AHFS teofilin

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86:16 Respiratory Smooth Muscle Relaxants

Theophyllines

Introduction

• Theophylline, a xanthine derivative, directly relaxes smooth muscle of the respiratory tract, producing relief of ronchospasm and increasing flo! rates and vital capacity"

Uses

• Bronchospasm

Theophylline is used as a ronchodilator in the symptomatic treatment of asthma and reversile ronchospasm that may occur in association !ith chronic ronchitis or emphysema"

AsthmaTheophylline is used as a ronchodilator in the symptomatic treatment of asthma" The drugrelieves the primary manifestations of asthma, including shortness of reath, !hee#ing anddyspnea, and improves pulmonary function as measured y increased flo! rates and vitalcapacity" Theophylline also suppresses exercise$induced ronchospasm and, in doses thatmaintain therapeutic serum concentrations, prevents symptoms of chronic asthma"

%n the stepped$care approach to antiasthmatic drug therapy, use of a selective, short$acting,inhaled &'$adrenergic agonist on an intermittent, as$needed asis to control acute symptoms (e"g",cough, !hee#ing, dyspnea) is recommended for all patients !ith asthma* such use of an inhaledshort$acting &'$agonist alone generally is sufficient as initial treatment for ne!ly diagnosed

patients !ith mild intermittent asthma"

'1',

'1+,

'1,

'1-

Short$acting theophylline (provided extended$release theophylline is not already used) is considered y some clinicians to e one of severalless effective alternatives (e"g", including an inhaled anticholinergic agent or a short$acting oral&'$agonist) to short$acting inhaled &'$agonists for relief of acute asthma symptoms, ut thesealternatives have a slo!er onset of action and.or a greater ris/ of adverse effects"'1'

0xtended$release theophylline may e administered orally for long$term symptom control inmild to moderate persistent asthma" hile theophylline is an effective ronchodilator, the druggenerally is considered alternative therapy in asthma ecause of its increased ris/ of adverseeffects and more difficult therapeutic monitoring re2uirements compared !ith inhaled &'$agonistand corticosteroid therapy"'11, '1' 3se of an extended$release oral theophylline preparation isconsidered one of several alternatives (including mast$cell staili#ers 4e"g", cromolyn,nedocromil5 or leu/otriene modifiers 4e"g", montelu/ast, #afirlu/ast, #ileuton5) to lo!$doseinhaled corticosteroids for adults and children older than - years of age !ith mild persistentasthma"'11, '1' Theophylline or a leu/otriene modifier also are considered less$effectivealternatives to long$acting inhaled &'$adrenergic agonists for use in conunction !ith inhaledcorticosteroids for long$term control of symptoms in patients !ith moderate persistent asthma"'11,'1' 7onsiderations favoring theophylline in comination !ith orally inhaled corticosteroidsinclude intolerance to long$acting inhaled &'$adrenergic agonists, mar/ed preference for oraltherapy, demonstration of superior responsiveness to theophylline, and cost"'11 o!ever, in


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comparative studies in patients !ith moderate persistent asthma, the addition of theophylline tolo!$dose orally inhaled corticosteroid therapy has not een sho!n to e more effective thandouling the dosage of inhaled corticosteroids alone"'11 0xtended$release theophylline, aleu/otriene modifier, a long$acting oral &'$agonist, and.or an oral corticosteroid arerecommended as adunctive therapy to high dosages of orally inhaled corticosteroids and a long$

acting inhaled &'$adrenergic agonist in adults and children !ith severe persistent asthma"'1'

9imited evidence does not support the addition of theophylline to orally inhaled corticosteroidsand inhaled long$acting &'$adrenergic agonists in order to avoid oral corticosteroid therapy"'11

%n children younger than - years of age !ith mild persistent asthma, some experts considerextended$release theophylline to e an alternative to orally inhaled corticosteroids"'1' %nfantshave fre2uent ferile illnesses, !hich increase theophylline concentrations and the potential foradverse effects"'11 ther experts state that extended$release theophylline may e considered asadunctive therapy in young children !ith mild or moderate persistent asthma if there aredemonstrale adverse effects !ith orally inhaled corticosteroids"'11 %f extended$releasetheophylline is used as adunctive therapy in young children, serum theophylline concentrationsshould e carefully monitored"'11

;n %< xanthine derivative (e"g", theophylline or aminophylline) also may e used as alternativeadd$on therapy in patients !ho are hospitali#ed for severe exacerations of asthma"'1' %nitialhospital management of such exacerations includes oxygen and inhaled short$acting &'$agonisttherapy via metered$dose inhaler aerosol or neuli#ation"'1' %f therapeutic response is notimmediate, if the patient used oral corticosteroids as self$medication prior to hospitali#ation, or if the episode is severe, systemic corticosteroids should e added to the regimen"'1' ;n inhaledanticholinergic ronchodilator also may e added for continuing moderate or severe asthmaexacerations (pea/ expiratory flo! 4=0>5 8?@ or less of predicted or personal est)"'1' >orsevere asthma exacerations not responding to the aove regimen, administration of %<methylxanthines may e used ut should e considered as alternative therapy to inhaled short$

acting &'$agonist therapy ecause of an increased ris/ of adverse effects !ith methylxanthinetherapy"'1'

>or more information on the stepped$care approach for drug therapy in asthma, see ;sthmaunder 3ses: Aronchospasm, in ;luterol 1':1'"

Aminophylline and dyphylline generally share the same indications as theophylline. Aecause ofits short half$life, some clinicians elieve that dyphylline is impractical for chronic ronchodilator therapy" Most clinicians elieve that the use of special theophylline vehicles,salts, and preparations is unnecessary and that uncoated oral theophylline talets provide themost efficacious and convenient formulation for chronic therapy in many patients" Relialy

asored extended$release preparations allo! longer dosing intervals !ith less variation in serumtheophylline concentration and can improve compliance"

Many clinicians have 2uestioned the routine, prolonged administration of drug cominationscontaining theophylline derivatives, sympathomimetic agents (e"g", ephedrine), sedatives (e"g", phenoarital), and.or expectorants to asthmatic patients" Theophylline doses in mostcomination preparations are inade2uate" Single$ingredient preparations are more effective,facilitate necessary dosage adustment, and are safer than comination preparations" 7oncomitant

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full glass of li2uid, or !ith antacids" 0xtended$release preparations should not e che!ed orcrushed* the contents of some extended$release capsules may e mixed !ith soft food and ta/en!ithout che!ing in patients !ho have difficulty s!allo!ing solid dosage forms" ;dministrationof some extended$release theophylline preparations !ith food may affect the rate and.or extent of asorption of the drug, and the manufacturerGs recommendations for administration of specific

products should e follo!ed" 0xtended$release preparations should e administered in aconsistent manner, either al!ays !ith or al!ays !ithout food"''', ''+, '' =atients should not alterthe administration schedule of theophylline preparations !ithout consulting their clinician"''1, ''', ''+, '', ''-, ''6, ''D

0xtended$release theophylline preparations are indicated in patients !ith relatively continuous or fre2uently recurring asthma symptoms, and may e particularly useful in patients in !homtheophylline elimination is rapid (e"g", children, adult smo/ers)" 0xtended$release preparationsdesigned for once$daily dosing (e"g", 3niphylH talets) should e administered at the same timeeach day, either morning or evening"''+ The manufacturer of Theo$'H capsules states that this preparation should e administered at the same time each morning !hen given once daily* once$daily administration at night is not recommended ecause the effect of circadian rhythm, food, posture, and other factors on theophylline asorption and.or clearance rates re2uires additionalstudy"''' The manufacturer of Theo$'H capsules suggests that patients !ho re2uire t!ice$dailydosing should receive the second dose 1?$1' hours after the morning dose and efore theevening meal"''' =atients !ith more rapid metaolism (e"g", young individuals, smo/ers, somenonsmo/ing adults) may re2uire smaller doses administered more fre2uently (e"g", t!ice daily)to avoid rea/through symptoms resulting from lo! trough concentrations"''', ''+

;minophylline and theophylline also may e administered undiluted y slo! %< inection or, preferaly, in large volume parenteral fluids y slo! %< infusion"''C, ''8 ;minophylline solutionsmay e prepared y diluting an appropriate volume of a commercially availale inection or pharmacy ul/ pac/age inection in a compatile %< infusion fluid" 9oading doses usually are

given over +? minutes"''C, ''8 %f patients experience acute adverse effects !hile %< loading dosesof theophylline are eing infused, the infusion may e stopped for -$1? minutes or administeredat a slo!er rate"''8

;minophylline has een, and dyphylline may e administered %M, ut this route is rarely used*%M inection of aminophylline causes intense local pain and is not recommended"

• Dosage

Theophyllines

Theophylline has a low therapeutic index; thereore! cautious dosage determination is essential. Aecause individuals metaoli#e theophylline at different rates, appropriate dosages must e

determined for each patient y carefully monitoring patient response and tolerance, pulmonaryfunction, and serum theophylline concentrations" Bosages re2uired to achieve a therapeuticserum theophylline concentration vary fourfold among other!ise similar patients in the asenceof factors /no!n to alter theophylline clearance"''1 ;lthough extended$release preparations have een formulated to release the drug at various rates suitale for dosing every 8$1', 1', or 'hours, the actual dosing fre2uency for a given patient and preparation depends on the patientGsindividual pharmaco/inetic parameters" Dosage should be calculated on the basis o lean bodyweight.


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>or maintenance therapy, serum theophylline concentrations should e otained after a patienthas received a given dosage for + days" =ea/ serum concentrations can e estimated y otaining lood samples +? minutes after administration of an %< loading dose,''C, ''8 1$' hours afteradministration of an oral solution or uncoated talet, or +$1' (usually +$8) hours (depending onthe specific formulation) after administration of an extended$release preparation" Trough

concentrations of theophylline can e determined y ta/ing lood samples ust efore the nextdose" "hen the recommended maximum dosage is exceeded! dosage ad#ustment should be basedon measurement o pea$ serum theophylline concentrations. >or dosage adustments ased onserum theophylline concentrations determined in such circumstances, it is important that dosagein the previous 8 hours e reasonaly typical of the prescried regimen and that the patient nothave missed a dose nor ta/en an additional dose in this time period" Dosage ad#ustments basedon serum theophylline concentration when these conditions have not been ulilled may result in

dosages that present ris$ o toxicity to the patient. Therapeutic serum concentrations for ronchospastic disease generally range from 1?$1- mcg.m9, although lo!er concentrations may provide eneficial effects in some patients !ith mild asthma and may e effective for neonatalapnea" hen serum theophylline concentrations exceed '? mcg.m9, toxicity often ecomes

apparent"

Dosage o theophylline preparations may be conveniently expressed in terms o anhydrous

theophylline. The approximate anhydrous theophylline content in the various theophyllinederivatives is sho!n in Tale 1"

Tale 1" ;nhydrous Theophylline 7ontent in Theophylline BerivativesBrug ;nhydrous Theophylline 7ontent aminophylline anhydrous 8-"C@ (I1"C@) aminophyllinehydrous C8"D@ (I1"6@) theophylline monohydrate D?"C@ (I1"1@)

Acute Bronchospasm" >or the treatment of acute ronchospasm, theophylline (oraminophylline) is preferaly administered %


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7hildren D$1' years of age ?"C mg./g per hour Mariuana$ or cigarette$smo/ing adolescents 1'$16 ?"C mg./g per hour years of age Jonsmo/ing adolescents 1'$16 years of age ?"- mg./g perhour (maximum D?? mg daily) Jonsmo/ing adolescents and adults 16$6? years of ?" mg./g per hour (maximum D?? mg daily) age Feriatric patients L6? years of age ?"+ mg./g per hour up tomaximum 1C mg.hour Maximum daily theophylline dosage ?? mg 7ardiac decompensation,

cor pulmonale, hepatic ?"' mg./g per hour up to a maximum infusion rate dysfunction, sepsis!ith multi$organ failure, of 1C mg.hour unless serum theophylline shoc/ concentrations aremonitored at '$hour intervals Maximum daily theophylline dosage ?? mg$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$To achieve a target theophylline concentration of 1? mcg.m9"''8

;pproximate aminophylline dosage theophylline dosage.?"8"''8

3se ideal ody !eight for oese patients" 9o!er initial dosage may e re2uired for patients !ithconditions or receiving drugs that decrease theophylline clearance" (See 7autions: =recautionsand 7ontraindications and also see Brug %nteractions")''C, ''8

To achieve a target theophylline concentration of C"- mcg.m9"''C, ''8

3nless serum concentration indicates need for larger dosage"''C, ''8

; serum theophylline concentration should e measured at 1 expected half$life after starting thecontinuous %< infusion (i"e", after approximately hours for children 1$D years of age, after 8hours for nonsmo/ing adults) to determine if theophylline concentrations are decreasing orincreasing from the postloading dose drug concentration"''8 %f theophylline concentrations aredecreasing from the postloading drug concentration, an additional loading dose may eadministered and.or the rate of infusion may e increased"''8 %f the theophylline concentrationafter initiation of the continuous infusion is higher than the postloading drug concentration, the

infusion rate should e decreased efore the theophylline concentration exceeds '? mcg.m9"''8

;n additional serum theophylline concentration should e measured 1'$' hours later todetermine if dosage adustments are re2uired, then at '$hour intervals, to adust for changes intheophylline concentrations in the initial period of theophylline administration"''8

%n patients who are currently receiving theophylline preparations! estimation of serumtheophylline concentration ased upon patient history is unreliale, and a serum theophyllineconcentration should e measured immediately to determine a loading dose"''8 ; loading doseshould not e given efore otaining a serum theophylline concentration if the patient hasreceived any theophylline in the past ' hours"''89oading doses of theophylline are ased on thegeneral expectation that each ?"- mg./g (of lean ody !eight) of theophylline !ill result in a 1$

mcg.m9 increase in serum theophylline concentration" ; loading dose in patients who arecurrently receiving theophylline preparations should e determined using the follo!ing formula:

9oading dose (desired serum concentration $ measured serum concentration) O volume ofdistriution"''8


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%< dosage adustments should e ased on pea/ serum theophylline concentrations and theclinical response and tolerance of the patient as sho!n in Tale +:

Tale +" %< Bosage ;dustment Aased on Serum Theophylline 7oncentration''8

Serum Bosage ;dustment Theophylline 7oncentration (mcg.m9) PD"D %ncrease infusion rate y

'-@ if symptoms are not controlled and current dosage is tolerated* rechec/ serum concentrationafter 1' hours in pediatric patients and ' hours in adults 1?$1"D Maintain infusion rate ifsymptoms are controlled and current dosage is tolerated* rechec/ serum concentration after 'hours 7onsider adding additional agents if symptoms are not controlled and current dosage istolerated 1-$1D"D 7onsider 1?@ decrease in infusion rate to provide greater margin of safetyeven if current dosage is tolerated '?$'"D Becrease infusion rate y '-@ even if no adverseeffects are present* rechec/ serum concentration after 1' hours in pediatric patients and ' hoursin adults '-$+? Stop infusion for 1' hours in pediatric patients and ' hours in adults*suse2uently, decrease infusion rate y Q'-@ even if no adverse effects are present Rechec/serum concentration after 1' hours in pediatric patients and ' hours in adults* if symptomatic,stop infusion and consider !hether treatment for overdose is indicated L+? Stop infusion and

treat overdose as indicated %f therapy is resumed, decrease suse2uent infusion rate y Q-?@ andrechec/ serum concentration after 1' hours in pediatric patients and ' hours in adults$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$Bose reduction and.or serum theophylline concentration measurement is indicated !heneveradverse effects are present, physiologic anormalities that can reduce theophylline clearanceoccur (e"g", sustained fever), or a drug that interacts !ith theophylline is added or discontinued"(See 7autions: =recautions and 7ontraindications and see Brug %nteractions")

%< theophylline is preferred over other routes of administration for the treatment of acute ronchospasm" ral extended$release dosage forms should not e used for the treatment of acute ronchospasm"''', '' ;n inhaled, short$acting &'$adrenergic agonist alone or in comination !ithsystemic corticosteroids is the most effective treatment for acute exacerations of reversileair!ay ostruction"'11, '1', ''-, ''6, ''D %f an inhaled or parenteral &'$adrenergic agonist is notavailale, a loading dose of oral theophylline using immediate$release preparations can e usedas a temporary measure"''-, ''6, ''D Some experts suggest initiating therapy !ith a theophyllinedosage of 1? mg./g (up to +?? mg) daily in divided doses, !ith titration up to a usual maximumdaily dosage of 8?? mg in divided doses in adults and children older than 1' years of age or amaximum daily dosage of 16 mg./g in divided doses in children 1$1' years of age"'11 Patientswho have not received any theophylline preparations in the previous %& hours may receive atheophylline loading dose of - mg./g using an immediate$release preparation"''-, ''6, ''D

>ollo!ing the loading dose, theophylline dosage for suse2uent therapy using an immediate$release preparation in children older than 1 year of age and adults may e titrated as follo!s:

Tale " Recommended Bosage Titration 3sing %mmediate$Release =reparations for 7hildren Q1ear of ;ge and ;dults''-, ''6, ''D

;ge Bosage Titration 7hildren 1$1- years of age !eighing P- /g %nitially, 1'$1 mg./g(maximum +?? mg) daily in divided doses* after + days, i tolerated , increase dosage to 16 mg./g(maximum ?? mg) daily in divided doses* after + more days, i tolerated and i needed , increasedosage to '? mg./g (maximum 6?? mg) daily in divided doses ;dminister in divided dosesevery $6 hours 7hildren 1$1- years of age !eighing L- /g and %nitially, +?? mg daily in


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divided doses* after + days, i adults 16$6? years of age tolerated , increase dosage to ?? mgdaily in divided doses* after + more days, i tolerated and i needed , increase dosage to 6?? mgdaily in divided doses ;dminister in divided doses every 6$8 hours 7hildren 1$1- years of age!ith ris/ factors for %nitially 1'$1 mg./g (maximum +?? mg) daily in divided reducedtheophylline clearance or in !hom doses* after + days, i tolerated , increase dosage to serum

concentrations cannot e monitored maximum 16 mg./g (maximum ?? mg) daily in divideddoses ;dminister in divided doses every $6 hours ;dults L16 years of age !ith ris/ factors for%nitially, +?? mg daily in divided doses* after + days, i reduced theophylline clearance or in!hom tolerated , increase dosage to maximum ?? mg daily in serum concentrations cannot emonitored divided doses ;dminister in divided doses every 6$8 hours$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$=atients !ith more rapid metaolism, identified clinically y higher than average dosagere2uirements, may re2uire smaller doses given more fre2uently to prevent rea/throughsymptoms resulting from lo! trough theophylline concentrations* such patients may enefit fromtherapy !ith an extended$release preparation"

See 7autions: =recautions and 7ontraindications and also see Brug %nteractions for informationon additional ris/ factors for decreased theophylline clearance"

Serum theophylline concentrations should e monitored at '$hour intervals to adust finaldosage"''-, ''6

Chronic Bronchospasm" 0xtended$release preparations of theophylline may e administeredevery 8, 1', or ' hours to provide therapeutic serum theophylline concentrations in patients !hohave relatively continuous or recurrent symptoms" ''1, ''', ''+, '' >or chronic maintenance ronchodilator therapy in patients receiving certain extended$release preparations designed to egiven every 8$1' hours, dosage titration is sho!n in Tale -"

Tale -" Bosage Titration 3sing 7ertain 0xtended$Release =reparations 0very 8$1' ours''1, ''

;ge Baily Bosage 7hildren 6$1- years of age !eighing P- /g %nitially, 1'$1 mg./g (maximum+?? mg) daily in divided doses* after + days, i tolerated , increase dosage to 16 mg./g (maximum?? mg) daily in divided doses* after + more days, i tolerated and needed , increase dosage to '?mg./g (maximum 6?? mg) daily in divided doses 7hildren 6$1- years of age !eighing L- /g,%nitially, +?? mg daily in divided doses* after + days, i adolescents Q16 years of age, and adultstolerated , increase dose to ?? mg daily in divided doses* after + more days, i tolerated andneeded , increase dosage to 6?? mg daily in divided doses 7hildren 6$1- years of age !ith ris/factors %nitially, 1'$1 mg./g (maximum +?? mg) daily in divided for reduced theophyllineclearance or in !hom doses* after + days, i tolerated , increase dosage to serum concentrationscannot e monitored maximum 16 mg./g (maximum ?? mg) daily in divided doses ;dults Q16

years of age !ith ris/ factors for %nitially, +?? mg daily in divided doses* after + days, i reducedtheophylline clearance or in !hom tolerated , increase dosage to maximum ?? mg daily inserum concentrations cannot e monitored divided doses Feriatric patients L6? years of ageMaximum ?? mg daily unless patient continues to e symptomatic, and pea/ serumconcentration P1? mcg.m9 ;dminister dosages L?? mg daily !ith caution$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$Bosage given as total daily dosage" Brug should e administered in divided doses every 8 or 1'hours* manufacturerGs laeling for individual preparations should e consulted for recommended


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dosing intervals"''1, '' %t is generally recommended that the daily dosage re2uirement first eestalished y monitoring serum theophylline concentrations !hile the patient is receiving animmediate$release dosage form efore s!itching to therapy !ith an extended$release preparation" (See text")

Some generic extended$release preparations (e"g",extended$release capsules from %n!ood9aoratories) are >B;$laeled for use in children 1$1- years of age"''1

See 7autions: =recautions and 7ontraindications and also see Brug %nteractions for informationon additional ris/ factors for decreased theophylline clearance"

Regardless of oral dosage form, dosage for the treatment of chronic ronchospasm should notexceed the 6?? mg maximum daily dosage without measurement o serum theophyllineconcentration"''1, ''', ''+, '', ''-, ''6, ''D

hen extended$release preparations are to e administered, it is generally recommended that thedaily dosage re2uirement first e estalished y monitoring serum theophylline concentrations

!hile the patient is receiving a rapidly asored dosage form* then, therapy !ith an extended$release preparation may e started y administering one$half of the total daily dose every 1'hours" hen transferring therapy from conventional talets or 8$1' hour extended$release preparations to a once$daily ('$hour) extended$release preparation (i"e", 3niphylH) in patients 1'years of age and older, to sustitution of 3niphyl dosage using the ??$ or 6??$mg talets on amg$for$mg asis is recommended"''+

ral dosage adustments may e ased on pea/ serum theophylline concentrations and theclinical response and tolerance of the patient as follo!s:

Tale 6" ral Bosage ;dustment Aased on Serum Theophylline 7oncentration

Serum Bosage ;dustment Theophylline 7oncentration (mcg.m9) PD"D %f symptoms are not controlled and current dosage is tolerated, increase dosage y '-@" Rechec/ serum theophyllineconcentration after + days for further dosage adustment" 1?$1"D %f symptoms are controlled andcurrent dosage is tolerated, maintain dosage and rechec/ serum theophylline concentration at 6$to 1'$month intervals" %f symptoms are not controlled and current dosage is tolerated, consideradding additional agents" 1-$1D"D 7onsider decreasing dosage y aout 1?@ to provide greatermargin of safety even if current dosage is tolerated" '?$'"D Becrease dosage y '-@ even if noadverse effects are present" Rechec/ serum theophylline concentration after + days to guidefurther dosage adustment" '-$+? S/ip next dose and decrease suse2uent doses y at least '-@even if no adverse effects are present" Rechec/ serum theophylline concentration after + days toguide further dosage adustment" %f symptomatic, consider !hether treatment for overdose is

indicated" (See ;cute Toxicity") L+? Treat overdose as indicated" (See ;cute Toxicity") %ftheophylline is resumed, decrease suse2uent doses y at least -?@ and rechec/ serumtheophylline concentration after + days to guide further dosage adustment"$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$The clinical characteristics of each patient must e considered !hen applying these generaldosage recommendations to individual patients" %n general, dosage adustments should notexceed these recommendations in order to decrease the ris/ of potentially serious adverse effectsassociated !ith unexpected large increases in serum theophylline concentration"


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Bosage reduction and.or serum theophylline concentration measurement is indicated !heneveradverse effects are present, physiologic anormalities that can reduce theophylline clearanceoccur (e"g", sustained fever), or a drug that interacts !ith theophylline is added or discontinued"(See 7autions: =recautions and 7ontraindications and see Brug %nteractions")

hen adusting dosage in this manner, it is important that dosage in the previous 8 hours ereasonaly typical of the prescried regimen and that the patient not have missed a dose norta/en an additional dose in this time period"

%< dosage adustments may e ased on pea/ serum theophylline concentrations and the clinicalresponse and tolerance of the patient as follo!s:

Tale C" %< Bosage ;dustment Aased on Serum Theophylline 7oncentration''8

Serum Bosage ;dustment Theophylline 7oncentration (mcg.m9) PD"D %ncrease infusion rate y'-@ if symptoms are not controlled and current dosage is tolerated* rechec/ serum concentrationafter 1' hours in pediatric patients and ' hours in adults 1?$1"D Maintain infusion rate ifsymptoms are controlled and current dosage is tolerated* rechec/ serum concentration after 'hours 7onsider adding additional agents if symptoms are not controlled and current dosage istolerated 1-$1D"D 7onsider 1?@ decrease in infusion rate to provide greater margin of safetyeven if current dosage is tolerated '?$'"D Becrease infusion rate y '-@ even if no adverseeffects are present* rechec/ serum concentration after 1' hours in pediatric patients and ' hoursin adults '-$+? Stop infusion for 1' hours in pediatric patients and ' hours in adults*suse2uently, decrease infusion rate y Q'-@ even if no adverse effects are present Rechec/serum concentration after 1' hours in pediatric patients and ' hours in adults* if symptomatic,stop infusion and consider !hether treatment for overdose is indicated L+? Stop infusion andtreat overdose as indicated %f therapy is resumed, decrease suse2uent infusion rate y Q-?@ andrechec/ serum concentration after 1' hours in pediatric patients and ' hours in adults$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$

Bose reduction and.or serum theophylline concentration measurement is indicated !heneveradverse effects are present, physiologic anormalities that can reduce theophylline clearanceoccur (e"g", sustained fever), or a drug that interacts !ith theophylline is added or discontinued"(See 7autions: =recautions and 7ontraindications and see Brug %nteractions")

Dosage in Children Younger than 1 Year of Age " Bosage of theophylline in children youngerthan 1 year of age, particularly in premature and term neonates, must e carefully individuali#ed"0limination of the drug in children younger than 1 year of age, especially in neonates, generallyappears to e reduced" Aecause of potential toxicity, use of the drug in children younger than 1year of age should e carefully considered and, if used, the initial and maintenance dosages(particularly the latter) should e conservative" Maintenance dosage should not e exceeded and

therapy !ith the drug should not e continued unless the drug is !ell tolerated and clinically eneficial" Recommended initial maintenance dosages for neonates and infants for the treatmentof ronchospasm are sho!n in the follo!ing tale:"

Tale 8" Recommended Bosage Titration for 7hildren P1 ear of ;ge using %mmediate$Release=reparations''-, ''6, ''D

;ge Bosage Titration =remature neonates P' days %nitially, 1 mg./g every 1' hours postnatalage ;dust dosage to maintain a pea/ steady$state serum concentration of -$1? mcg.m9


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=remature neonates Q' days %nitially, 1"- mg./g every 1' hours postnatal age ;dust dosage tomaintain a pea/ steady$state serum concentration of -$1? mcg.m9 >ull$term infants P'6 !ee/sof age 4(?"' x age in !ee/s) N -5 x ody !eight (/g) total daily dosage (mg)* administer in +e2ually divided doses every 8 hours ;dust dose to maintain a pea/ steady$state serumconcentration of -$1? mcg.m9 in neonates or 1?$1- mcg.m9 in older infants %nfants '6$-' !ee/s

of age 4(?"' x age in !ee/s) N -5 x ody !eight (/g) total daily dosage (mg)* administer in e2ually divided doses every 6 hours ;dust dosage to maintain a pea/ steady$state serumconcentration of 1?$1- mcg.m9

Other Uses" %n infants !ith cystic firosisE, daily %< theophylline (as aminophylline)maintenance doses of 1?$1' mg./g have een given" %n adults, %< olus theophylline doses ofapproximately '??$?? mg have een used to promote diuresisE and to treat 7heyne$Sto/esrespirationE and paroxysmal nocturnal dyspneaE"

Dyphylline>or acute ronchospasm in adults, the usual oral dosage of dyphylline recommended y themanufacturer is 1- mg./g or '??$?? mg every 6 hours"'+?, '+1 Bosage must e carefully adustedaccording to individual re2uirements and response" %n patients !ith renal impairment, dosagereduction should e considered"'+? =ediatric dosage has not een estalished"

Cautions

• GI and er!ous "ystem #ffects

Theophyllines produce F% irritation and 7JS stimulation follo!ing administration y any route"Theophyllines are all some!hat irritating to gastric mucosa* the importance of reporteddifferences among the individual agents is doutful" The most common adverse F% effects (othlocally and centrally mediated) include nausea, vomiting, epigastric pain, adominal cramps,anorexia, and, rarely, diarrhea" ematemesis has also occurred" ;dverse 7JS effects, !hich are

often more severe in children than in adults, include headache, irritaility, restlessness,nervousness, insomnia, di##iness, reflex hyperexcitaility, and sei#ures" Reduction oftheophylline dosage usually reduces the incidence and severity of adverse gastric and 7JSeffects* ho!ever, if these adverse effects persist, the drug may have to e !ithdra!n" The drugsmay e administered orally efore or after meals, !ith a full glass of li2uid, or !ith antacids tominimi#e locally mediated F% irritation"

• Cardio!ascular #ffects

;dverse cardiovascular effects of theophyllines include palpitation, sinus tachycardia,extrasystoles, and increased pulse rate" These adverse cardiovascular effects are usually mild andtransient" >lushing, hypotension, circulatory failure, and ventricular arrhythmias may also occur"

• Other Ad!erse #ffects

Theophyllines may also produce transiently increased urinary fre2uency, dehydration, t!itchingof fingers and hands, tachypnea, and elevated serum ;ST (SFT) concentrations"ypersensitivity reactions characteri#ed y urticaria, generali#ed pruritus, and angioedema have een reported !ith aminophylline administration" ; contact$type dermatitis, caused yhypersensitivity to the ethylenediamine component of aminophylline, has also een reported"Aone marro! suppression, leu/openia, thromocytopenia, and hemorrhagic diathesis have also


12/25

een reported, ut their association !ith theophylline therapy is 2uestionale" ther adverseeffects of theophyllines include aluminuria, increased urinary excretion of renal tuular cellsand erythrocytes, hyperglycemia, and syndrome of inappropriate secretion of antidiuretichormone (S%;B)"

• Ad!erse #ffects Associated $ith %oute and &ethod of AdministrationRapid %< inection of aminophylline may produce di##iness, faintness, lightheadedness, palpitation, syncope, precordial pain, flushing, profound radycardia, premature ventricularcontractions, severe hypotension, or cardiac arrest" %M inection of aminophylline producesintense local pain and sloughing of tissue* %M dyphylline reportedly produces little tissueirritation" hen administered rectally as suppositories (dosage form no longer commerciallyavailale in the 3S), theophyllines have caused rectal irritation and inflammation"

• 'recautions and Contraindications

hen therapeutic doses of theophylline are administered simultaneously y more than one routeor in more than one preparation, the ha#ard of serious toxicity is increased* theophyllines shouldnot e administered concomitantly !ith other xanthine drugs" Smo/ers (cigarettes and.ormariuana) may re2uire larger than usual or more fre2uent doses, since theophylline clearancemay e increased and its half$life decreased in smo/ers !hen compared !ith nonsmo/ers"Theophylline should e administered cautiously to young children" Theophylline should eadministered cautiously to patients older than 6? years of age (particularly males and those !ithchronic ostructive pulmonary disease),''1, ''', ''+, '', ''-, ''6, ''8 neonates and infants under 1 yearof age, patients receiving concomitant therapy !ith certain drugs (see Brug %nteractions), patients undergoing influen#a immuni#ation or !ho have an active influen#a infection, patients!ith sustained high fever, and patients !ho have cardiac failure from any cause, chronicostructive pulmonary disease, cor pulmonale, or renal (in infants younger than + months ofage)''8 or hepatic dysfunction, since clearance of theophylline is usually decreased, oftenresulting in higher and potentially toxic serum concentrations* dosage should generally e

reduced and serum theophylline concentrations should e monitored cautiously in these patients"%n addition, these patients may have mar/edly prolonged serum theophylline concentrationsfollo!ing discontinuance of the drug"

The drugs should e used !ith caution in patients !ith peptic ulcer, hyperthyroidism, glaucoma,diaetes mellitus, severe hypoxemia, hypertension, or in patients !ith compromised cardiac orcirculatory function" Theophylline preparations should e used cautiously in patients !ith angina pectoris or acute myocardial inury !hen myocardial stimulation !ould e harmful" Sincetheophylline may cause dysrhythmia and.or !orsen preexisting arrhythmias, any sustantialchange in rate and.or rhythm !arrants 07F monitoring and further investigation"

Some commercially availale formulations of theophyllines contain sulfites that may causeallergic$type reactions, including anaphylaxis and life$threatening or less severe asthmaticepisodes, in certain susceptile individuals" The overall prevalence of sulfite sensitivity in thegeneral population is un/no!n ut proaly lo!* such sensitivity appears to occur morefre2uently in asthmatic than in nonasthmatic individuals"

Theophyllines are contraindicated in patients !ho are allergic to any of the theophyllines,caffeine, or theoromine* aminophylline should not e used in patients hypersensitive to


13/25

ethylenediamine" ;t least one manufacturer states that theophyllines also are contraindicated in patients !ith active peptic ulcer disease and in those !ith underlying sei#ure disorders, unlessthe latter patients are receiving ade2uate anticonvulsant therapy"

Aecause of their erratic and unpredictale asorption and accumulation, theophylline rectal

suppositories (no longer commercially availale in the 3S) have een associated !ith toxicitymore fre2uently than other formulations"

• 'regnancy and (actation

Pregnancy

;nimal reproduction studies have not een performed !ith theophyllines" %t is not /no!n!hether theophyllines can cause fetal harm !hen administered to pregnant !omen" ;lthoughsafe use of theophyllines during pregnancy has not een estalished relative to the potential ris/to the fetus, the drugs have een used during pregnancy !ithout teratogenicity or other adversefetal effect* ecause of the ris/ of uncontrolled asthma, their safety during pregnancy !henclearly needed is generally not seriously 2uestioned"

'actationTheophylline is distriuted into mil/ and may occasionally induce irritaility or other signs oftoxicity in nursing infants" The ris/ to the reast$fed infant must e !eighed against the enefitof nursing in lactating !omen !ho are receiving theophylline"

Drug Interactions

Theophylline increases excretion of lithium and may decrease its therapeutic effectiveness"igher doses of lithium may e re2uired during concurrent administration of theophylline" Thedirect stimulatory effect of theophylline on the myocardium may enhance the sensitivity andtoxic potential of the cardiac glycosides" Theophylline may exhiit synergistic toxicity !ith

ephedrine and other sympathomimetics and, !hen administered concomitantly, these agents mayfurther predispose the patient to the development of cardiac arrhythmias"

Theophylline may enhance the effects of the oral anticoagulants y increasing plasma prothromin and factor


14/25

fe! reports have suggested that such a comination may have the potential for producing cardiacarrhythmias" >urther accumulation of clinical data is needed to determine !hether this potentialinteraction exists in humans"

(a)oratory Test Interferences

Theophylline produces false$positive elevations of serum uric acid as measured y the Aittner orcolorimetric method ut !ill not affect serum uric acid !hen measured y the uricase method"

%n vitro, serum theophylline concentrations, as measured y spectrophotometric methods, may efalsely elevated y furosemide, sulfathia#ole, phenyluta#one, proenecid, theoromine,caffeine$containing everages, chocolate, and acetaminophen" These sustances do not interfere!ith results !hen theophylline concentrations are measured y high$pressure li2uidchromatography"

Acute To*icity

• &anifestationsTheophylline has a lo! therapeutic index" Theophylline toxicity is most li/ely to occur !henserum concentrations exceed '? mcg.m9 and ecomes progressively more severe at higherserum concentrations" Tachycardia, in the asence of hypoxia, fever, or administration ofsympathomimetic drugs, may e an indication of theophylline toxicity" ;norexia, nausea andoccasional vomiting, diarrhea, insomnia, irritaility, restlessness, and headache commonly occur"The distinguishing symptoms of toxicity may include agitated maniacal ehavior, fre2uentvomiting, extreme thirst, slight fever, tinnitus, palpitation, and arrhythmias" =atients mayexperience delirium, muscle t!itching, severe dehydration, aluminuria, emesis of a coffeeground material, hyperthermia, and profuse diaphoresis" Sei#ures may occur even !ithout other preceding symptoms of toxicity and often result in death"

>atalities in adults have generally occurred during or follo!ing %< administration of large dosesof aminophylline in patients !ith renal, hepatic, or cardiovascular complications" %n other patients, the rapidity of the inection, rather than the dose used, appears to e the more importantfactor precipitating acute hypotension, sei#ures, coma, cardiac standstill, ventricular firillation,and death" %< aminophylline or theophylline should therefore e given slo!ly" %n children,fatalities usually are a result of overdosage and mar/ed sensitivity to the 7JS stimulation oftheophylline"

• Treatment

Treatment of theophylline overdosage is supportive and includes !ithdra!al of the drug" %f

sei#ures have not occurred follo!ing acute overdosage, the stomach should e emptiedimmediately y inducing emesis or y gastric lavage, follo!ed y administration of activatedcharcoal and a cathartic (particularly !hen extended$release preparations have een ta/en)" %f the patient is comatose, having sei#ures, or lac/s the gag reflex, gastric lavage may e performed ifan endotracheal tue !ith cuff inflated is in place to prevent aspiration of gastric contents*activated charcoal and.or a cathartic may e administered via a large$ore gastric lavage tue" %fthe patient is having sei#ures, an ade2uate air!ay should first e estalished and maintained andoxygen administered* sei#ures may e treated !ith %< dia#epam ?"1$?"+ mg./g up to 1? mg"


15/25

Some clinicians recommend the use of ariturates or anesthetics to control sei#ures" %n oneclinical report, ho!ever, theophylline$induced sei#ures !ere relatively refractory to %<dia#epam, phenytoin, and phenoarital" Restoration of fluid and electrolyte alance isnecessary" ;dministration of phenothia#ines for intractale hyperthermia and propranolol forextreme tachycardia may e !arranted in life$threatening situations"

%n general, theophylline is metaoli#ed rapidly and hemodialysis is not !arranted" %n patients!ith congestive heart failure or liver disease, hemodialysis or charcoal hemoperfusion mayincrease theophylline clearance y as much as '$fold" 7harcoal hemoperfusion can rapidlyremove theophylline and may e clinically indicated !hen the serum theophylline concentrationexceeds -? mcg.m9, even in the asence of ovious signs of toxicity" Some cliniciansrecommend that charcoal hemoperfusion generally e used for all patients !hose serumtheophylline concentration hours after ingestion is greater than 6? mcg.m9" hen the serumtheophylline concentration is ?$-? mcg.m9, the ris/s of hemoperfusion (e"g", hypotension,thromocytopenia) must e carefully !eighed against the potential enefits of the procedure*!hen the serum concentration is less than ? mcg.m9, the ris/s of hemoperfusion proalyout!eigh any potential enefits" Some clinicians recommend that charcoal hemoperfusion eused in patients !ith a serum theophylline concentration of +? mcg.m9 or greater and + of thefollo!ing ris/ factors: the patient is 6? years of age or older, the patient has sustantial liverdisease and.or congestive heart failure, the theophylline half$life for the patient is calculated to e ' hours or more, and.or the patientGs serum theophylline concentration is -? mcg.m9 orgreater" %f hemoperfusion is not performed, some clinicians recommend oral administration ofactivated charcoal every hours until the serum theophylline concentration decreases to less than'? mcg.m9"

'harmacology

Theophyllines and dyphylline exert identical pharmacologic actions" Theophylline competitively

inhiits phosphodiesterase, the en#yme that degrades cyclic +U,-U$adenosine monophosphate(c;M=)" %ncreased concentrations of intracellular c;M= may mediate most of the pharmacologic effects of the drug" The actions of theophylline on the myocardium and onneuromuscular transmission may result from intracellular translocation of ioni#ed calcium" Theui2uitous nature of calcium and c;M= accounts for the diversity of theophyllineGs pharmacologic actions"

• 'ulmonary #ffects

Theophylline directly relaxes smooth muscle of the respiratory tract, producing relief of ronchospasm and increasing flo! rates and vital capacity" The ronchodilator effect of the drugis minimal if ronchospasm is not the principal cause of respiratory distress" Theophylline also

dilates pulmonary arterioles, reduces pulmonary hypertension and alveolar caron dioxidetension, and increases pulmonary lood flo!" 3nli/e sympathomimetics, tolerance to the ronchodilator effects of theophylline rarely occurs" (See also =harmacology: Jervous System0ffects")

• er!ous "ystem #ffects

Theophylline stimulates all levels of the 7JS, ut to a lesser degree than does caffeine"Stimulation of the vasomotor and vagal centers promotes vasoconstriction and radycardia,


16/25

respectively, ut the overall effect of theophylline on heart rate and lood pressure depends on!hether 7JS or peripheral effects predominate" %n the medulla, theophylline also lo!ers thethreshold of the respiratory center to caron dioxide, ut sustantial increases in rate and depthof respiration occur only if respiration is depressed" ;lleviation of neonatal apnea and the apneaof 7heyne$Sto/es respiration y these drugs may e caused y direct stimulation of the

medullary respiratory center" Theophylline constricts cereral vasculature* in some patients, theresultant decrease in cereral lood flo! and increase in caron dioxide tension may result inrespiratory center stimulation" The ethylenediamine component of aminophylline reportedlycontriutes to the respiratory stimulant action of theophylline* ho!ever, the importance andvalidity of this action are doutful" Therapeutic serum concentrations of theophylline maystimulate the vomiting center !hile toxic serum concentrations activate all levels of the cortexand spinal cord, often producing sei#ures" Tolerance of a lo! magnitude may develop to thesleep$disturing effect of theophylline"

• Cardio!ascular #ffects

%n doses larger than those re2uired for ronchodilation, theophylline produces a positiveinotropic effect on the myocardium and a positive chronotropic effect at the sinoatrial (S;) node";lthough heart rate, force of contraction, cardiac output, and myocardial oxygen demand may eincreased transiently, theophylline rarely alters heart rate to a sustantial degree !ith usual doses";t high serum concentrations, ho!ever, the central vagal effects of the drug may e mas/ed yincreased sinus rate, and acute hypotension, tachycardia, extrasystoles, or ventricular arrhythmiamay result" The ethylenediamine component of aminophylline reportedly contriutes to the positive inotropic action of theophylline* ho!ever, the importance and validity of this action aredoutful" (See also =harmacology: Jervous System 0ffects")

Theophylline directly dilates coronary, pulmonary, renal, and general systemic arterioles andveins, decreasing peripheral vascular resistance and venous pressure" The effect of this decreasein peripheral resistance (and possily that of vagal stimulation) on lood pressure is offset y

increased cardiac output (and possily stimulation of the medullary vasomotor area)* there isgenerally only a slight increase in lood pressure follo!ing administration of moderate doses oftheophylline" Rapid %< inection, ho!ever, may cause transient hypotension" %n a similar manner, peripheral lood flo! increases initially, ut this increase is of short duration" Bilation ofcoronary lood vessels may e a direct effect of theophylline or may result from increasedcardiac !or/" 7oronary lood flo! increases and, theoretically, myocardial oxygen supply isimproved y theophylline" o!ever, some studies report an increase in myocardial oxygenconsumption resulting from increased heart !or/" %n contrast to its peripheral vasodilation,theophylline constricts cereral vasculature"

• %enal #ffects

The diuretic effect of theophylline is more potent than that of theoromine ut is of shorterduration" Mild diuresis is produced y the comined effect of theophylline on renalhemodynamics and on tuular reasorption" %ncreased cardiac output and dilation of efferent andafferent renal arterioles result in increased glomerular filtration rate (F>R) and renal lood flo!"%n congestive heart failure, theophylline$induced changes in F>R are variale" Theophylline alsoinhiits sodium and chloride reasorption at the proximal tuule" =otassium excretion is notmar/edly increased" Tolerance of a lo! magnitude may develop to the diuretic effect oftheophylline"


17/25

• #ndocrine and &eta)olic #ffects

;t therapeutic serum concentrations, theophylline may stimulate release of catecholamines fromthe adrenal medulla and increase the urinary excretion of epinephrine" Theophylline exhiitsmany of the &$;drenergic effects of epinephrine* their cardiac and hyperglycemic effects may esynergistic" 7onversely, theophylline may potentiate corticotropin and catecholamine$induced

insulin secretion" The net effect on lood glucose is variale" The lipolytic action of theophyllinere2uires the presence of gro!th hormone or glucocorticoid to produce maximum increase in plasma free fatty acids" Theophylline may potentiate the calcemic response to parathyroidhormone and inhiit that of calcitonin" Theophylline may also increase asal metaolic rate"

• Other #ffects

Theophylline relaxes smooth muscle of the iliary and F% tract, and stimulates gastric secretion"Theophylline stimulates s/eletal muscle in vitro, increasing the force of contraction anddecreasing muscular fatigue* this action of theophylline may e mediated y acetylcholine"

'harmaco+inetics

• A)sorptionBissolution appears to e the rate$limiting step in the asorption of oral theophylline" 3nder theacidic conditions of the stomach, the theophylline salts and compounds release free theophylline"Byphylline is asored through the gastric mucosa and appears in the plasma intact"Microcrystalline dosage forms and oral solutions of theophyllines are asored more rapidly, utnot to a greater extent, than are uncoated talets" ;lthough the rate of asorption is slo!er,extended$release preparations (capsules and talets) of theophylline are generally asored to thesame extent as uncoated talets* ho!ever, the actual rate of asorption of extended$release preparations may differ" 0xtended$release preparations of theophyllines have een formulated torelease the drug at various rates suitale for dosing every 8$1', 1', or ' hours* ho!ever, theactual dosing fre2uency for a given patient depends on their individual pharmaco/inetic

parameters" Since the rate and extent of asorption may differ et!een various extended$release preparations and sometimes et!een different dosage si#es of the same preparation, patientsshould generally e staili#ed on a given preparation* sustitution of one extended$release preparation for another should generally only e made !hen the preparations have een sho!n to e e2uivalent and.or the patient is evaluated pharmaco/inetically during the transition period";sorption of theophyllines may also e delayed, ut is generally not reduced, y the presenceof food in the F% tract* ho!ever, the effect of food on the asorption of extended$release preparations appears to e variale, and the manufacturerGs recommendations for administrationof specific preparations should e follo!ed" hen administered %M, theophylline is usuallyasored slo!ly and incompletely" Rectal suppositories (no longer commercially availale in the3S) are slo!ly and erratically asored, regardless of !hether the suppository ase is

hydrophilic or lipophilic"

Serum theophylline concentrations of aout 1?$'? mcg.m9 are usually needed to produceoptimum ronchodilator response" Reports indicate that serum concentrations of dyphylline inthis same range produce a ronchodilator response" Some patients !ith mild pulmonary disease!ill experience relief of ronchospasm !ith serum theophylline concentrations of - mcg.m9"ith serum concentrations ranging from 8$'? mcg.m9, a linear relationship exists et!eenimprovement in pulmonary function and the logarithm of serum theophylline concentration" %n


18/25

premature infants, serum theophylline concentrations of aout C$1 mcg.m9 may e sufficient toreverse apnea" Serum theophylline concentrations of aout 1? mcg.m9 produce a transientdiuretic response" ;dverse reactions to theophylline often occur !hen serum concentrationsexceed '? mcg.m9"

%< theophylline produces the highest and most rapid serum theophylline concentration">ollo!ing a single %< dose of theophylline (as aminophylline) of aout - mg./g over +? minutesto healthy adults, mean pea/ serum theophylline concentrations of aout 1? mcg.m9 are reached"Slightly lo!er or e2ual pea/ serum concentrations are reached after oral administration of e2ualamounts of theophylline in uncoated talet, capsule, or li2uid formulations" >ollo!ing oraladministration of theophylline capsules or uncoated talets, pea/ serum concentrations areusually reached in 1$' hours" =ea/ serum theophylline concentrations are usually otained afteraout 1 hour !hen theophylline oral solutions or microcrystalline talets are administered"0nteric$coated theophylline talets produce variale serum concentrations !hich usually pea/ ataout - hours" Single doses of extended$release theophylline capsules or talets usually produce pea/ serum concentrations after hours, ut commercial products vary in their rates andcompleteness of asorption" 0xtended$release theophylline preparations are generally associated!ith relatively small fluctuations in steady$state pea/ and trough serum concentration* ho!ever,clinically important steady$state pea/$trough differences may occur in individuals !ho rapidlyeliminate theophylline" Theophylline retention enemas usually produce pea/ serumconcentrations in 1$' hours" Serum theophylline concentrations generally have een apparent +$-hours after administration of the drug as rectal suppositories (no longer commercially availalein the 3S)"

• Distri)ution

Theophylline is rapidly distriuted throughout extracellular fluids and ody tissues !ithdistriution e2uilirium eing reached 1 hour after an %< loading dose" The drug partially penetrates erythrocytes and readily crosses the placenta"

The drug is also distriuted into mil/ in concentrations aout C?@ those in serum"

The apparent volume of distriution of theophylline ranges from ?"+$?"C 9./g and averages aout?"- 9./g in children and adults" %n premature infants, theophyllineGs apparent volume ofdistriution is generally almost ' times that in adults" ;t serum concentrations of 1C mcg.m9,approximately -6@ of theophylline in adults and children, and +6@ of that in premature infants,is ound to plasma proteins" ;lthough saliva concentrations of theophylline have een reportedto e -?@ of serum concentrations in relatively healthy patients, saliva concentrations rangedfrom -?$1??@ of serum concentrations in one study in severely ill patients"

• #limination%n maintenance$dose theophylline schedules, serum concentrations among patients vary at least6$fold and serum half$lives (t 1.') exhiit !ide interpatient variation ecause of differences in rateof metaolism" Serum t 1.' ranges from aout +$1'"8 (average C$D) hours in other!ise healthy,nonsmo/ing asthmatic adults, from aout 1"-$D"- hours in children, and from aout 1-$-8 hoursin premature infants" Theophylline clearances (mean I standard deviation) have een reported to e 1"- I ?"-8 m9./g per minute in children older than 6 months of age and ?"6- I ?"1D m9./g per hour in other!ise healthy, nonsmo/ing asthmatic adults" %n adults, a shorter serum t 1.' of


19/25

aout ' hours has een demonstrated for dyphylline" hen compared !ith that of other!isehealthy, nonsmo/ing asthmatic adults, the serum t 1.' of theophylline may e increased and total ody clearance decreased in patients !ith congestive heart failure, chronic ostructive pulmonary disease, cor pulmonale, or liver disease, and in geriatric patients" %n cigarette and.ormariuana smo/ers, theophylline serum t 1.' averages $- hours and total ody clearance is

increased compared !ith nonsmo/ers"

Theophylline is metaoli#ed y the liver to 1,+$dimethyluric acid, 1$methyluric acid, and +$methylxanthine" The metaolism of dyphylline has not een fully elucidated, ut the drug is not metaoli#ed to theophylline" %ndividuals metaoli#e theophylline at different rates* ho!ever,individual metaolism of the drug is generally reproducile" Theophylline and its metaolites areexcreted mainly y the /idneys" Renal clearance of the drug, ho!ever, contriutes only 8$1'@ of the overall plasma clearance of theophylline" Small amounts of theophylline are excreted in fecesunchanged"

Chemistry

• Theophylline9i/e caffeine and theoromine, theophylline may e structurally classified as a xanthinederivative" Theophylline occurs naturally in tea, ut it is prepared synthetically for commercialuse" The drug may contain one molecule of !ater or e anhydrous" ;t physiologic p,theophylline functions as a !ea/ ase (pV 1+$1)" Tautomeric shift of the hydrogen from theunsustituted C nitrogen is possile at high p, creating a !ea/ organic acid (pV a 8"CD) thatreacts !ith al/ali salts of !ea/ organic acids and certain organic amines" Theophylline occurs asa !hite, odorless, crystalline po!der having a itter taste and is sparingly solule in alcohol" Thedrug is only slightly solule in !ater at p C* the !ater soluility increases !ith increases in p"

• Aminophylline

;minophylline is a !ater$solule theophylline compound !ith ethylenediamine and occurs as!hite or slightly yello!ish granules or po!der having a slight ammoniacal odor and a ittertaste" ;minophylline is solule in !ater and insolule in alcohol" ;minophylline has a pV a of -";minophylline may e anhydrous or may contain not more than ' molecules of !ater ofhydration" 3pon exposure to air, aminophylline and aminophylline solutions gradually loseethylenediamine, asor caron dioxide, and lierate free theophylline* aminophylline solutionsshould not e used if they contain crystals" ;minophylline inection has a p of 8"6$D and should e stored in single$dose containers from !hich caron dioxide has een excluded"

;minophylline inections reportedly are not stale in solutions having a p sustantially lessthan 8* ho!ever, the drug appears to e relatively stale in large volume parenteral solutions over

a !ide p range (+"-$8"6) if aminophylline concentrations do not exceed ? mg (+1"6 mg ofanhydrous theophylline) per m9" The activity of al/ali$sensitive drugs !ill e reduced yaminophylline* these drugs should not e added to %< fluids containing aminophylline" =ulisheddata on specific incompatiilities of aminophylline are varied and.or limited* speciali#edreferences should e consulted for specific compatiility information"

• Dyphylline


20/25

Byphylline, !hich is a distinct chemical entity, is structurally and pharmacologically similar totheophylline ut has a ',+$dihydroxypropyl radical at position C" Byphylline is not metaoli#edto theophylline in vivo" Byphylline occurs as a !hite, odorless, amorphous or crystalline solidhaving an extremely itter taste" Byphylline is freely solule in !ater and sparingly solule inalcohol" Byphylline inection has a p of 6"$C" and should e protected from light"

• O*triphylline

xtriphylline (no longer commercially availale in the 3S), the choline salt of theophylline,occurs as a !hite, crystalline po!der having an amine$li/e odor and a slightly saline taste"xtriphylline is freely solule in !ater and in alcohol"

'reparations

availale generically

;minophylline (ydrous)Routes Bosage Strengths Arand James Manufacturer >orms ral Talets 1?? mg (C8"D mg of

anhydrous ;minophylline est$!ard theophylline) Talets '?? mg (1-C"8 mg of anhydrous;minophylline est$!ard theophylline) Talets =arenteral %nection '- mg (1D"C mg ofanhydrous ;minophylline ;merican theophylline) per m9 %nection Regent, ospira


;minophylline (;nhydrous)Routes Bosage Strengths Arand James Manufacturer >orms ral Solution 1?- mg (D? mg ofAminophylline D,- (dye$free) ;ctavis anhydrous theophylline) per - m9 ;minophylline ralSolution Roxane

ByphyllineRoutes Bosage Strengths Arand James Manufacturer >orms ral Solution ++ mg.- m9 Dyli*- #li*ir (!ith alcohol '?@) 9unsco (ufyllin- #li*ir (!ith alcohol '?@) Med=ointe Talets '??mg Dilor- (!ith povidone* scored) Savage (ufyllin- (scored) Med=ointe ?? mg Dilor- (!ith povidone* scored) Savage (ufyllin- (scored) Med=ointe

Byphylline and FuaifenesinRoutes Bosage Strengths Arand James Manufacturer >orms ral Solution ++"+ mg.- m9Byphylline Dyphylline GG- (!ith alcohol ;ctavis, and Fuaifenesin ++"+ mg. 1C@) 7ypress -m9 (ufyllin-.GG #li*ir (!ith Med=ointe alcohol 1C@) 1?? mg.- m9 Byphylline and Dilor.G- (!ith paraens) Savage Fuaifenesin 1?? mg.- m9 Dy.G- (alcohol$free, dye$free) 7ypress

Dyline.GG-

Seatrace Talets '?? mg Byphylline and Dilor.G-

(!ith povidone* SavageFuaifenesin '?? mg scored) Dyfle*-.G 0conoMed Dyline.GG- (scored) Seatrace Dyphylline.GG- 3nited Research (ufyllin-.GG (scored) Med=ointe

Byphylline 7ominationsRoutes Bosage Strengths Arand James Manufacturer >orms ral Talets 1?? mg !ith0phedrine ydrochloride 16 (ufyllin-.#'G Med=ointe mg, Fuaifenesin '?? mg, and=henoarital 16 mg


21/25


Theophylline (;nhydrous)Routes Bosage Strengths Arand James Manufacturer >orms Aul/ =o!der ral 7apsules, 1??

mg Theo./0

-

(' hours) 37A extended$ release 1'- mg Theophylline 0xtended$Release7apsules (1' %n!ood hours) '?? mg Theo./0- (' hours) 37A Theophylline 0xtended$Release7apsules (1' %n!ood hours) +?? mg Theo./0- (' hours) 37A Theophylline 0xtended$Release7apsules (1' %n!ood hours) ?? mg Theo./0- (' hours) 37A Solution 'C mg.- m9#li*ophyllin- #li*ir (!ith alcohol '?@) >orest Theophylline "olution ;ctavis, Roxane Talets1'- mg Theolair- (scored) +M '-? mg Theolair- (scored) +M +?? mg ui)ron-.T (scored)Monarch Talets, 1?? mg Theochron- (1' hours, scored) >orest extended$ releaseTheophylline #*tended.%elease Ta)lets (1' hours) %n!ood '?? mg Theochron- (1' hours,scored) >orest Theophylline #*tended.%elease Ta)lets (1' hours) %n!ood +?? mg ui)ron-.T2"% (1' hours, scored) Monarch Theochron- (1' hours, scored) >orest Theophylline#*tended.%elease Ta)lets (1' hours) %n!ood ?? mg Uniphyl- Unicontin- (' hours, scored*!ith =urdue povidone) >rederic/ 6?? mg Uniphyl- Unicontin- (' hours, scored* !ith =urdue providone) >rederic/

Theophylline (;nhydrous) in BextroseRoutes Bosage >orms Strengths Arand James Manufacturer =arenteral %nection, ?" mg.m9(?? mg) Theophylline Theophylline and -@ Bextrose %nection


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Theo$' '??MF 7=' (37A =;RM;): 6?.X8"DD or 18?.X1+?"DC

Theo$' +??MF 7=' (37A =;RM;): 6?.X6'"DD or 18?.X1C"D6

Theo$' ??MF 7=' (37A =;RM;): 6?.XCD"DD or 18?.X'''"DC

Theochron '??MF TA1' (>R0ST): 6?.X+?"C or 18?.X88"C'

Theophylline 7R 1??MF TA1' (=9%


23/25

'1" Jational ;sthma 0ducation =rogram" 0xecutive summary: guidelines for the diagnosis andmanagement of asthma" J% =ul" Jo"D$+?';" ashington, B7: 3S Fovernment =rintingffice* 1DD Zul"

'1-" Aritish Thoracic Society" Fuidelines on the management of asthma" Thorax" '??+* -8(1

Suppl):i1$D"

'16" GBonnell B0, ;aron S, Aoureau Z et al" State of the art compendium: 7anadian ThoracicSociety recommendations for management of chronic ostructive pulmonary disease" Can 3espir 4 " '??* 11 (Suppl" A):CA$-DA" 4=uMed 1-+?-815

'1C" 7elli AR, Macnee " Standard for the diagnosis and treatment of patients !ith 7=B: asummary of the ;TS.0RS position paper" 8ur 3espir 4 " '??* '+:D+'$6" 4=uMed 1-'1D?1?5

'18" ;TS.0RS Standards for the diagnosis and management of patients !ith 7=B" Je! or/, J: ;merican Thoracic Society, 0uropean Respiratory Society* '??" ;vailale athttp:..!!!"thoracic"org.7=B." ;ccessed Bec" 8, '??"

'1D" Sno!


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''C" ;merican Regent 9aoratories, %nc" ;minophylline inection, 3S= prescriing information"Shirley, J* 1DDD Zune"

''8" A" Araun Medical %nc" Theophylline in -@ dextrose inections 3S= prescriing information"%rvine, 7;* '??+ ;ug"

''D" >orest =harmaceuticals, %nc" 0lixophyllinH(theophylline anhydrous) elixir prescriinginformation" St" 9ouis, M* 1DDD May"

'+?" 9unsco, %nc" Bylix H(dyphylline elixir, 3S=) prescriing information" =ulus/i,


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