Injeksi Aminofilin Tiap 1 ml mengandung: Aminofilin 25 mg Aqua pi ad 1 ml Volume ampul yang digunakan : Kelarutan : 1 g dalam 25 ml air menghasilkan larutan

jernih V = 25 mg x 25 ml = ! 25 g x 25 ml = !"25 ml # 1 ml Volume larutan yang akan di$uat V = %&n ' 2( ) ' &2 x *(+ ml = % &1" ' 2( 1!1 ' &2 x *( + ml = 25!, ml # * ml -imana: ) : )olume ampul ' kele$ihan )olume n : jumlah ampul 2 : .adangan 2 x * ml : untuk pem$ilasan /enim$angan -i$uat )olume 1 ampul = 1 ml Aminofilin = 25 mg x * ml = 05 mg Aminofilin terdiri dari : Teofilin = ,51 2 3tilendiamin = 151 4 Teofilin = ,5 x 05 mg = "*0!5 mg 4 3tilendiamin = 15 x 05 mg = 112!5 mg Aqua pi ad * ml

AMINOPHYLLINE INJECTION, USP Rx Only DESCRIPTION Aminophylline Aminophylline is a !" #omplex o$ %heophylline an& e%hylene&iamine' Theophylline is s%()#%)(ally #lassi$ie& as a me%hylxan%hine' Aminophylline o##)(s as a *hi%e o( sli+h%ly yello*ish +(an)le o( po*&e(, *i%h a sli+h% ammonia#al o&o(' Aminophylline has %he #hemi#al name "H,P)(ine, ,-,&ione,.,/,&ihy&(o,",.,&ime%hyl,, #ompo)n& *i%h ", ,e%hane&iamine 0 !"1 an& is (ep(esen%e& 2y %he $ollo*in+ s%()#%)(al $o(m)la! The mole#)la( $o(m)la o$ anhy&(o)s aminophylline is C"-H 3N"4O3 *i%h a mole#)la( *ei+h% o$ 3 4'3.' Ea#h mL #on%ains! Aminophylline 0#al#)la%e& as %he &ihy&(a%e1 5 m+ 0e6)i7alen% %o "8'/ m+ o$ anhy&(o)s %heophylline1, an& is in%en&e& $o( in%(a7eno)s a&minis%(a%ion' Ina#%i7e In+(e&ien%s! E%hylene&iamine ''''''''''''''''''''''' .'/3 m+ 9a%e( $o( In:e#%ion '''''''''''''''''''''''''''''' 6's' The pH is 2e%*een ;'- an& 8'4' CLINICAL PHARMACOLO<Y Me#hanism o$ A#%ion! Theophylline has %*o &is%in#% a#%ions in %he ai(*ays o$ pa%ien%s *i%h (e7e(si2le o2s%()#%ion= smoo%h m)s#le (elaxa%ion 0i'e', 2(on#ho&ila%ion1 an& s)pp(ession o$ %he (esponse o$ %he ai(*ays %o s%im)li 0i'e', non, 2(on#ho&ila%o( p(ophyla#%i# e$$e#%s1' 9hile %he me#hanisms o$ a#%ion o$ %heophylline a(e no% >no*n *i%h #e(%ain%y, s%)&ies in animals s)++es% %ha% 2(on#ho&ila%a%ion is me&ia%e& 2y %he inhi2i%ion o$ %*o iso?ymes o$ phospho&ies%e(ase 0PDE III an&, %o a lesse( ex%en%, PDE I@1 *hile non,2(on#ho&ila%o( p(ophyla#%i# a#%ions a(e p(o2a2ly me&ia%e& %h(o)+h one o( mo(e &i$$e(en% mole#)la( me#hanisms, %ha% &o no% in7ol7e inhi2i%ion o$ PDE III o( an%a+onism o$ a&enosine (e#ep%o(s' Some o$ %he a&7e(se e$$e#%s asso#ia%e& *i%h %heophylline appea( %o 2e me&ia%e& 2y inhi2i%ion o$ PDE III 0e'+', hypo%ension, %a#hy#a(&ia, hea&a#he, an& emesis1 an& a&enosine (e#ep%o( an%a+onism 0e'+', al%e(a%ions in #e(e2(al 2loo& $lo*1' Theophylline in#(eases %he $o(#e o$ #on%(a#%ion o$ &iaph(a+ma%i# m)s#les' This a#%ion appea(s %o 2e &)e %o enhan#emen% o$ #al#i)m )p%a>e %h(o)+h an a&enosine,me&ia%e& #hannel' Se()m Con#en%(a%ion,E$$e#% Rela%ionship! A(on#ho&ila%ion o##)(s o7e( %he se()m %heophylline #on#en%(a%ion (an+e o$ 5, 4 m#+BmL' Clini#ally impo(%an% imp(o7emen% in symp%om #on%(ol an& p)lmona(y $)n#%ion has 2een $o)n& in mos% s%)&ies %o (e6)i(e se()m %heophylline #on#en%(a%ions C "4 m#+BmL' A% se()m %heophylline #on#en%(a%ions C 4 m#+BmL, 2o%h %he $(e6)en#y an& se7e(i%y o$ a&7e(se (ea#%ions in#(ease' In +ene(al, main%ainin+ %he a7e(a+e se()m %heophylline #on#en%(a%ion 2e%*een "4 an& "5 m#+BmL *ill a#hie7e mos% o$ %he &()+Ds po%en%ial %he(ape)%i# 2ene$i% *hile minimi?in+ %he (is> o$ se(io)s a&7e(se e7en%s' Pha(ma#o>ine%i#s! Spe#ial Pop)la%ions 0See Ta2le I $o( mean #lea(an#e an& hal$,li$e 7al)es1 Clini#al S%)&ies! Inhale& 2e%a, sele#%i7e a+onis%s an& sys%emi#ally a&minis%e(e& #o(%i#os%e(oi&s a(e %he %(ea%men%s o$ $i(s%

#hoi#e $o( mana+emen% o$ a#)%e exa#e(2a%ions o$ as%hma' The (es)l%s o$ #on%(olle& #lini#al %(ials on %he e$$i#a#y o$ a&&in+ in%(a7eno)s %heophylline %o inhale& 2e%a, sele#%i7e a+onis%s an& sys%emi#ally a&minis%e(e& #o(%i#os%e(oi&s in %he mana+emen% o$ a#)%e exa#e(2a%ions o$ as%hma ha7e 2een #on$li#%in+' Mos% s%)&ies in pa%ien%s %(ea%e& $o( a#)%e as%hma exa#e(2a%ions in an eme(+en#y &epa(%men% ha7e sho*n %ha% a&&i%ion o$ in%(a7eno)s %heophylline &oes no% p(o&)#e +(ea%e( 2(on#ho&ila%ion an& in#(eases %he (is> o$ a&7e(se e$$e#%s' In #on%(as%, o%he( s%)&ies ha7e sho*n %ha% a&&i%ion o$ in%(a7eno)s %heophylline is 2ene$i#ial in %he %(ea%men% o$ a#)%e as%hma exa#e(2a%ions in pa%ien%s (e6)i(in+ hospi%ali?a%ion, pa(%i#)la(ly in pa%ien%s *ho a(e no% (espon&in+ a&e6)a%ely %o inhale& 2e%a, sele#%i7e a+onis%s' In pa%ien%s *i%h #h(oni# o2s%()#%i7e p)lmona(y &isease 0COPD1, #lini#al s%)&ies ha7e sho*n %ha% %heophylline &e#(eases &yspnea, ai( %(appin+, %he *o(> o$ 2(ea%hin+, an& imp(o7es #on%(a#%ili%y o$ &iaph(a+ma%i# m)s#les *i%h li%%le o( no imp(o7emen% in p)lmona(y $)n#%ion meas)(emen%s' INDICATIONS AND USA<E In%(a7eno)s %heophylline is in&i#a%e& as an a&:)n#% %o inhale& 2e%a, sele#%i7e a+onis%s an& sys%emi#ally a&minis%e(e& #o(%i#os%e(oi&s $o( %he %(ea%men% o$ a#)%e exa#e(2a%ions o$ %he symp%oms an& (e7e(si2le ai($lo* o2s%()#%ion asso#ia%e& *i%h as%hma an& o%he( #h(oni# l)n+ &iseases, e'+', emphysema an& #h(oni# 2(on#hi%is' CONTRAINDICATIONS Aminophylline In:e#%ion, USP is #on%(ain&i#a%e& in pa%ien%s *i%h a his%o(y o$ hype(sensi%i7i%y %o %heophylline o( o%he( #omponen%s in %he p(o&)#%! in#l)&in+ e%hylene&iamine' 9ARNIN<S Con#)((en% Illness! Theophylline sho)l& 2e )se& *i%h ex%(eme #a)%ion in pa%ien%s *i%h %he $ollo*in+ #lini#al #on&i%ions &)e %o %he in#(ease& (is> o$ exa#e(2a%ion o$ %he #on#)((en% #on&i%ion! A#%i7e pep%i# )l#e( &isease Sei?)(e &iso(&e(s Ca(&ia# a((hy%hmias 0no% in#l)&in+ 2(a&ya((hy%hmias1 Con&i%ions Tha% Re&)#e Theophylline Clea(an#e! The(e a(e se7e(al (ea&ily i&en%i$ia2le #a)ses o$ (e&)#e& %heophylline #lea(an#e' I$ %he in$)sion (a%e is no% app(op(ia%ely (e&)#e& in %he p(esen#e o$ %hese (is> $a#%o(s, se7e(e an& po%en%ially $a%al %heophylline %oxi#i%y #an o##)(' Ca(e$)l #onsi&e(a%ion m)s% 2e +i7en %o %he 2ene$i%s an& (is>s o$ %heophylline )se an& %he nee& $o( mo(e in%ensi7e moni%o(in+ o$ se()m %heophylline #on#en%(a%ions in pa%ien%s *i%h %he $ollo*in+ (is> $a#%o(s! Cessa%ion o$ Smo>in+ 9hen Si+ns o( Symp%oms o$ Theophylline Toxi#i%y A(e P(esen%! 9hene7e( a pa%ien% (e#ei7in+ %heophylline &e7elops na)sea o( 7omi%in+, pa(%i#)la(ly (epe%i%i7e 7omi%in+, o( o%he( si+ns o( symp%oms #onsis%en% *i%h %heophylline %oxi#i%y 0e7en i$ ano%he( #a)se may 2e s)spe#%e&1, %he in%(a7eno)s in$)sion sho)l& 2e s%oppe& an& a se()m %heophylline #on#en%(a%ion meas)(e& imme&ia%ely' Dosa+e In#(eases! In#(eases in %he &ose o$ in%(a7eno)s %heophylline sho)l& no% 2e ma&e in (esponse %o an a#)%e exa#e(2a%ion o$ symp%oms )nless %he s%ea&y,s%a%e se()m %heophylline #on#en%(a%ion is E"4 m#+BmL' As %he (a%e o$ %heophylline #lea(an#e may 2e &ose,&epen&en% 0i'e', s%ea&y,s%a%e se()m #on#en%(a%ions may in#(ease &isp(opo(%iona%ely %o %he in#(ease in &ose1, an in#(ease in &ose 2ase& )pon a s)2,%he(ape)%i# se()m #on#en%(a%ion meas)(emen% sho)l& 2e #onse(7a%i7e' In +ene(al, limi%in+ in$)sion (a%e in#(eases %o a2o)% 5F o$ %he p(e7io)s in$)sion (a%e *ill (e&)#e %he (is> o$ )nin%en&e& ex#essi7e in#(eases in se()m %heophylline #on#en%(a%ion 0see DOSA<E AND ADMINISTRATION, Ta2le @I1' PRECAUTIONS <ene(al! Ca(e$)l #onsi&e(a%ion o$ %he 7a(io)s in%e(a#%in+ &()+s an& physiolo+i# #on&i%ions %ha% #an al%e( %heophylline

#lea(an#e an& (e6)i(e &osa+e a&:)s%men% sho)l& o##)( p(io( %o ini%ia%ion o$ %heophylline %he(apy an& p(io( %o in#(eases in %heophylline &ose 0see 9ARNIN<S1' E$$e#%s on La2o(a%o(y Tes%s! As a (es)l% o$ i%s pha(ma#olo+i#al e$$e#%s, %heophylline a% se()m #on#en%(a%ions *i%hin %he "4, 4 m#+BmL (an+e mo&es%ly in#(eases plasma +l)#ose 0$(om a mean o$ ;; m+F %o 8; m+F1, )(i# a#i& 0$(om a mean o$ 3 m+B&l %o - m+B&l1, $(ee $atty acids (from a mean of 451 q/l to 800 q/l), total cholesterol (from a mean of 140 vs 160 mg/dl), HD (from a mean of !6 to 50 mg/dl), HD / D ratio (from a mean of 0"5 to 0"#), and $rinary free cortisol e%cretion (from a mean of 44 to 6! mcg/&4 hr)' Theophylline a% se()m #on#en%(a%ions *i%hin %he "4, 4 m#+BmL (an+e may also %(ansien%ly &e#(ease se()m #on#en%(a%ions o$ %(iio&o%hy(onine 0"33 2e$o(e, "." a$%e( one *ee> an& "3 n+B&l a$%e( 3 *ee>s o$ %heophylline1' The #lini#al impo(%an#e o$ %hese #han+es sho)l& 2e *ei+he& a+ains% %he po%en%ial %he(ape)%i# 2ene$i% o$ %heophylline in in&i7i&)al pa%ien%s' D()+ In%e(a#%ions! Theophylline in%e(a#%s *i%h a *i&e 7a(ie%y o$ &()+s' The in%e(a#%ion may 2e pha(ma#o&ynami#, i'e', al%e(a%ions in %he %he(ape)%i# (esponse %o %heophylline o( ano%he( &()+ o( o##)((en#e o$ a&7e(se e$$e#%s *i%ho)% a #han+e in se()m %heophylline #on#en%(a%ion' Mo(e $(e6)en%ly, ho*e7e(, %he in%e(a#%ion is pha(ma#o>ine%i#, i'e', %he (a%e o$ %heophylline #lea(an#e is al%e(e& 2y ano%he( &()+ (es)l%in+ in in#(ease& o( &e#(ease& se()m %heophylline #on#en%(a%ions' Theophylline only (a(ely al%e(s %he pha(ma#o>ine%i#s o$ o%he( &()+s' The &()+s )le& in Ta2le II ha7e %he po%en%ial %o p(o&)#e #lini#ally si+ni$i#an% pha(ma#o&ynami# o( pha(ma#o>ine%i# in%e(a#%ions *i%h %heophylline' The in$o(ma%ion in %he GGE$$e#%HH #ol)mn o$ Ta2le II ass)mes %ha% %he in%e(a#%in+ &()+ is 2ein+ a&&e& %o a s%ea&y,s%a%e %heophylline (e+imen' I$ %heophylline is 2ein+ ini%ia%e& in a pa%ien% *ho is al(ea&y %a>in+ a &()+ %ha% inhi2i%s %heophylline #lea(an#e 0e'+', #ime%i&ine, e(y%h(omy#in1, %he &ose o$ %heophylline (e6)i(e& %o a#hie7e a %he(ape)%i# se()m %heophylline #on#en%(a%ion *ill 2e smalle(' Con7e(sely, i$ %heophylline is 2ein+ ini%ia%e& in a pa%ien% *ho is al(ea&y %a>in+ a &()+ %ha% enhan#es %heophylline #lea(an#e 0e'+', (i$ampin1, %he &ose o$ %heophylline (e6)i(e& %o a#hie7e a %he(ape)%i# se()m %heophylline #on#en%(a%ion *ill 2e la(+e(' Dis#on%in)a%ion o$ a #on#omi%an% &()+ %ha% in#(eases %heophylline #lea(an#e *ill (es)l% in a##)m)la%ion o$ %heophylline %o po%en%ially %oxi# le7els, )nless %he %heophylline &ose is app(op(ia%ely (e&)#e&' Dis#on%in)a%ion o$ a #on#omi%an% &()+ %ha% inhi2i%s %heophylline #lea(an#e *ill (es)l% in &e#(ease& se()m %heophylline #on#en%(a%ions, )nless %he %heophylline &ose is app(op(ia%ely in#(ease&' The &()+s )le& in Ta2le III ha7e ei%he( 2een &o#)men%e& no% %o in%e(a#% *i%h %heophylline o( &o no% p(o&)#e a #lini#ally si+ni$i#an% in%e(a#%ion 0i'e', E"5F #han+e in %heophylline #lea(an#e1' The )lin+ o$ &()+s in Ta2les II an& III a(e #)((en% as o$ Sep%em2e( ", "885' Ne* in%e(a#%ions a(e #on%in)o)sly 2ein+ (epo(%e& $o( %heophylline, espe#ially *i%h ne* #hemi#al en%i%ies' The #lini#ian sho)l& no% ass)me %ha% a &()+ &oes no% in%e(a#% *i%h %heophylline i$ i% is no% )le& in Ta2le II' Ae$o(e a&&i%ion o$ a ne*ly a7aila2le &()+ in a pa%ien% (e#ei7in+ %heophylline, %he pa#>a+e inse(% o$ %he ne* &()+ an&Bo( %he me&i#al li%e(a%)(e sho)l& 2e #ons)l%e& %o &e%e(mine i$ an in%e(a#%ion 2e%*een %he ne* &()+ an& %heophylline has 2een (epo(%e&' Ta2le II' Clini#ally si+ni$i#an% &()+ in%e(a#%ions *i%h %heophyllineI'D()+ Type o$ In%e(a#%ion E$$e#%II A&enosine Theophylline 2lo#>s a&enosine (e#ep%o(s' Hi+he( &oses o$ a&enosine may 2e (e6)i(e& %o a#hie7e &esi(e& e$$e#%' Al#ohol A sin+le la(+e &ose o$ al#ohol 0. mLB>+ o$ *his>ey1 &e#(eases %heophylline #lea(an#e $o( )p %o 3 ho)(s' .4F in#(ease Allop)(inol De#(eases %heophylline #lea(an#e a% allop)(inol &oses J -44 m+B&ay' 5F in#(ease Amino+l)%e%himi&e In#(eases %heophylline #lea(an#e 2y in&)#%ion o$ mi#(osomal en?yme a#%i7i%y' 5F &e#(ease Ca(2ama?epine Simila( %o amino+l)%e%himi&e' .4F &e#(ease Cime%i&ine De#(eases %heophylline #lea(an#e 2y inhi2i%in+ #y%o#h(ome P354 "A ' /4F in#(ease Cip(o$loxa#in Simila( %o #ime%i&ine' 34F in#(ease Cla(i%h(omy#in Simila( %o e(y%h(omy#in' 5F in#(ease

Dia?epam Aen?o&ia?epines in#(ease CNS #on#en%(a%ions o$ a&enosine, a po%en% CNS &ep(essan% *hile %heophylline 2lo#>s a&enosine (e#ep%o(s' La(+e( &ia?epam &oses may 2e (e6)i(e& %o p(o&)#e &esi(e& le7el o$ se&a%ion' Dis#on%in)a%ion o$ %heophylline *i%ho)% (e&)#%ion o$ &ia?epam &ose may (es)l% in (espi(a%o(y &ep(ession' Dis)l$i(am De#(eases %heophylline #lea(an#e 2y inhi2i%in+ hy&(oxyla%ion an& &eme%hyla%ion' 54F in#(ease Enoxa#in Simila( %o #ime%i&ine' .44F in#(ease Ephe&(ine Syne(+is%i# CNS e$$e#%s In#(ease& $(e6)en#y o$ na)sea, ne(7o)sness, an& insomnia' E(y%h(omy#in E(y%h(omy#in me%a2oli%e &e#(eases %heophylline #lea(an#e 2y inhi2i%in+ #y%o#h(ome P354 .A.' .5F in#(ease E(y%h(omy#in s%ea&y,s%a%e se()m #on#en%(a%ions &e#(ease 2y a simila( amo)n%' Es%(o+en Es%(o+en #on%ainin+ o(al #on%(a#ep%i7es &e#(ease %heophylline #lea(an#e in a &ose, &epen&en% $ashion' The e$$e#% o$ p(o+es%e(one on %heophylline #lea(an#e is )n>no*n' .4F in#(ease Kl)(a?epam Simila( %o &ia?epam' Simila( %o &ia?epam' Kl)7oxamine Simila( %o #ime%i&ine Simila( %o #ime%i&ine Halo%hane Halo%hane sensi%i?es %he myo#a(&i)m %o #a%e#holamines, %heophylline in#(eases (elease o$ en&o+eno)s #a%e#holamines' In#(ease& (is> o$ 7en%(i#)la( a((hy%hmias' In%e($e(on, h)man (e#om2inan% alpha,A De#(eases %heophylline #lea(an#e' "44F in#(ease Isop(o%e(enol 0I@1 In#(eases %heophylline #lea(an#e' 4F &e#(ease Le%amine Pha(ma#olo+i# May lo*e( %heophylline sei?)(e %h(eshol&' Li%hi)m Theophylline in#(eases (enal li%hi)m #lea(an#e' Li%hi)m &ose (e6)i(e& %o a#hie7e a %he(ape)%i# se()m #on#en%(a%ion in#(ease& an a7e(a+e o$ -4F' Lo(a?epam Simila( %o &ia?epam' Simila( %o &ia?epam' Me%ho%(exa%e 0MTM1 De#(eases %heophylline #lea(an#e 4F in#(ease a$%e( lo* &ose MTM, hi+he( &ose MTM may ha7e a +(ea%e( e$$e#%' Mexile%ine Simila( %o &is)l$i(am' ;4F in#(ease Mi&a?olam Simila( %o &ia?epam' Simila( %o &ia?epam' Mo(i#i?ine In#(eases %heophylline #lea(an#e' 5F &e#(ease Pan#)(oni)m Theophylline may an%a+oni?e non,&epola(i?in+ ne)(om)s#)la( 2lo#>in+ e$$e#%s= possi2ly &)e %o phospho&ies%e(ase inhi2i%ion' La(+e( &ose o$ pan#)(oni)m may 2e (e6)i(e& %o a#hie7e ne)(om)s#)la( 2lo#>a&e' Pen%oxi$ylline De#(eases %heophylline #lea(an#e' .4F in#(ease Pheno2a(2i%al 0PA1 Simila( %o amino+l)%e%himi&e' 5F &e#(ease a$%e( %*o *ee>s o$ #on#)((en% PA' Pheny%oin Pheny%oin in#(eases %heophylline #lea(an#e 2y in#(easin+ mi#(osomal en?yme a#%i7i%y' Se()m %heophylline an& pheny%oin #on#en%(a%ions &e#(ease a2o)% 34F' Theophylline &e#(eases pheny%oin a2so(p%ion' P(opa$enone De#(eases %heophylline #lea(an#e an& pha(ma#olo+i# in%e(a#%ion' 34F in#(ease' Ae%a, 2lo#>in+ e$$e#% may &e#(ease e$$i#a#y o$ %heophylline' P(op(anolol Simila( %o #ime%i&ine an& pha(ma#olo+i# in%e(a#%ion' "44F in#(ease' Ae%a, 2lo#>in+ e$$e#% may &e#(ease e$$i#a#y o$ %heophylline' Ri$ampin In#(eases %heophylline #lea(an#e 2y in#(easin+ #y%o#h(ome P354 "A an& .A. a#%i7i%y' 4,34F &e#(ease S)l$inpy(a?one In#(eases %heophylline #lea(an#e 2y in#(easin+ &eme%hyla%ion an& hy&(oxyla%ion' De#(eases (enal #lea(an#e o$ %heophylline' 4F &e#(ease Ta#(ine Simila( %o #ime%i&ine, also in#(eases (enal #lea(an#e o$ %heophylline' 84F in#(ease Thia2en&a?ole De#(eases %heophylline #lea(an#e' "84F in#(ease Ti#lopi&ine De#(eases %heophylline #lea(an#e' -4F in#(ease T(olean&omy#in Simila( %o e(y%h(omy#in' ..,"44F in#(ease &epen&in+ on %(olean&omy#in &ose' @e(apamil Simila( %o &is)l$i(am' 4F in#(ease I Re$e( %o PRECAUTIONS, D()+ In%e(a#%ions $o( $)(%he( in$o(ma%ion (e+a(&in+ %a2le' II A7e(a+e e$$e#% on s%ea&y s%a%e %heophylline #on#en%(a%ion o( o%he( #lini#al e$$e#% $o( pha(ma#olo+i# in%e(a#%ions' In&i7i&)al pa%ien%s may expe(ien#e la(+e( #han+es in se()m %heophylline #on#en%(a%ion %han %he 7al)e )le&'

Ta2le III' D()+s %ha% ha7e 2een &o#)men%e& no% %o in%e(a#% *i%h %heophylline o( &()+s %ha% p(o&)#e no #lini#ally si+ni$i#an% in%e(a#%ion *i%h %heophylline'Ial2)%e(ol, $elo&ipine no($loxa#in sys%emi# an& inhale& $inas%e(i&e o$loxa#in amoxi#illin hy&(o#o(%isone omep(a?ole ampi#illin, iso$l)(ane p(e&nisone, p(e&nisolone *i%h o( *i%ho)% s)l2a#%am isonia?i& (ani%i&ine a%enolol is(a&ipine (i$a2)%in a?i%h(omy#in in$l)en?a 7a##ine (oxi%h(omy#in #a$$eine, >e%o#ona?ole so(2i%ol &ie%a(y in+es%ionlome$loxa#in 0p)(+a%i7e &oses &o no% #e$a#lo( me2en&a?ole inhi2i% %heophylline #o,%(imoxa?ole me&(oxyp(o+es%e(one a2so(p%ion1 0%(ime%hop(im me%hylp(e&nisolone s)#(al$a%e s)l$ame%hoxa?ole1 me%(oni&a?ole %e(2)%aline, sys%emi# &il%ia?em me%op(olol %e($ena&ine &i(i%h(omy#in na&olol %e%(a#y#line en$l)(ane ni$e&ipine %o#aini&e $amo%i&ine ni?a%i&ine I Re$e( %o PRECAUTIONS, D()+ In%e(a#%ions $o( in$o(ma%ion (e+a(&in+ %a2le' The E$$e#% o$ O%he( D()+s on Theophylline Se()m Con#en%(a%ion Meas)(emen%s! Mos% se()m %heophylline assays in #lini#al )se a(e imm)noassays *hi#h a(e spe#i$i# $o( %heophylline' O%he( xan%hines s)#h as #a$$eine, &yphylline, an& pen%oxi$ylline a(e no% &e%e#%e& 2y %hese assays' Some &()+s 0e'+', #e$a?olin, #ephalo%hin1, ho*e7e(, may in%e($e(e *i%h #e(%ain HPLC %e#hni6)es' Ca$$eine an& xan%hine me%a2oli%es in neona%es o( pa%ien%s *i%h (enal &ys$)n#%ion may #a)se %he (ea&in+ $(om some &(y (ea+en% o$$i#e me%ho&s %o 2e hi+he( %han %he a#%)al se()m %heophylline #on#en%(a%ion' Ca(#ino+enesis, M)%a+enesis, an& Impai(men% o$ Ke(%ili%y! Lon+ %e(m #a(#ino+eni#i%y s%)&ies ha7e 2een #a((ie& o)% in mi#e 0o(al &oses .4,"54 m+B>+1 an& (a%s 0o(al &oses 5,/5 m+B>+1' Res)l%s a(e pen&in+' Theophylline has 2een s%)&ie& in Ames salmonella, in 7i7o an& in 7i%(o #y%o+ene%i#s, mi#(on)#le)s an& Chinese hams%e( o7a(y %es% sys%ems an& has no% 2een sho*n %o 2e +eno%oxi#' In a "3 *ee> #on%in)o)s 2(ee&in+ s%)&y, %heophylline, a&minis%e(e& %o ma%in+ pai(s o$ A-C.K" mi#e a% o(al &oses o$ " 4, /4 an& 544 m+B>+ 0app(oxima%ely "'4, .'4 %imes %he h)man &ose on a m+Bm 2asis1 impai(e& $e(%ili%y, as e7i&en#e& 2y &e#(eases in %he n)m2e( o$ li7e p)ps pe( li%%e(, &e#(eases in %he mean n)m2e( o$ li%%e(s pe( $e(%ile pai(, an& in#(eases in %he +es%a%ion pe(io& a% %he hi+h &ose as *ell as &e#(eases in %he p(opo(%ion o$ p)ps 2o(n ali7e a% %he mi& an& hi+h &ose' In ". *ee> %oxi#i%y s%)&ies, %heophylline *as a&minis%e(e& %o K.33 (a%s an& A-C.K" mi#e a% o(al &oses o$ 34,.44 m+B>+ 0app(oxima%ely '4 %imes %he h)man &ose on a m+Bm 2asis1' A% %he hi+h &ose, sys%emi# %oxi#i%y *as o2se(7e& in 2o%h spe#ies in#l)&in+ &e#(eases in %es%i#)la( *ei+h%' P(e+nan#y! N)(sin+ Mo%he(s! Theophylline is ex#(e%e& in%o 2(eas% mil> an& may #a)se i((i%a2ili%y o( o%he( si+ns o$ mil& %oxi#i%y in n)(sin+ h)man in$an%s' The #on#en%(a%ion o$ %heophylline in 2(eas% mil> is a2o)% e6)i7alen% %o %he ma%e(nal se()m #on#en%(a%ion' An in$an% in+es%in+ a li%e( o$ 2(eas% mil> #on%ainin+ "4, 4 m#+BmL o$ %heophylline pe( &ay is li>ely %o (e#ei7e "4, 4 m+ o$ %heophylline pe( &ay' Se(io)s a&7e(se e$$e#%s in %he in$an% a(e )nli>ely )nless %he mo%he( has %oxi# se()m %heophylline #on#en%(a%ions' Pe&ia%(i# Use! Theophylline is sa$e an& e$$e#%i7e $o( %he app(o7e& in&i#a%ions in #hil&(en 0See INDICATIONS AND USA<E1' The #ons%an% in$)sion (a%e o$ in%(a7eno)s %heophylline m)s% 2e sele#%e& *i%h #a)%ion in #hil&(en

sin#e %he (a%e o$ %heophylline #lea(an#e is hi+hly 7a(ia2le a#(oss %he a+e (an+e o$ neona%es %o a&oles#en%s 0see CLINICAL PHARMACOLO<Y, Ta2le I, 9ARNIN<S, an& DOSA<E AND ADMINISTRATION, Ta2le @1' D)e %o %he imma%)(i%y o$ %heophylline me%a2oli# pa%h*ays in #hil&(en )n&e( %he a+e o$ one yea(, pa(%i#)la( a%%en%ion %o &osa+e sele#%ion an& $(e6)en% moni%o(in+ o$ se()m %heophylline #on#en%(a%ions a(e (e6)i(e& *hen %heophylline is p(es#(i2e& %o #hil&(en in %his a+e +(o)p' <e(ia%(i# Use! El&e(ly pa%ien%s a(e a% si+ni$i#an%ly +(ea%e( (is> o$ expe(ien#in+ se(io)s %oxi#i%y $(om %heophylline %han yo)n+e( pa%ien%s &)e %o pha(ma#o>ine%i# an& pha(ma#o&ynami# #han+es asso#ia%e& *i%h a+in+' Theophylline #lea(an#e is (e&)#e& in pa%ien%s +(ea%e( %han -4 yea(s o$ a+e, (es)l%in+ in in#(ease& se()m %heophylline #on#en%(a%ions in (esponse %o a +i7en %heophylline in$)sion (a%e' P(o%ein 2in&in+ may 2e &e#(ease& in %he el&e(ly (es)l%in+ in a la(+e( p(opo(%ion o$ %he %o%al se()m %heophylline #on#en%(a%ion in %he pha(ma#olo+i#ally a#%i7e )n2o)n& $o(m' El&e(ly pa%ien%s also appea( %o 2e mo(e sensi%i7e %o %he %oxi# e$$e#%s o$ %heophylline a$%e( #h(oni# o7e(&osa+e %han yo)n+e( pa%ien%s' Ko( %hese (easons, %he maxim)m in$)sion (a%e o$ %heophylline in pa%ien%s +(ea%e( %han -4 yea(s o$ a+e o(&ina(ily sho)l& no% ex#ee& "/ m+Bh( 0 " m+Bh( as aminophylline1 )nless %he pa%ien% #on%in)es %o 2e symp%oma%i# an& %he s%ea&y s%a%e se()m %heophylline #on#en%(a%ion is E"4 m#+BmL 0see DOSA<E AND ADMINISTRATION1' Theophylline in$)sion (a%es +(ea%e( %han "/ m+Bh( 0 " m+Bh( as aminophylline1 sho)l& 2e p(es#(i2e& *i%h #a)%ion in el&e(ly pa%ien%s' AD@ERSE REACTIONS A&7e(se (ea#%ions asso#ia%e& *i%h %heophylline a(e +ene(ally mil& *hen se()m %heophylline #on#en%(a%ions a(e E 4 m#+BmL an& mainly #onsis% o$ %(ansien% #a$$eine,li>e a&7e(se e$$e#%s s)#h as na)sea, 7omi%in+, hea&a#he, an& insomnia' 9hen se()m %heophylline #on#en%(a%ions ex#ee& 4 m#+BmL, ho*e7e(, %heophylline p(o&)#es a *i&e (an+e o$ a&7e(se (ea#%ions in#l)&in+ pe(sis%en% 7omi%in+, #a(&ia# a((hy%hmias, an& in%(a#%a2le sei?)(es *hi#h #an 2e le%hal 0see O@ERDOSA<E1' O%he( a&7e(se (ea#%ions %ha% ha7e 2een (epo(%e& a% se()m %heophylline #on#en%(a%ions E 4 m#+BmL in#l)&e &ia((hea, i((i%a2ili%y, (es%lessness, $ine s>ele%al m)s#le %(emo(s, an& %(ansien% &i)(esis' In pa%ien%s *i%h hypoxia se#on&a(y %o COPD, m)l%i$o#al a%(ial %a#hy#a(&ia an& $l)%%e( ha7e 2een (epo(%e& a% se()m %heophylline #on#en%(a%ions J "5 m#+BmL' The(e ha7e 2een a $e* isola%e& (epo(%s o$ sei?)(es a% se()m %heophylline #on#en%(a%ions E 4 m#+BmL in pa%ien%s *i%h an )n&e(lyin+ ne)(olo+i#al &isease o( in el&e(ly pa%ien%s' The o##)((en#e o$ sei?)(es in el&e(ly pa%ien%s *i%h se()m %heophylline #on#en%(a%ions E 4 m#+BmL may 2e se#on&a(y %o &e#(ease& p(o%ein 2in&in+ (es)l%in+ in a la(+e( p(opo(%ion o$ %he %o%al se()m %heophylline #on#en%(a%ion in %he pha(ma#olo+i#ally a#%i7e )n2o)n& $o(m' The #lini#al #ha(a#%e(is%i#s o$ %he sei?)(es (epo(%e& in pa%ien%s *i%h se()m %heophylline #on#en%(a%ions E 4 m#+BmL ha7e +ene(ally 2een mil&e( %han sei?)(es asso#ia%e& *i%h ex#essi7e se()m %heophylline #on#en%(a%ions (es)l%in+ $(om an o7e(&ose 0i'e', %hey ha7e +ene(ally 2een %(ansien%, o$%en s%oppe& *i%ho)% an%i#on7)lsan% %he(apy, an& &i& no% (es)l% in ne)(olo+i#al (esi&)a1' P(o&)#%s #on%ainin+ aminophylline may (a(ely p(o&)#e se7e(e alle(+i# (ea#%ions o$ %he s>in, in#l)&in+ ex$olia%i7e &e(ma%i%is, a$%e( sys%emi# a&minis%(a%ion in a pa%ien% *ho has 2een p(e7io)sly sensi%i?e& 2y %opi#al appli#a%ion o$ a s)2s%an#e #on%ainin+ e%hylene&iamine' In s)#h pa%ien%s s>in pa%#h %es%s a(e posi%i7e $o( e%hylene&iamine, a #omponen% o$ aminophylline, an& ne+a%i7e $o( %heophylline' Pha(ma#is%s an& o%he( in&i7i&)als *ho expe(ien#e (epea%e& s>in expos)(e *hile physi#ally han&lin+ aminophylline may &e7elop a #on%a#% &e(ma%i%is &)e %o %he e%hylene&iamine #omponen%' Ta2le I@' Mani$es%a%ions o$ %heophylline %oxi#i%y'I Pe(#en%a+e o$ pa%ien%s (epo(%e&*i%h si+n o( symp%om A#)%e O7e(&ose 0La(+e Sin+le In+es%ion1 Ch(oni# O7e(&osa+e 0M)l%iple Ex#essi7e Doses1 S%)&y " S%)&y S%)&y " S%)&y Si+nBSymp%om 0nN"5/1 0nN"31 0nN8 1 0nN"4 1 Asymp%oma%i# NRII 4 NRII <as%(oin%es%inal @omi%in+ /. 8. .4 -" A2&ominal Pain NRII " NRII "

Dia((hea NRII 4 NRII Hema%emesis NRII 4 NRII Me%a2oli#BO%he( Hypo>alemia ;5 /8 33 Hype(+ly#emia 8; NRII A#i&B2ase &is%)(2an#e .3 " Rha2&omyolysis NRII / Ca(&io7as#)la( Sin)s %a#hy#a(&ia "44 ;O%he( s)p(a7en%(i#)la( %a#hy#a(&ias @en%(i#)la( p(ema%)(e 2ea%s . A%(ial $i2(illa%ion o( $l)%%e( " M)l%i$o#al a%(ial %a#hy#a(&ia 4 @en%(i#)la( a((hy%hmias *i%h / hemo&ynami# ins%a2ili%y Hypo%ensionBsho#> NRII " Ne)(olo+i# Ne(7o)sness NRII -3 NRII T(emo(s .; 8 "Diso(ien%a%ion NRII / NRII Sei?)(es 5 "3 "3 Dea%h . " "4 3

"3 3. "; 8 NRII "44 " NRII NRII "3 NRII " "3 "" 5

NRII 5 4 " "4 " 34 ; " "8 NRII NRII 4 "3

I These &a%a a(e &e(i7e& $(om %*o s%)&ies in pa%ien%s *i%h se()m %heophylline #on#en%(a%ions C.4 m#+BmL' In %he $i(s% s%)&y 0S%)&y O" , Shanon, Ann In%e(n Me& "88.=""8!""-",-/1, &a%a *e(e p(ospe#%i7ely #olle#%e& $(om 38 #onse#)%i7e #ases o$ %heophylline %oxi#i%y (e$e((e& %o a (e+ional poison #en%e( $o( #ons)l%a%ion' In %he se#on& s%)&y 0S%)&y O , Sessle(, Am J Me& "884=;;!5-/,/-1, &a%a *e(e (e%(ospe#%i7ely #olle#%e& $(om ""- #ases *i%h se()m %heophylline #on#en%(a%ions C.4 m#+BmL amon+ -444 2loo& samples o2%aine& $o( meas)(emen% o$ se()m %heophylline #on#en%(a%ions in %h(ee eme(+en#y &epa(%men%s' Di$$e(en#es in %he in#i&en#e o$ mani$es%a%ions o$ %heophylline %oxi#i%y 2e%*een %he %*o s%)&ies may (e$le#% sample sele#%ion as a (es)l% o$ s%)&y &esi+n 0e'+', in S%)&y O", 3;F o$ %he pa%ien%s ha& a#)%e in%oxi#a%ions 7e(s)s only "4F in S%)&y O 1 an& &i$$e(en% me%ho&s o$ (epo(%in+ (es)l%s' II NR N No% (epo(%e& in a #ompa(a2le manne(' O@ERDOSA<E <ene(al! The #h(oni#i%y an& pa%%e(n o$ %heophylline o7e(&osa+e si+ni$i#an%ly in$l)en#es #lini#al mani$es%a%ions o$ %oxi#i%y, mana+emen% an& o)%#ome' The(e a(e %*o #ommon p(esen%a%ions! 0"1 a#)%e o7e(&ose, i'e', in$)sion o$ an ex#essi7e loa&in+ &ose o( ex#essi7e main%enan#e in$)sion (a%e $o( less %han 3 ho)(s, an& 0 1 #h(oni# o7e(&osa+e, i'e', ex#essi7e main%enan#e in$)sion (a%e $o( +(ea%e( %han 3 ho)(s' The mos% #ommon #a)ses o$ #h(oni# %heophylline o7e(&osa+e in#l)&e #lini#ian p(es#(i2in+ o$ an ex#essi7e &ose o( a no(mal &ose in %he p(esen#e o$ $a#%o(s >no*n %o &e#(ease %he (a%e o$ %heophylline #lea(an#e an& in#(easin+ %he &ose in (esponse %o an exa#e(2a%ion o$ symp%oms *i%ho)% $i(s% meas)(in+ %he se()m %heophylline #on#en%(a%ion %o &e%e(mine *he%he( a &ose in#(ease is sa$e' Se7e(al s%)&ies ha7e &es#(i2e& %he #lini#al mani$es%a%ions o$ %heophylline o7e(&ose $ollo*in+ o(al a&minis%(a%ion an& a%%emp%e& %o &e%e(mine %he $a#%o(s %ha% p(e&i#% li$e,%h(ea%enin+ %oxi#i%y' In +ene(al, pa%ien%s *ho expe(ien#e an a#)%e o7e(&ose a(e less li>ely %o expe(ien#e sei?)(es %han pa%ien%s *ho ha7e expe(ien#e& a #h(oni# o7e(&osa+e, )nless %he pea> se()m %heophylline #on#en%(a%ion is C"44 m#+BmL' A$%e( a #h(oni# o7e(&osa+e, +ene(ali?e& sei?)(es, li$e,%h(ea%enin+ #a(&ia# a((hy%hmias, an& &ea%h may o##)( a% se()m %heophylline #on#en%(a%ions C .4 m#+BmL' The se7e(i%y o$ %oxi#i%y a$%e( #h(oni# o7e(&osa+e is mo(e s%(on+ly #o((ela%e& *i%h %he pa%ien%Ds a+e %han %he pea> se()m %heophylline #on#en%(a%ion= pa%ien%s C -4 yea(s a(e a% %he +(ea%es% (is> $o( se7e(e %oxi#i%y an& mo(%ali%y a$%e( a #h(oni# o7e(&osa+e' P(e,exis%in+ o( #on#)((en% &isease may also si+ni$i#an%ly in#(ease %he s)s#ep%i2ili%y o$ a pa%ien% %o a pa(%i#)la( %oxi#

mani$es%a%ion, e'+', pa%ien%s *i%h ne)(olo+i# &iso(&e(s ha7e an in#(ease& (is> o$ sei?)(es an& pa%ien%s *i%h #a(&ia# &isease ha7e an in#(ease& (is> o$ #a(&ia# a((hy%hmias $o( a +i7en se()m %heophylline #on#en%(a%ion #ompa(e& %o pa%ien%s *i%ho)% %he )n&e(lyin+ &isease' The $(e6)en#y o$ 7a(io)s (epo(%e& mani$es%a%ions o$ o(al %heophylline o7e(&ose a##o(&in+ %o %he mo&e o$ o7e(&ose a(e )le& in Ta2le I@' O%he( mani$es%a%ions o$ %heophylline %oxi#i%y in#l)&e in#(eases in se()m #al#i)m, #(ea%ine >inase, myo+lo2in an& le)>o#y%e #o)n%, &e#(eases in se()m phospha%e an& ma+nesi)m, a#)%e myo#a(&ial in$a(#%ion, an& )(ina(y (e%en%ion in men *i%h o2s%()#%i7e )(opa%hy' Sei?)(es asso#ia%e& *i%h se()m %heophylline #on#en%(a%ions C.4 m#+BmL a(e o$%en (esis%an% %o an%i#on7)lsan% %he(apy an& may (es)l% in i((e7e(si2le 2(ain in:)(y i$ no% (api&ly #on%(olle&' Dea%h $(om %heophylline %oxi#i%y is mos% o$%en se#on&a(y %o #a(&io(espi(a%o(y a((es% an&Bo( hypoxi# en#ephalopa%hy $ollo*in+ p(olon+e& +ene(ali?e& sei?)(es o( in%(a#%a2le #a(&ia# a((hy%hmias #a)sin+ hemo&ynami# #omp(omise' O7e(&ose Mana+emen%! Spe#i$i# Re#ommen&a%ions! Ex%(a#o(po(eal Remo7al! In#(easin+ %he (a%e o$ %heophylline #lea(an#e 2y ex%(a#o(po(eal me%ho&s may (api&ly &e#(ease se()m #on#en%(a%ions, 2)% %he (is>s o$ %he p(o#e&)(e m)s% 2e *ei+he& a+ains% %he po%en%ial 2ene$i%' Cha(#oal hemope($)sion is %he mos% e$$e#%i7e me%ho& o$ ex%(a#o(po(eal (emo7al, in#(easin+ %heophylline #lea(an#e )p %o six,$ol&, 2)% se(io)s #ompli#a%ions, in#l)&in+ hypo%ension, hypo#al#emia, pla%ele% #ons)mp%ion an& 2lee&in+ &ia%heses may o##)(' Hemo&ialysis is a2o)% as e$$i#ien% as m)l%iple,&ose o(al a#%i7a%e& #ha(#oal an& has a lo*e( (is> o$ se(io)s #ompli#a%ions %han #ha(#oal hemope($)sion' Hemo&ialysis sho)l& 2e #onsi&e(e& as an al%e(na%i7e *hen #ha(#oal hemope($)sion is no% $easi2le an& m)l%iple,&ose o(al #ha(#oal is ine$$e#%i7e 2e#a)se o$ in%(a#%a2le emesis' Se()m %heophylline #on#en%(a%ions may (e2o)n& 5,"4 m#+BmL a$%e( &is#on%in)a%ion o$ #ha(#oal hemope($)sion o( hemo&ialysis &)e %o (e&is%(i2)%ion o$ %heophylline $(om %he %iss)e #ompa(%men%' Pe(i%oneal &ialysis is ine$$e#%i7e $o( %heophylline (emo7al= ex#han+e %(ans$)sions in neona%es ha7e 2een minimally e$$e#%i7e' DOSA<E AND ADMINISTRATION <ene(al Consi&e(a%ions! The s%ea&y,s%a%e se()m %heophylline #on#en%(a%ion is a $)n#%ion o$ %he in$)sion (a%e an& %he (a%e o$ %heophylline #lea(an#e in %he in&i7i&)al pa%ien%' Ae#a)se o$ ma(>e& in&i7i&)al &i$$e(en#es in %he (a%e o$ %heophylline #lea(an#e, %he &ose (e6)i(e& %o a#hie7e a se()m %heophylline #on#en%(a%ion in %he "4, 4 m#+BmL (an+e 7a(ies $o)(,$ol& amon+ o%he(*ise simila( pa%ien%s in %he a2sen#e o$ $a#%o(s >no*n %o al%e( %heophylline #lea(an#e' Ko( a +i7en pop)la%ion %he(e is no sin+le %heophylline &ose %ha% *ill p(o7i&e 2o%h sa$e an& e$$e#%i7e se()m #on#en%(a%ions $o( all pa%ien%s' A&minis%(a%ion o$ %he me&ian %heophylline &ose (e6)i(e& %o a#hie7e a %he(ape)%i# se()m %heophylline #on#en%(a%ion in a +i7en pop)la%ion may (es)l% in ei%he( s)2,%he(ape)%i# o( po%en%ially %oxi# se()m %heophylline #on#en%(a%ions in in&i7i&)al pa%ien%s' The &ose o$ %heophylline m)s% 2e in&i7i&)ali?e& on %he 2asis o$ se()m %heophylline #on#en%(a%ion meas)(emen%s in o(&e( %o a#hie7e a &ose %ha% *ill p(o7i&e maxim)m po%en%ial 2ene$i% *i%h minimal (is> o$ a&7e(se e$$e#%s' 9hen %heophylline is )se& as an a#)%e 2(on#ho&ila%o(, %he +oal o$ o2%ainin+ a %he(ape)%i# se()m #on#en%(a%ion is 2es% a##omplishe& *i%h an in%(a7eno)s loa&in+ &ose' Ae#a)se o$ (api& &is%(i2)%ion in%o 2o&y $l)i&s, %he se()m #on#en%(a%ion 0C1 o2%aine& $(om an ini%ial loa&in+ &ose 0LD1 is (ela%e& p(ima(ily %o %he 7ol)me o$ &is%(i2)%ion 0@1, %he appa(en% spa#e in%o *hi#h %he &()+ &i$$)ses! C N LDB@ I$ a mean 7ol)me o$ &is%(i2)%ion o$ a2o)% 4'5 LB>+ is ass)me& 0a#%)al (an+e is 4'. %o 4'/ LB>+1, ea#h m+B>+ 0i&eal 2o&y *ei+h%1 o$ %heophylline a&minis%e(e& as a loa&in+ &ose o7e( .4 min)%es (es)l%s in an a7e(a+e m#+BmL in#(ease in se()m %heophylline #on#en%(a%ion' The(e$o(e, in a pa%ien% *ho has (e#ei7e& no %heophylline in %he p(e7io)s 3 ho)(s, a loa&in+ &ose o$ in%(a7eno)s %heophylline o$ 3'- m+B>+ 05'/ m+B>+ as

aminophylline1, #al#)la%e& on %he 2asis o$ i&eal 2o&y *ei+h% an& a&minis%e(e& o7e( .4 min)%es, on a7e(a+e, *ill p(o&)#e a maxim)m pos%,&is%(i2)%ion se()m #on#en%(a%ion o$ "4 m#+BmL *i%h a (an+e o$ -,"- m#+BmL' 9hen a loa&in+ &ose 2e#omes ne#essa(y in %he pa%ien% *ho has al(ea&y (e#ei7e& %heophylline, es%ima%ion o$ %he se()m #on#en%(a%ion 2ase& )pon %he his%o(y is )n(elia2le, an& an imme&ia%e se()m le7el &e%e(mina%ion is in&i#a%e&' The loa&in+ &ose #an %hen 2e &e%e(mine& as $ollo*s! D N 0Desi(e& C , Meas)(e& C10@1 *he(e D is %he loa&in+ &ose, C is %he se()m %heophylline #on#en%(a%ion, an& @ is %he 7ol)me o$ &is%(i2)%ion' The mean 7ol)me o$ &is%(i2)%ion #an 2e ass)me& %o 2e 4'5 LB>+ an& %he &esi(e& se()m #on#en%(a%ion sho)l& 2e #onse(7a%i7e 0e'+', "4 m#+BmL1 %o allo* $o( %he 7a(ia2ili%y in %he 7ol)me o$ &is%(i2)%ion' A loa&in+ &ose sho)l& no% 2e +i7en 2e$o(e o2%ainin+ a se()m %heophylline #on#en%(a%ion i$ %he pa%ien% has (e#ei7e& any %heophylline in %he p(e7io)s 3 ho)(s' A se()m #on#en%(a%ion o2%aine& .4 min)%es a$%e( an in%(a7eno)s loa&in+ &ose, *hen &is%(i2)%ion is #omple%e, #an 2e )se& %o assess %he nee& $o( an& si?e o$ s)2se6)en% loa&in+ &oses, i$ #lini#ally in&i#a%e&, an& $o( +)i&an#e o$ #on%in)in+ %he(apy' On#e a se()m #on#en%(a%ion o$ "4 %o "5 m#+BmL has 2een a#hie7e& *i%h %he )se o$ a loa&in+ &ose0s1, a #ons%an% in%(a7eno)s in$)sion is s%a(%e&' The (a%e o$ a&minis%(a%ion is 2ase& )pon mean pha(ma#o>ine%i# pa(ame%e(s $o( %he pop)la%ion an& #al#)la%e& %o a#hie7e a %a(+e% se()m #on#en%(a%ion o$ "4 m#+BmL 0see Ta2le @1' Ko( example, in non,smo>in+ a&)l%s, ini%ia%ion o$ a #ons%an% in%(a7eno)s %heophylline in$)sion o$ 4'3 m+B>+Bh( 04'5 m+B>+Bh( as aminophylline1 a% %he #omple%ion o$ %he loa&in+ &ose, on a7e(a+e, *ill (es)l% in a s%ea&y,s%a%e #on#en%(a%ion o$ "4 m#+BmL *i%h a (an+e o$ /, m#+BmL' The mean an& (an+e o$ s%ea&y,s%a%e se()m #on#en%(a%ions a(e simila( *hen %he a7e(a+e #hil& 0a+e " %o 8 yea(s1 is +i7en a loa&in+ &ose o$ 3'- m+B>+ %heophylline 05'/ m+B>+ as aminophylline1 $ollo*e& 2y a #ons%an% in%(a7eno)s in$)sion o$ 4'; m+B>+Bh( 0"'4 m+B>+Bh( as aminophylline1' Sin#e %he(e is la(+e in%e(pa%ien% 7a(ia2ili%y in %heophylline #lea(an#e, se()m #on#en%(a%ions *ill (ise o( $all *hen %he pa%ien%Ds #lea(an#e is si+ni$i#an%ly &i$$e(en% $(om %he mean pop)la%ion 7al)e )se& %o #al#)la%e %he ini%ial in$)sion (a%e' The(e$o(e, a se#on& se()m #on#en%(a%ion sho)l& 2e o2%aine& one expe#%e& hal$ li$e a$%e( s%a(%in+ %he #ons%an% in$)sion 0e'+', app(oxima%ely 3 ho)(s $o( #hil&(en a+e " %o 8 an& ; ho)(s $o( nonsmo>in+ a&)l%s= See Ta2le I $o( %he expe#%e& hal$ li$e in a&&i%ional pa%ien% pop)la%ions1 %o &e%e(mine i$ %he #on#en%(a%ion is a##)m)la%in+ o( &e#linin+ $(om %he pos% loa&in+ &ose le7el' I$ %he le7el is &e#linin+ as a (es)l% o$ a hi+he( %han a7e(a+e #lea(an#e, an a&&i%ional loa&in+ &ose #an 2e a&minis%e(e& an&Bo( %he in$)sion (a%e in#(ease&' In #on%(as%, i$ %he se#on& sample &emons%(a%es a hi+he( le7el, a##)m)la%ion o$ %he &()+ #an 2e ass)me&, an& %he in$)sion (a%e sho)l& 2e &e#(ease& 2e$o(e %he #on#en%(a%ion ex#ee&s 4 m#+BmL' An a&&i%ional sample is o2%aine& " %o 3 ho)(s la%e( %o &e%e(mine i$ $)(%he( a&:)s%men%s a(e (e6)i(e& an& %hen a% 3,ho)( in%e(7als %o a&:)s% $o( #han+es, i$ %hey o##)(' This empi(i# me%ho&, 2ase& )pon mean pha(ma#o>ine%i# pa(ame%e(s, *ill p(e7en% la(+e $l)#%)a%ions in se()m #on#en%(a%ion &)(in+ %he mos% #(i%i#al pe(io& o$ %he pa%ien%Ds #o)(se' In pa%ien%s *i%h #o( p)lmonale, #a(&ia# &e#ompensa%ion, o( li7e( &ys$)n#%ion, o( in %hose %a>in+ &()+s %ha% ma(>e&ly (e&)#e %heophylline #lea(an#e 0e'+', #ime%i&ine1, %he ini%ial %heophylline in$)sion (a%e sho)l& no% ex#ee& "/ m+Bh( 0 " m+Bh( as aminophylline1 )nless se()m #on#en%(a%ions #an 2e moni%o(e& a% 3,ho)( in%e(7als' In %hese pa%ien%s, 5 &ays may 2e (e6)i(e& 2e$o(e s%ea&y,s%a%e is (ea#he&' Theophylline &is%(i2)%es poo(ly in%o 2o&y $a%, %he(e$o(e, m+B>+ &ose sho)l& 2e #al#)la%e& on %he 2asis o$ i&eal 2o&y *ei+h%' Ta2le @ #on%ains ini%ial %heophylline in$)sion (a%es $ollo*in+ an app(op(ia%e loa&in+ &ose (e#ommen&e& $o( pa%ien%s in 7a(io)s a+e +(o)ps an& #lini#al #i(#)ms%an#es' Ta2le @I #on%ains (e#ommen&a%ions $o( $inal %heophylline &osa+e a&:)s%men% 2ase& )pon se()m %heophylline #on#en%(a%ions' Appli#a%ion o$ %hese +ene(al &osin+ (e#ommen&a%ions %o in&i7i&)al pa%ien%s m)s% %a>e in%o a##o)n% %he )ni6)e #lini#al #ha(a#%e(is%i#s o$ ea#h pa%ien%' In +ene(al, %hese (e#ommen&a%ions sho)l& se(7e as %he )ppe( limi% $o( &osa+e a&:)s%men%s in o(&e( %o &e#(ease %he (is> o$ po%en%ially se(io)s a&7e(se e7en%s asso#ia%e& *i%h )nexpe#%e& la(+e in#(eases in se()m %heophylline #on#en%(a%ion' Ta2le @' Ini%ial aminophylline in$)sion (a%es $ollo*in+ an app(op(ia%e loa&in+ &ose'Pa%ien% pop)la%ion A+e Aminophylline in$)sion (a%e 0m+B>+Bh(1IP

Neona%es Pos%na%al a+e )p %o 3 &ays "' / m+B>+ 6 " h 0"'4 m+B>+ 6 " h1IQ Pos%na%al a+e 2eyon& 3 &ays "'84 m+B>+ 6 " h 0"'5 m+B>+ 6 " h1IQ In$an%s -,5 *ee>s ol& m+B>+Bh(N0R4'44;SRa+e in *ee>sS T 4' "1B4'/8 0R4'44;SRa+e in *ee>sST4' "1I Yo)n+ #hil&(en ",8 yea(s "'4" m+B>+Bh( 04'; m+B>+Bh(1I Ol&e( #hil&(en 8," yea(s 4';8 m+B>+Bh( 04'/ m+B>+Bh(1I A&oles#en%s 0#i+a(e%%e o( ma(i:)ana smo>e(s1 " ,"- yea(s 4';8 m+B>+Bh( 04'/ m+B>+Bh(1I A&oles#en%s 0nonsmo>e(s1 " ,"- yea(s 4'-. m+B>+Bh( 04'5 m+B>+Bh(1IU A&)l%s 0o%he(*ise heal%hy nonsmo>e(s1 "-,-4 yea(s 4'5" m+B>+Bh( 04'3 m+B>+Bh(1IU El&e(ly C -4 yea(s 4'.; m+B>+Bh( 04'. m+B>+Bh(1IVV Ca(&ia# &e#ompensa%ion, #o( p)lmonale, li7e( &ys$)n#%ion, sepsis *i%h m)l%i, o(+an $ail)(e, o( sho#> 4' 5 m+B>+Bh( 04' m+B>+Bh(1IVV I E6)i7alen% Theophylline Dosa+e In&i#a%e& in Pa(en%hesis P Lo*e( ini%ial &osa+e may 2e (e6)i(e& $o( pa%ien%s (e#ei7in+ o%he( &()+s %ha% &e#(ease %heophylline #lea(an#e 0e'+', #ime%i&ine1' Q To a#hie7e a %a(+e% #on#en%(a%ion o$ /'5 m#+BmL $o( neona%al apnea U No% %o ex#ee& 844 m+B&ay, )nless se()m le7els in&i#a%e %he nee& $o( a la(+e( &ose' VV No% %o ex#ee& 344 m+B&ay, )nless se()m le7els in&i#a%e %he nee& $o( a la(+e( &ose' Ta2le @I' Kinal &osa+e a&:)s%men% +)i&e& 2y se()m %heophylline #on#en%(a%ion'Pea> Se()m Con#en%(a%ion Dosa+e A&:)s%men% E8'8 m#+BmL I$ symp%oms a(e no% #on%(olle& an& #)((en% &osa+e is %ole(a%e&, in#(ease in$)sion (a%e a2o)% 5F' Re#he#> se()m #on#en%(a%ion a$%e( " ho)(s in #hil&(en an& 3 ho)(s in a&)l%s $o( $)(%he( &osa+e a&:)s%men%' "4 %o "3'8 m#+BmL I$ symp%oms a(e #on%(olle& an& #)((en% &osa+e is %ole(a%e&, main%ain in$)sion (a%e an& (e#he#> se()m #on#en%(a%ion a% 3,ho)( in%e(7als'W I$ symp%oms a(e no% #on%(olle& an& #)((en% &osa+e is %ole(a%e& #onsi&e( a&&in+ a&&i%ional me&i#a%ion0s1 %o %(ea%men% (e+imen' "5,"8'8 m#+BmL Consi&e( "4F &e#(ease in in$)sion (a%e %o p(o7i&e +(ea%e( ma(+in o$ sa$e%y e7en i$ #)((en% &osa+e is %ole(a%e&'W 4, 3'8 m#+BmL De#(ease in$)sion (a%e 2y 5F e7en i$ no a&7e(se e$$e#%s a(e p(esen%' Re#he#> se()m #on#en%(a%ion a$%e( " ho)(s in #hil&(en an& 3 ho)(s in a&)l%s %o +)i&e $)(%he( &osa+e a&:)s%men%' 5,.4 m#+BmL S%op in$)sion $o( " ho)(s in #hil&(en an& 3 ho)(s in a&)l%s an& &e#(ease s)2se6)en% in$)sion (a%e a% leas% 5F e7en i$ no a&7e(se e$$e#%s a(e p(esen%' Re#he#> se()m #on#en%(a%ion a$%e( " ho)(s in #hil&(en an& 3 ho)(s in a&)l%s %o +)i&e $)(%he( &osa+e a&:)s%men%' I$ symp%oma%i#, s%op in$)sion an& #onsi&e( *he%he( o7e(&ose %(ea%men% is in&i#a%e& 0see (e#ommen&a%ions $o( #h(oni# o7e(&osa+e1' C.4 m#+BmL S%op %he in$)sion an& %(ea% o7e(&ose as in&i#a%e& 0see (e#ommen&a%ions $o( #h(oni# o7e(&osa+e1' I$ %heophylline is s)2se6)en%ly (es)me&, &e#(ease in$)sion (a%e 2y a% leas% 54F an& (e#he#> se()m #on#en%(a%ion a$%e( " ho)(s in #hil&(en an& 3 ho)(s in a&)l%s %o +)i&e $)(%he( &osa+e a&:)s%men%' W Dose (e&)#%ion an&Bo( se()m %heophylline #on#en%(a%ion meas)(emen% is in&i#a%e& *hene7e( a&7e(se e$$e#%s a(e p(esen%, physiolo+i# a2no(mali%ies %ha% #an (e&)#e %heophylline #lea(an#e o##)( 0e'+', s)s%aine& $e7e(1, o( a &()+ %ha% in%e(a#%s *i%h %heophylline is a&&e& o( &is#on%in)e& 0see 9ARNIN<S1' Pa(en%e(al &()+ p(o&)#%s sho)l& 2e inspe#%e& 7is)ally $o( pa(%i#)la%e ma%%e( an& &is#olo(a%ion p(io( %o a&minis%(a%ion, *hene7e( sol)%ion an& #on%aine( pe(mi%' HO9 SUPPLIED Aminophylline In:e#%ion, USP 0 5 m+BmL1 is a7aila2le as $ollo*s!NDC 45"/,.;"4, 5 Dose @ial 54 m+B"4 mL 0 5 m+BmL1 Pa#>e& in 2oxes o$ 5 NDC 45"/,.; 4, 5 4 mL Sin+le Dose @ial 544 m+B 4 mL 0 5 m+BmL1 Pa#>e& in 2oxes o$ 5 "4 mL Sin+le

PROTECT KROM LI<HT' Leep 7ials in #a(%on )n%il %ime o$ )se' S%o(e a% #on%(olle& (oom %empe(a%)(e "5X,.4XC 058X,;-XK1 0See USP1' Do no% )se i$ #(ys%als a(e p(esen%' SIN<LE DOSE CONTAINER' Dis#a(& )n)se& po(%ion' IN.;"4 Re7' -B88 M< O;88 AMERICAN RE<ENT LAAORATORIES, INC' SHIRLEY, NY ""8-/

h%%p!BB***'me&i#ineonline'#omB&()+sBAB ""/BAMINOPHYLLINE,INJECTION,USP'h%mlO%.45