Prescribing Information

650348

ALOPRIM (allopurinol sodium) for Injection [al'-o-prim] For Intravenous Infusion Onl !"#$RIP%IO&' ALOPRIM (allopurinol sodium) for Inje !ion is !"e #rand name for allopurinol$ a %an!"ine o%idase in"i#i!or& ALOPRIM (allopurinol sodium) for Inje !ion is a s!erile solu!ion for in!ra'enous infusion onl(& I! is a'aila#le in 'ials as !"e s!erile l(op"ili)ed sodium sal! of allopurinol e*ui'alen! !o 500 m+ of allopurinol& ALOPRIM (allopurinol sodium) for Inje !ion on!ains no preser'a!i'es& ,"e "emi al name for allopurinol sodium is -$5.di"(dro.4 H.p(ra)olo/3$4.d0 p(rimidin.4.one monosodium sal!& I! is a 1"i!e amorp"ous mass 1i!" a mole ular 1ei+"! of -58&02 and mole ular formula 3 543545aO& ,"e s!ru !ural formula is6

,"e p7a of allopurinol sodium is 2&3-& $LI&I$AL P(ARMA$OLO)*' Allopurinol a !s on purine a!a#olism 1i!"ou! disrup!in+ !"e #ios(n!"esis of purines& I! redu es !"e produ !ion of uri a id #( in"i#i!in+ !"e #io "emi al rea !ions immedia!el( pre edin+ i!s forma!ion& ,"e de+ree of !"is de rease is dose dependen!& Allopurinol is a s!ru !ural analo+ue of !"e na!ural purine #ase$ "(po%an!"ine& I! is an in"i#i!or of %an!"ine o%idase$ !"e en)(me responsi#le for !"e on'ersion of "(po%an!"ine !o %an!"ine and of %an!"ine !o uri a id$ !"e end produ ! of purine me!a#olism in man& Allopurinol is me!a#oli)ed !o !"e orrespondin+ %an!"ine analo+ue$ o%(purinol (allo%an!"ine)$ 1"i " also is an in"i#i!or of %an!"ine o%idase& Reu!ili)a!ion of #o!" "(po%an!"ine and %an!"ine for nu leo!ide and nu lei a id s(n!"esis is mar8edl( en"an ed 1"en !"eir o%ida!ions are in"i#i!ed #( allopurinol and o%(purinol& ,"is reu!ili)a!ion does no! disrup! normal nu lei a id ana#olism$ "o1e'er$ #e ause feed#a 8 in"i#i!ion is an in!e+ral par! of purine #ios(n!"esis& As a resul! of %an!"ine o%idase in"i#i!ion$ !"e serum on en!ra!ion of "(po%an!"ine plus %an!"ine in pa!ien!s re ei'in+ allopurinol

for !rea!men! of "(peruri emia is usuall( in !"e ran+e of 0&3 !o 0&4 m+9dL ompared !o a normal le'el of appro%ima!el( 0&-5 m+9dL& A ma%imum of 0&2 m+9dL of !"ese o%(purines "as #een repor!ed 1"en !"e serum ura!e 1as lo1ered !o less !"an : m+9dL #( "i+" doses of allopurinol& ,"ese 'alues are far #elo1 !"e sa!ura!ion le'els$ a! 1"i " poin! !"eir pre ipi!a!ion 1ould #e e%pe !ed !o o ur (a#o'e ; m+9dL)& ,"e renal learan e of "(po%an!"ine and %an!"ine is a! leas! -0 !imes +rea!er !"an !"a! of uri a id& ,"e in reased %an!"ine and "(po%an!"ine in !"e urine "a'e no! #een a ompanied #( pro#lems of nep"roli!"iasis& ,"ere are isola!ed ase repor!s of %an!"ine r(s!alluria in pa!ien!s 1"o 1ere !rea!ed 1i!" oral allopurinol& ,"e a !ion of oral allopurinol differs from !"a! of uri osuri a+en!s$ 1"i " lo1er !"e serum uri a id le'el #( in reasin+ urinar( e% re!ion of uri a id& Allopurinol redu es #o!" !"e serum and urinar( uri a id le'els #( in"i#i!in+ !"e forma!ion of uri a id& ,"e use of allopurinol !o #lo 8 !"e forma!ion of ura!es a'oids !"e "a)ard of in reased renal e% re!ion of uri a id posed #( uri osuri dru+s& P(ARMA$O+I&"%I$#' <ollo1in+ in!ra'enous adminis!ra!ion in si% "eal!"( male and female su#je !s$ allopurinol 1as rapidl( elimina!ed from !"e s(s!emi ir ula!ion primaril( 'ia o%ida!i'e me!a#olism !o o%(purinol$ 1i!" no de!e !a#le plasma on en!ra!ion of allopurinol af!er 5 "ours pos! dosin+& Appro%ima!el( -:= of !"e allopurinol in!ra'enous dose 1as e% re!ed un "an+ed$ ;6= e% re!ed as o%(purinol$ and !"e remainin+ dose e% re!ed as ri#oside onju+a!es in !"e urine& ,"e rapid on'ersion of allopurinol !o o%(purinol 1as no! si+nifi an!l( differen! af!er repea!ed allopurinol dosin+& O%(purinol 1as presen! in s(s!emi ir ula!ion in mu " "i+"er on en!ra!ions and for a mu " lon+er period !"an allopurinol> !"us$ i! is +enerall( #elie'ed !"a! !"e p"arma olo+i al a !ion of allopurinol is media!ed 'ia o%(purinol& O%(purinol 1as primaril( elimina!ed un "an+ed in urine #( +lomerular fil!ra!ion and !u#ular rea#sorp!ion$ 1i!" a ne! renal learan e of a#ou! 30 mL9min& ,o ompare !"e p"arma o8ine!i s of allopurinol and o%(purinol #e!1een in!ra'enous (i&'&) and oral (p&o&) adminis!ra!ion of ALOPRIM (allopurinol sodium) for Inje !ion$ a 1ell. on!rolled$ four.1a( rosso'er s!ud( 1as ondu !ed in -6 male "eal!"( 'olun!eers& ALOPRIM (allopurinol sodium) for Inje !ion 1as adminis!ered 'ia an in!ra'enous infusion o'er 30 minu!es& P"arma o8ine!i parame!er es!ima!es of allopurinol (mean ? @&A&) follo1in+ sin+le i&'& and p&o& adminis!ra!ion of ALOPRIM (allopurinol sodium) for Inje !ion are summari)ed as follo1s6 Administration of ALOPRIM (allopurinol sodium) for Injection Allopurinol -00 m+ 300 m+ -00 m+ 300 m+

Parame!ers

i&'&

i&'&

p&o&B

p&o&

3ma% (C+9mL)

-&58 ? 0&::

5&-: ? 0&8:

0&53 ? 0&-0

-&35 ? 0&42

,ma% ("r)

0&50

0&50

-&00 ? 0&32

-&6; ? 0&26

, -9: ("r)

-&00 ? 0&46

-&:- ? 0&33

0&28 ? 0&43

-&3: ? 0&3:

AD30.E("rFC+9mL)

-&22 ? 0&63

;&-0 ? -&:8

-&03 ? 0&:4

3&62 ? 0&26

3L (mL9min98+)

-:&: ? 3&--

2&24 ? :&36

Gss (L98+)H

0&84 ? 0&-3

0&8; ? 0&-3

<a#solu!e (=)HH

48&8 ? -2&;

5:&; ? -3&-

BnI; H Golume of Ais!ri#u!ion (@!ead(.@!a!e) HH A#solu!e Jioa'aila#ili!( O%(purinol 1as measura#le in !"e plasma 1i!"in -0 !o -5 minu!es follo1in+ !"e adminis!ra!ion of ALOPRIM (allopurinol sodium) for Inje !ion& P"arma o8ine!i parame!er es!ima!es of o%(purinol follo1in+ i&'& and p&o& adminis!ra!ion of ALOPRIM (allopurinol sodium) for Inje !ion are s"o1n #elo16 Adminis!ra!ion of ALOPRIM (allopurinol sodium) for Inje !ion

O%(purinol Parame!ers

-00 m+ i&'&

300 m+ i&'&

-00 m+ p&o&

300 m+ p&o&

3ma% (C+9mL)

:&:0 ? 0&3-

6&-8 ? 0&;8

:&36 ? 0&30

6&36 ? 0&83

,ma% ("r)

3&82 ? -&4-

4&-6 ? -&:

3&-0 ? -&42

4&-3 ? -&35

, -9: ("r)

:4&- ? 5&4

:3&5 ? 4&5

:4&2 ? 8&4

:3&; ? 3&4

AD30. ("rFC+9mL)

80 ? :4

:3- ? 54

83 ? ::

:45 ? 42

<rela!i'e (=)B B Rela!i'e Jioa'aila#ili!(

-0; ? :5

-08 ? 2

In +eneral$ !"e ra!io of !"e area under !"e plasma on en!ra!ion 's !ime ur'e (AD30.E) #e!1een o%(purinol and allopurinol 1as in !"e ma+ni!ude of 30 !o 40& ,"e 3ma% and AD30.E$ for #o!" allopurinol and o%(purinol follo1in+ i&'& adminis!ra!ion of ALOPRIM (allopurinol sodium) for Inje !ion 1ere dose propor!ional in !"e dose ran+e of -00 !o 300 m+& ,"e "alf.life of allopurinol and o%(purinol 1as no! influen ed #( !"e rou!e of ALOPRIM (allopurinol sodium) for Inje !ion adminis!ra!ion& Oral and in!ra'enous adminis!ra!ion of ALOPRIM (allopurinol sodium) for Inje !ion a! e*ual doses produ ed nearl( superimposa#le o%(purinol plasma on en!ra!ion 's !ime profiles$ and !"e rela!i'e #ioa'aila#ili!( of o%(purinol (<rela!i'e) 1as appro%ima!el( -00=& ,"us$ !"e p"arma o8ine!i s and plasma profiles of o%(purinol$ !"e major p"arma olo+i al omponen! deri'ed from allopurinol$ are similar af!er in!ra'enous and oral adminis!ra!ion of ALOPRIM (allopurinol sodium) for Inje !ion& $linical %rials' A ompassiona!e plea !rial 1as ondu !ed from -2;; !"rou+" -282 in 1"i " ;-8 e'alua#le pa!ien!s 1i!" mali+nan ies re*uirin+ !rea!men! 1i!" (!o!o%i "emo!"erap($ #u! 1"o 1ere una#le !o in+es! or re!ain oral medi a!ion$ re ei'ed i&'& ALOPRIM (allopurinol sodium) for Inje !ion in !"e D&@& Of

!"ese pa!ien!s$ 4-- "ad es!a#lis"ed "(peruri emia and 30; "ad normal serum ura!e le'els a! !"e !ime !"a! !rea!men! 1as ini!ia!ed& 5ormal serum uri a id le'els 1ere a "ie'ed in 68= (redu !ion of serum uri a id 1as do umen!ed in 23=) of !"e former$ and 1ere main!ained !"rou+"ou! "emo!"erap( in 2;= of !"e la!!er& Je ause of !"e s!ud( desi+n$ i! 1as no! possi#le !o assess !"e impa ! of !"e !rea!men! upon !"e lini al ou! ome of !"e pa!ien! +roups& I&!I$A%IO&# A&! ,#A)"' ALOPRIM (allopurinol sodium) for Inje !ion is indi a!ed for !"e mana+emen! of pa!ien!s 1i!" leu8emia$ l(mp"oma$ and solid !umor mali+nan ies 1"o are re ei'in+ an er !"erap( 1"i " auses ele'a!ions of serum and urinar( uri a id le'els and 1"o anno! !olera!e oral !"erap(& $O&%RAI&!I$A%IO&#' Pa!ien!s 1"o "a'e de'eloped a se'ere rea !ion !o allopurinol s"ould no! #e res!ar!ed on !"e dru+& -AR&I&)#' ALLOPDRI5OL @4ODLA JK AI@3O5,I5DKA A, ,4K <IR@, APPKARA53K O< @7I5 RA@4 OR O,4KR @IL5@ M4I34 MAN I5AI3A,K A5 ALLKRLI3 RKA3,IO5& In some ins!an es 1i!" oral allopurinol$ a s8in ras" ma( #e follo1ed #( more se'ere "(persensi!i'i!( rea !ions su " as e%folia!i'e$ ur!i arial$ and purpuri lesions as 1ell as @!e'ens.Oo"nson s(ndrome (er(!"ema mul!iforme e%uda!i'um)$ and9or +enerali)ed 'as uli!is$ irre'ersi#le "epa!o!o%i i!( and$ on rare o asions$ dea!"& In pa!ien!s re ei'in+ mer ap!opurine or a)a!"ioprine$ !"e on omi!an! adminis!ra!ion of 300 !o 600 m+ of ALOPRIM (allopurinol sodium) for Inje !ion per da( 1ill re*uire a redu !ion in dose !o appro%ima!el( one.!"ird !o one.four!" of !"e usual dose of mer ap!opurine or a)a!"ioprine& @u#se*uen! adjus!men! of doses of mer ap!opurine or a)a!"ioprine s"ould #e made on !"e #asis of !"erapeu!i response and !"e appearan e of !o%i effe !s (see PRK3AD,IO5@6 Aru+ In!era !ions)& A fe1 ases of re'ersi#le lini al "epa!o!o%i i!( "a'e #een no!ed in pa!ien!s !a8in+ oral allopurinol$ and in some pa!ien!s as(mp!oma!i rises in serum al8aline p"osp"a!ase or serum !ransaminase "a'e #een o#ser'ed& If anore%ia$ 1ei+"! loss$ or pruri!us de'elop in pa!ien!s on allopurinol$ e'alua!ion of li'er fun !ion s"ould #e par! of !"eir dia+nos!i 1or8up& In pa!ien!s 1i!" pre.e%is!in+ li'er disease$ periodi li'er fun !ion !es!s are re ommended durin+ !"e earl( s!a+es of !"erap(& Aue !o !"e o asional o urren e of dro1siness$ pa!ien!s s"ould #e aler!ed !o !"e need for due pre au!ion 1"en en+a+in+ in a !i'i!ies 1"ere aler!ness is manda!or(&

,"e o urren e of "(persensi!i'i!( rea !ions !o allopurinol ma( #e in reased in pa!ien!s 1i!" de reased renal fun !ion re ei'in+ !"ia)ides and allopurinol on urren!l(& ,"us$ in pa!ien!s 1i!" de reased renal fun !ion$ su " om#ina!ions s"ould #e adminis!ered 1i!" au!ion& PR"$A,%IO&#' )eneral6 A fluid in!a8e suffi ien! !o (ield a dail( urinar( ou!pu! of a! leas! !1o li!ers in adul!s and !"e main!enan e of a neu!ral or$ prefera#l($ sli+"!l( al8aline urine are desira#le !o (-) a'oid !"e !"eore!i al possi#ili!( of forma!ion of %an!"ine al uli under !"e influen e of allopurinol !"erap( and (:) "elp pre'en! renal pre ipi!a!ion of ura!es in pa!ien!s re ei'in+ on omi!an! uri osuri a+en!s& A fe1 pa!ien!s 1i!" pre.e%is!in+ renal disease or poor ura!e learan e "a'e s"o1n a rise in JD5 durin+ allopurinol adminis!ra!ion$ al!"ou+" a de rease in JD5 "as also #een o#ser'ed& In pa!ien!s 1i!" "(peruri emia due !o mali+nan ($ !"e 'as! majori!( of "an+es in renal fun !ion are a!!ri#u!a#le !o !"e underl(in+ mali+nan ( ra!"er !"an !o !"erap( 1i!" allopurinol& 3on urren! ondi!ions su " as mul!iple m(eloma and on+es!i'e m(o ardial disease 1ere presen! amon+ !"ose pa!ien!s 1"ose renal fun !ion de!eriora!ed af!er allopurinol 1as #e+un& Renal failure is rarel( asso ia!ed 1i!" "(persensi!i'i!( rea !ions !o allopurinol& Pa!ien!s 1i!" de reased renal fun !ion do re*uire lo1er doses of allopurinol& Pa!ien!s s"ould #e arefull( o#ser'ed durin+ !"e earl( s!a+es of allopurinol adminis!ra!ion so !"a! !"e dosa+e an #e appropria!el( adjus!ed for renal fun !ion& In pa!ien!s 1i!" se'erel( impaired renal fun !ion or de reased ura!e learan e$ !"e "alf.life of o%(purinol in !"e plasma is +rea!l( prolon+ed& Pa!ien!s s"ould #e !rea!ed 1i!" !"e lo1es! effe !i'e dose$ in order !o minimi)e possi#le side effe !s& ,"e appropria!e dose of ALOPRIM (allopurinol sodium) for Inje !ion for pa!ien!s 1i!" a rea!inine learan e P-0 mL9min is -00 m+ per da(& <or pa!ien!s 1i!" a rea!inine learan e #e!1een -0 and :0 mL9min$ a dose of :00 m+ per da( is re ommended& Mi!" e%!reme renal impairmen! ( rea!inine learan e less !"an 3 mL9min)$ !"e in!er'al #e!1een doses ma( also need !o #e e%!ended& Jone marro1 suppression "as #een repor!ed in pa!ien!s re ei'in+ allopurinol> "o1e'er$ mos! of !"ese pa!ien!s 1ere re ei'in+ on omi!an! medi a!ions 1i!" !"e 8no1n po!en!ial !o ause su " an effe !& ,"e suppression "as o ured from as earl( as 6 1ee8s !o as lon+ as 6 (ears af!er !"e ini!ia!ion of allopurinol !"erap(& Laborator %ests' ,"e orre ! dosa+e and s "edule for main!ainin+ !"e serum uri a id 1i!"in !"e normal ran+e is #es! de!ermined #( usin+ !"e serum uri a id as an inde%&

In pa!ien!s 1i!" pre.e%is!in+ li'er disease$ periodi li'er fun !ion !es!s are re ommended durin+ !"e earl( s!a+es of !"erap( (see MAR5I5L@)& Allopurinol and i!s primar( a !i'e me!a#oli!e$ o%(purinol$ are elimina!ed #( !"e 8idne(s> !"erefore$ "an+es in renal fun !ion "a'e a profound effe ! on dosa+e& In pa!ien!s 1i!" de reased renal fun !ion$ or 1"o "a'e on urren! illnesses 1"i " an affe ! renal fun !ion su " as "(per!ension and dia#e!es melli!us$ periodi la#ora!or( parame!ers of renal fun !ion$ par!i ularl( JD5 and serum rea!inine or rea!inine learan e$ s"ould #e performed and !"e pa!ien!Qs allopurinol dosa+e reassessed& ,"e pro!"rom#in !ime s"ould #e reassessed periodi all( in !"e pa!ien!s re ei'in+ di umarol 1"o are +i'en allopurinol& !rug Interactions' ,"e follo1in+ dru+ in!era !ions 1ere o#ser'ed in some pa!ien!s under+oin+ !rea!men! 1i!" oral allopurinol& Al!"ou+" !"e pa!!ern of use for oral allopurinol in ludes lon+er !erm !"erap($ par!i ularl( for +ou! and renal al uli$ !"e e%perien e +ained ma( #e rele'an!& Mercaptopurine/Azathioprine: Allopurinol in"i#i!s !"e en)(ma!i o%ida!ion of mer ap!opurine and a)a!"ioprine !o 6.!"iouri a id& ,"is o%ida!ion$ 1"i " is a!al()ed #( %an!"ine o%idase$ ina !i'a!es mer ap!opurine& ,"erefore$ !"e on omi!an! adminis!ra!ion of 300 !o 600 m+ of oral allopurinol per da( 1ill re*uire a redu !ion in dose !o appro%ima!el( one.!"ird !o one.four!" of !"e usual dose of mer ap!opurine or a)a!"ioprine& @u#se*uen! adjus!men! of doses of mer ap!opurine or a)a!"ioprine s"ould #e made on !"e #asis of !"erapeu!i response and !"e appearan e of !o%i effe !s& Dicumarol: I! "as #een repor!ed !"a! allopurinol prolon+s !"e "alf.life of !"e an!i oa+ulan!$ di umarol$ 3onse*uen!l($ pro!"rom#in !ime s"ould #e reassessed periodi all( in pa!ien!s re ei'in+ #o!" dru+s& ,"e lini al #asis of !"is dru+ in!era !ion "as no! #een es!a#lis"ed& Uricosuric Agents: @in e !"e e% re!ion of o%(purinol is similar !o !"a! of ura!e$ uri osuri a+en!s$ 1"i " in rease !"e e% re!ion of ura!e$ are also li8el( !o in rease !"e e% re!ion of o%(purinol& As a resul!$ !"e on omi!an! adminis!ra!ion of uri osuri a+en!s de reases !"e in"i#i!ion of %an!"ine o%idase #( o%(purinol and in reases !"e urinar( e% re!ion of uri a id& Thiazide Diuretics: Repor!s !"a! !"e on omi!an! adminis!ra!ion of allopurinol and !"ia)ide diure!i s on!ri#u!ed !o in reased allopurinol !o%i i!( 1ere re'ie1ed> a ausal me "anism or ause.and.effe ! rela!ions"ip 1as no! found& Renal fun !ion s"ould #e moni!ored in pa!ien!s on !"ia)ide diure!i s and allopurinol (see MAR5I5L@)& Ampicillin/Amoxicillin: An in rease in !"e fre*uen ( of s8in ras" "as #een repor!ed amon+ pa!ien!s re ei'in+ ampi illin or amo%i illin on urren!l( 1i!" allopurinol ompared !o pa!ien!s 1"o are no! re ei'in+ #o!" dru+s& ,"e ause of !"is rea !ion "as no! #een es!a#lis"ed&

Cytotoxic Agents: Kn"an ed #one marro1 suppression #( ( lop"osp"amide and o!"er (!o!o%i a+en!s "as #een repor!ed amon+ pa!ien!s 1i!" neoplas!i disease$ e% ep! leu8emia$ in !"e presen e of allopurinol& 4o1e'er$ in a 1ell. on!rolled s!ud( of pa!ien!s 1i!" l(mp"oma on om#ina!ion !"erap($ allopurinol did no! in rease !"e marro1 !o%i i!( of pa!ien!s !rea!ed 1i!" ( lop"osp"amide$ do%oru#i in$ #leom( in$ pro ar#a)ine$ and9or me "lore!"amine& Chlorpropamide: ,"e "alf.life of "lorpropamide in !"e plasma ma( #e prolon+ed #( allopurinol$ sin e allopurinol and "lorpropamide ma( ompe!e for e% re!ion in !"e renal !u#ule& ,"e ris8 of "(po+l( emia se ondar( !o !"is me "anism ma( #e in reased if allopurinol and "lorpropamide are +i'en on omi!an!l( in !"e presen e of renal insuffi ien (& Cyclosporin: Repor!s indi a!e !"a! ( losporine le'els ma( #e in reased durin+ on omi!an! !rea!men! 1i!" ALOPRIM (allopurinol sodium) for Inje !ion& Moni!orin+ of ( losporine le'els and possi#le adjus!men! of ( losporine dosa+e s"ould #e onsidered 1"en !"ese dru+s are o. adminis!ered& Drug/Laboratory Test Interactions: Allopurinol is no! 8no1n !o al!er !"e a ura ( of la#ora!or( !es!s& $arcinogenesis. Mutagenesis and Impairment of Fertilit ' Carcinogenesis: Allopurinol 1as adminis!ered a! doses up !o :0 m+98+9da( !o mi e and ra!s for !"e majori!( of !"eir life span& 5o e'iden e of ar ino+eni i!( 1as seen in ei!"er mi e or ra!s (a! doses a#ou! -96 or -93 !"e re ommended "uman dose on a m+9m: #asis$ respe !i'el()& Mutagenesis: Allopurinol adminis!ered in!ra'enousl( !o ra!s (50 m+98+) 1as no! in orpora!ed in!o rapidl( repli a!in+ in!es!inal A5A& 5o e'iden e of las!o+eni i!( 1as o#ser'ed in an in 'i'o mi ronu leus !es! in ra!s$ or in l(mp"o (!es !a8en from pa!ien!s !rea!ed 1i!" allopurinol (mean dura!ion of !rea!men! 40 mon!"s)$ or in an in 'i!ro assa( 1i!" "uman l(mp"o (!es& Impairment ! "ertility: Allopurinol oral doses of :0 m+98+9da( "ad no effe ! on male or female fer!ili!( in ra!s or ra##i!s (a#ou! -93 or -9: !"e "uman dose on a m+9m: #asis$ respe !i'el()& Pregnanc ' Teratogenic #!!ects: Pre+nan ( 3a!e+or( 3& ,"ere 1as no e'iden e of fe!o!o%i i!( or !era!o+eni i!( in ra!s or ra##i!s !rea!ed durin+ !"e period of or+ano+enesis 1i!" oral allopurinol a! doses up !o :00 m+98+9da( and up !o -00 m+98+9da($ respe !i'el( (a#ou! !"ree !imes !"e "uman dose on a m+9m: #asis)& 4o1e'er$ !"ere is a pu#lis"ed repor! in pre+nan! mi e !"a! sin+le in!raperi!oneal doses of 50 or -00 m+98+ (a#ou! -93 or 394 !"e "uman dose on a m+9m: #asis) of allopurinol on +es!a!ion da(s -0 or -3 produ ed si+nifi an! in reases in fe!al dea!"s and !era!o+eni effe !s ( lef! pala!e$ "arelip$ and di+i!al defe !s)& I! is un er!ain 1"e!"er !"ese findin+s represen!ed a fe!al effe ! or an effe ! se ondar( !o ma!ernal !o%i i!(& ,"ere are$ "o1e'er$ no ade*ua!e or 1ell. on!rolled s!udies in pre+nan! 1omen&

Je ause animal reprodu !ion s!udies are no! al1a(s predi !i'e of "uman response$ !"is dru+ s"ould #e used durin+ pre+nan ( onl( if !"e po!en!ial #enefi! jus!ifies !"e po!en!ial ris8 !o !"e fe!us& K%perien e 1i!" allopurinol durin+ "uman pre+nan ( "as #een limi!ed par!l( #e ause 1omen of reprodu !i'e a+e rarel( re*uire !rea!men! 1i!" allopurinol& ,1o unpu#lis"ed repor!s and one pu#lis"ed paper des ri#e 1omen +i'in+ #ir!" !o normal offsprin+ af!er re ei'in+ oral allopurinol durin+ pre+nan (& ,"ere "a'e #een no pre+nan ies repor!ed in pa!ien!s re ei'in+ ALOPRIM (allopurinol sodium) for Inje !ion$ #u! i! is assumed !"a! !"e same ris8s 1ould appl(& &ursing Mot/ers' Allopurinol and o%(purinol "a'e #een found in !"e mil8 of a mo!"er 1"o 1as re ei'in+ allopurinol& @in e !"e effe ! of allopurinol on !"e nursin+ infan! is un8no1n$ au!ion s"ould #e e%er ised 1"en allopurinol is adminis!ered !o a nursin+ 1oman& Pediatric ,se' 3lini al da!a are a'aila#le on appro%ima!el( :00 pedia!ri pa!ien!s !rea!ed 1i!" ALOPRIM (allopurinol sodium) for Inje !ion& ,"e effi a ( and safe!( profile o#ser'ed in !"is pa!ien! popula!ion 1ere similar !o !"a! o#ser'ed in adul!s (see I5AI3A,IO5@ and AO@ALK A5A AAMI5I@,RA,IO5)& )eriatric ,se' 3lini al s!udies of ALOPRIM (allopurinol sodium) for Inje !ion did no! in lude suffi ien! num#ers of pa!ien!s a+ed 65 and o'er !o de!ermine 1"e!"er !"e( respond differen!l( !"an (oun+er pa!ien!s& O!"er repor!ed lini al e%perien e "as no! iden!ified differen es in responses #e!1een !"e elderl( and (oun+er pa!ien!s& In +eneral$ dose sele !ion for an elderl( pa!ien! s"ould #e au!ious$ usuall( s!ar!in+ a! !"e lo1 end of !"e dosin+ ran+e$ refle !in+ !"e +rea!er fre*uen ( of de reased "epa!i $ renal$ or ardia fun !ion$ and of on omi!an! disease or o!"er dru+ !"erap(& A!0"R#" R"A$%IO&#' In an un on!rolled$ ompassiona!e plea pro!o ol$ -:5 of -$3;8 pa!ien!s repor!ed a !o!al of 30- ad'erse rea !ions 1"ile re ei'in+ ALOPRIM (allopurinol sodium) for Inje !ion& Mos! of !"e pa!ien!s "ad ad'an ed mali+nan ies or serious underl(in+ diseases and 1ere !a8in+ mul!iple on omi!an! medi a!ions& @ide effe !s dire !l( a!!ri#u!a#le !o ALOPRIM (allopurinol sodium) for Inje !ion 1ere repor!ed in -2 pa!ien!s& <if!een of !"ese ad'erse e%perien es 1ere aller+i in na!ure (ras"$ eosinop"ilia$ lo al inje !ion si!e rea !ion)& One ad'erse e%perien e of se'ere diarr"ea and one in iden e of nausea 1ere also repor!ed as #ein+ possi#l( a!!ri#u!a#le !o ALOPRIM (allopurinol sodium) for Inje !ion& ,1o pa!ien!s "ad serious ad'erse e%perien es (de reased renal fun !ion and +enerali)ed sei)ure) repor!ed as #ein+ possi#l( a!!ri#u!a#le !o ALOPRIM (allopurinol sodium) for Inje !ion& A lis!in+ of !"e ad'erse rea !ions re+ardless of ausali!( repor!ed from lini al !rials follo1s6

Incidence )reater %/an 12' 3u!aneous9Aerma!olo+i 6 Ras" (-&5=) Leni!ourinar(6 Las!roin!es!inal6 Renal failure9insuffi ien ( (-&:=) 5ausea (-&3=)$ 'omi!in+ (-&:=)

Incidence Less %/an 12' Jod( as M"ole6 fe'er$ pain$ "ills$ alope ia$ infe !ion$ sepsis$ enlar+ed a#domen$ mu osi!is9p"ar(n+i!is$ #las! risis$ elluli!is$ "(per'olemia "ear! failure$ ardiorespira!or( arres!$ "(per!ension$ pulmonar( em#olus$ "(po!ension$ de reased 'enous pressure$ flus"in+$ "eada "e$ s!ro8e$ sep!i s"o 8$ ardio'as ular disorder$ K3L a#normali!($ "emorr"a+e$ #rad( ardia$ !"rom#op"le#i!is$ 'en!ri ular fi#rilla!ion

3ardio'as ular6

3u!aneous9Aerma!olo+i 6 ur!i aria$ pruri!us$ lo al inje !ion si!e rea !ion Las!roin!es!inal6 diarr"ea$ +as!roin!es!inal #leedin+$ "(per#iliru#inemia$ splenome+al($ "epa!ome+al($ in!es!inal o#s!ru !ion$ jaundi e$ fla!ulen e$ ons!ipa!ion$ li'er failure$ pro !i!is "ema!uria$ in reased rea!inine$ oli+uria$ 8idne( fun !ion a#normali!($ urinar( !ra ! infe !ion leu8openia$ marro1 aplasia$ !"rom#o (!openia$ eosinop"ilia$ neu!ropenia$ anemia$ pan (!openia$ e "(mosis$ #one marro1 suppression$ dissemina!ed in!ra'as ular oa+ula!ion "(po al emia$ "(perp"osp"a!emia$ "(po8alemia$ "(peruri emia$ ele !rol(!e a#normali!($ "(per al emia$ "(per+l( emia$ "(perna!remia$ "(pona!remia$ me!a#oli a idosis$ edema$ +l( osuria$ "(per8alemia$ la !i a idosis$ 1a!er in!o%i a!ion$ "(poma+nesemia

Leni!ourinar(6

4ema!olo+i 6

Me!a#oli 6

5eurolo+i 6

sei)ure$ s!a!us epilep!i us$ m(o lonus$ !1i! "in+$ a+i!a!ion$ men!al s!a!us "an+es$ ere#ral infar !ion$ oma$ d(s!onia$ paral(sis$ !remor respira!or( failure9insuffi ien ($ ARA@$ in reased respira!ion ra!e$ apnea Ar!"ral+ia "(po!onia$ diap"oresis$ !umor l(sis s(ndrome

Pulmonar(6

Mus ulos8ele!al6 O!"er6

,"e mos! fre*uen! ad'erse rea !ion !o oral allopurinol is s8in ras"& @8in rea !ions an #e se'ere and some!imes fa!al& ,"erefore$ !rea!men! 1i!" ALOPRIM (allopurinol sodium) for Inje !ion s"ould #e dis on!inued immedia!el( if a ras" de'elops (see MAR5I5L@)& <or fur!"er de!ails on "(persensi!i'i!( rea !ions !o !rea!men! 1i!" oral allopurinol$ refer !o !"e pa 8a+e inser! for allopurinol !a#le!s& O0"R!O#A)"' Massi'e o'erdosin+ or a u!e poisonin+ #( ALOPRIM (allopurinol sodium) for Inje !ion "as no! #een repor!ed& In mi e$ !"e minimal le!"al dose is 45 m+98+ +i'en in!ra'enousl( or 500 m+98+ orall( (a#ou! -93 or 4 !imes !"e usual "uman dose on a m+9m : #asis)& 4(poa !i'i!( 1as o#ser'ed 1i!" !"ese doses& In ra!s$ !"e minimum le!"al dose is -00 m+98+ i&'&$ and 5000 m+98+ orall( (a#ou! -&5 and ;5 !imes !"e usual "uman dose on a m+9m: #asis)& In !"e mana+emen! of o'erdosa+e$ !"ere is no spe ifi an!ido!e for ALOPRIM (allopurinol sodium) for Inje !ion& ,"ere "as #een no lini al e%perien e in !"e mana+emen! of a pa!ien! 1"o "as !a8en massi'e amoun!s of allopurinol& Jo!" allopurinol and o%(purinol are dial()a#le> "o1e'er$ !"e usefulness of "emodial(sis or peri!oneal dial(sis in !"e mana+emen! of an o'erdose of ALOPRIM (allopurinol sodium) for Inje !ion is un8no1n& !O#A)" A&! A!MI&I#%RA%IO&' $/ildren and Adults' ,"e dosa+e of ALOPRIM (allopurinol sodium) for Inje !ion !o lo1er serum uri a id !o normal or near.normal 'aries 1i!" !"e se'eri!( of !"e disease& ,"e amoun! and fre*uen ( of dosa+e for main!ainin+ !"e serum uri a id jus! 1i!"in !"e normal ran+e is #es! de!ermined #( usin+ !"e serum uri a id le'el as an inde%& In adul!s$ in one lini al !rial$ doses o'er 600 m+ a da( did no! appear !o #e more effe !i'e& ,"e re ommended dail( dose of ALOPRIM (allopurinol sodium) for Inje !ion is as follo1s6

Recommended !ail Adul!6

!ose

:00 !o 400 m+9m:9da( Ma%imum 600 m+9da( @!ar!in+ Aose :00 m+9m:9da(

3"ild6

( dration' A fluid in!a8e suffi ien! !o (ield a dail( urinar( ou!pu! of a! leas! !1o li!ers in adul!s and !"e main!enan e of a neu!ral or$ prefera#l($ sli+"!l( al8aline urine are desira#le& Impaired Renal Function6 ,"e dose of ALOPRIM (allopurinol sodium) for Inje !ion s"ould #e redu ed in pa!ien!s 1i!" impaired renal fun !ion !o a'oid a umula!ion of allopurinol and i!s me!a#oli!es6 3rea!inine 3learan e -0 !o :0 mL9min 3 !o -0 mL9min R3 mL9min Re ommended Aail( Aose

:00 m+9da( -00 m+9da( -00 m+9da( a! e%!ended in!er'als

Administration6 In #o!" adul!s and "ildren$ !"e dail( dose an #e +i'en as sin+le infusion or in e*uall( di'ided infusions a! 6.$ 8.$ or -:. "our in!er'als a! !"e re ommended final on en!ra!ion of no! +rea!er !"an 6 m+9mL (see Prepara!ion of @olu!ion)& ,"e ra!e of infusion depends on !"e 'olume of infusa!e& M"ene'er possi#le$ !"erap( 1i!" ALOPRIM (allopurinol sodium) for Inje !ion s"ould #e ini!ia!ed :4 !o 48 "ours #efore !"e s!ar! of "emo!"erap( 8no1n !o ause !umor ell l(sis (in ludin+ adreno or!i o s!eroids)& ALOPRIM (allopurinol sodium) for Inje !ion s"ould no! #e mi%ed 1i!" or adminis!ered !"rou+" !"e same in!ra'enous por! 1i!" a+en!s 1"i " are in ompa!i#le in solu!ion 1i!" ALOPRIM (allopurinol sodium) for Inje !ion (see Prepara!ion of @olu!ion)& Preparation of #olution' ALOPRIM (allopurinol sodium) for Inje !ion mus! #e re ons!i!u!ed and dilu!ed& ,"e on!en!s of ea " 30 mL 'ial s"ould #e dissol'ed 1i!" :5 mL of @!erile Ma!er for Inje !ion$ Re ons!i!u!ion (ields a lear$ almos! olorless solu!ion 1i!" no more !"an a sli+"! opales en e& ,"is on en!ra!ed solu!ion "as a p4 of --&- !o --&8& I! s"ould #e dilu!ed !o !"e desired on en!ra!ion 1i!" 0&2= @odium 3"loride Inje !ion or 5= Ae%!rose for Inje !ion& @odium #i ar#ona!e. on!ainin+ solu!ions s"ould no! #e used& A final on en!ra!ion of no +rea!er !"an 6 m+9mL is re ommended& ,"e

solu!ion s"ould #e s!ored a! :0S !o :5S3 (68S !o ;;S<) and adminis!ra!ion s"ould #e+in 1i!"in -0 "ours af!er re ons!i!u!ion& Ao no! refri+era!e !"e re ons!i!u!ed and9or dilu!ed produ !& Paren!eral dru+ produ !s s"ould #e inspe !ed 'isuall( for par!i ula!e ma!!er and dis olora!ion prior !o adminis!ra!ion$ 1"ene'er solu!ion and on!ainer permi!& Ao no! use !"is produ ! if par!i ula!e ma!!er or dis olora!ion is presen!& ,"e follo1in+ !a#le lis!s dru+s !"a! are p"(si all( in ompa!i#le in solu!ion 1i!" ALOPRIM (allopurinol sodium) for Inje !ion& !rugs %/at are P/ sicall Incompatible in #olution 3it/ ALOPRIM (allopurinol sodium) for Injection Ami8a in sulfa!e Amp"o!ere in J 3armus!ine 3efo!a%ime sodium 3"lorproma)ine 43l 3ime!idine 43l 3lindam( in p"osp"a!e 3(!ara#ine Aa ar#a)ine Aaunoru#i in 43l Aip"en"(dramine 43l Ao%oru#i in 43l Ao%( ( line "( la!e Aroperidol <lo%uridine Len!ami in sulfa!e 4aloperidol la !a!e (O- #,PPLI"!' @,KRILK @I5LLK D@K GIAL <OR I5,RAGK5OD@ I5<D@IO5& ALOPRIM (allopurinol sodium) for Inje !ion$ 30 mL flin! +lass 'ials 1i!" ru##er s!oppers ea " on!ainin+ allopurinol sodium e*ui'alen! !o 500 m+ of allopurinol (1"i!e 4(dro%()ine 43l Idaru#i in 43l Imipenem. ilas!a!in sodium Me "lore!"amine 43l Meperidine 43l Me!o lopramide 43l Me!"(lprednisolone sodium su Mino ( line 43l 5al#up"ine 43l 5e!ilmi in sulfa!e Ondanse!ron 43l Pro "lorpera)ine edis(la!e Prome!"a)ine 43l @odium #i ar#ona!e @!rep!o)o in ,o#ram( in sulfa!e Ginorel#ine !ar!ra!e ina!e

l(op"ili)ed po1der)$ #o% of - (5A3 52;30.560-.-)& @!ore unre ons!i!u!ed po1der a! :5S3 (;;S<)> e% ursions permi!!ed !o -5S.30S3 (52S.86S<) /see D@P on!rolled room !empera!ure0& Ais!ri#u!ed #(6 5a#iT Jo a Ra!on$ <L 3348; ,oll <ree6 -.800.3:;.;-06 Oune -222 Manufa !ured #(6 3a!al(!i a P"arma eu!i als$ In & Lreen'ille$ 53 :;834