elh~c plasma
`e~h~e foJale levels can prcdic~ future ~oxLuhy (fi~},
`B¢c~ la~ doses o[ [olic acid can mask and
`~in B~ dcf~cn~, adequate vitamin B~ s(atus
`~ ~¢d ~[or¢ [diSc ~id suppiementalion (5~)- B~d
`
`~35
`
`1 Dc~cmb~r J9C~4 , Aan~L~ of ~mern~¢ ,’~h~ti~irw ¯ Volumu
`
`[21 ¯ Numberll
`
`Sandoz Inc.
`Exhibit 1010-0006
`
`Teva – Fresenius
`Exhibit 1010-00006
`
`

`
`Table 4. Ratios of Folic Acid te Meth~rexate add Foliate A~id to Methotrex~te and E[~cts en Clini~l E~eaey*
`
`Timing of Fo~ate ~la(i~e to
`M eTbolr~3!¢ ~
`
`2.3 : L
`
`II.~ : L
`
`Hare in di~ea~ acl]vity
`
`Fhtce in dL~zas~ a~]~ity
`
`Oral folinic ~(cid:128)]d 2 ~o~ .~l~r w~kly oraL
`m~th~re~le ~
`
`~oiinic acid ~p~lly ~cr 2 d~. ~pn~8 4
`
`Oral folinic acid 4 ho~. at!or o~1
`
`No chan~ i~ (cid:128)~e’a~(cid:128) ~tient i~
`
`Oral folinic acid ~ hou~ Mtcr oral
`
`O~1 f~linic a~d g~n ~imul(a~mly ~th
`
`L : L
`
`~ c~an~ irL
`
`Not
`Folk: acid
`mcthot[e~atc ~31
`
`+ |:Lille ~:id : [h.U.rL.~’l~L~:;.mir.: ;~; lt~ink" i~kl = 5-F~rmyI-U"Lrall,ydrD-pt,cR~Ft, lulamK a~d.
`+ Onl?." mt~ hidf ~d 11t~- I~di.i¢ ~:~d ~ i~ hmb.~gicalLy aE!~ I~.cau_~ fig tile pl~C-I~:~ fl~
`
`disease aethtity. [n contr~sl, when Ihc two highest ratio.
`
`which sure,Is that the tati~ of [olatc to mcthot~xate,
`not ~he dosing ~ntc~al, was more im~rtant in determin-
`ing whether e$ca~ Js
`The cost of fol~nic acid compared ~th that of fol~
`Ihct~ is a]~ ~lcvani (36J. A~ our eenteL ~he pr~ of
`
`~im[la~ ta COSls nationwide, Thus, ~[e~ and ~t
`sunni foEc acid as th~ ~tte~ sublimed!, A
`trial of folic acid and follnl¢ acid would answer ~h~
`
`The p~o~i ~o enrich flour ~ith logic acid to p~ent
`neural ta~ defects has led to co~ a~u~ the ~i-
`btlily of negating ~hc c~ca~’ of me,hotre~te therapy
`aatoimmune di~a~s (60, 67~. Neither our data nor
`~ata o[ othe~ su@rl ~h~ conce~ (61). Enrichment of
`flout ~o p~vidc R~[ic acid intakes of ~ !o 2~ amol
`(4~ ~g ~c I m~d) ~uld not aff~ ufft~T of ]~-~
`metho!~xate ~hc~aW [or rheumatic
`The cn~mc ~ en~es !~t m~s! be ~nh~bite~ 1o
`
`ha~ ~ul~tcd tha~ inhibhion of aminoim~d~ole ~x-
`amid~ fibotide transformylasc is nccc~a~ [or ~hc
`of me~hctre~tc thCrdpy
`Widely yawing dc~ levels of folio acid dec~
`~o~ci~y o[ metho~te~te ~hh~ut affecting i~ c~ca~. The
`flexibili~ in the d~tng ~ngc, ~u~]~ with its !~
`make [~lic acid ~he p~ferred vitamin fornt to t~a~ ~-
`tiaras with rheumatoid a~thri~is who arc ~king mmhotrex-
`ate,
`
`Appendix
`
`Toxicity ~’oz’e = duration af toxic ~renIs [weeks] x
`tonsil) :~ (cEntca.L .~verie.y factor) + w~.~ck~ in the proto-
`n]. where intensity ~s I (mild), 2 (moderal~), or 3
`~re), as gauged by patient tel~3rt; and ~h¢ clinical
`
`severity factor L~ I (alopccia, malaise or ~’at~gue. n~use~,
`pruritus, anorexia, or general g~t~ntcstSnal intulcmn~
`[py~, ~m~, and ~ onj), 2 (~iting, diarrhea, sto-
`
`4 (~o~aias~ ~umented in~ectio~s, or pulmofia~ toy
`
`m~i~ in llve~ fu~ns ~ ~p~ete bioo~ ~!1 c~unL
`d~ment~ in~ection, or pul~na~ L~city
`in~ens~ ~o~ of 3 (~ere), Abn~al I~¢r [uncUu~ t~ts
`~ defined as an aspa~l¢ am~not~ns[cra~ or an al-
`kaline ph~phat~ level greater than ~o ~Jmes ~line;
`~openi~ w~re defined as a [suk~¢ coun~ less than 3,5
`x 10~/L or a plate!et caum le~ ~h~ 150 x 10~/L; and
`s~um c~cat~n[nc ~n~nltalion w~ ~nside~ed ~ated
`mo~e than 133 ~moWL (1.5 m~dL). ~]mona~
`w~ dc~ed as ~ide~ ~f I~ ~nte~itial pul~na~
`~nf!~trat~ [~ b~line ch~t radiograph a~d
`~¢sttictive chan~ in pu[monaW ~nction tests, i~ludi~
`vi~a[ capa~ Ic~ ~hen 80% of p~di~ed
`expirato~ fl~ rates, nodal ~ma] ~]untaff ~nlila-
`fion, ~nd o~ monoxide diflus~on capadty I~ss than
`
`vira!, b~ctefial, or ~n~i [nf~tion that t~mpmm~d
`patient ~cat]y and ~qu~d hospita[i~tion or adminktra-
`~on of ~tem~c anlimic~ob~al agents, or ~h,
`
`C.~.a~’ar A~thot Ad, d~(cid:128)..~ Dr. Modem: 212 Wd~, Del~rtm¢,~ o[ Num.
`!too .[~(cid:128)~, U.A.B. Slamit-~, BL’mingham, AL 35294-3360.
`
`1994 . Annubr ~flnterno~Medgcine ¯ Volum¢121 ¯ Numbcrft 839
`
`Sandoz Inc.
`Exhibit 1010-0007
`
`Teva – Fresenius
`Exhibit 1010-00007
`
`

`
`Sandoz Inc.
`Exhibit 1010-0008
`
`Teva – Fresenius
`Exhibit 1010-00008
`
`

`
`Sandoz Inc.
`Exhibit 1010-0009
`
`Teva – Fresenius
`Exhibit 1010-00009