Download Theo-24®(theophylline anhydrous) Extended

T HEO-24 - theo phylline anhydro us caps ule, extended releas e
Actient Pharmaceuticals LLC
---------T heo -24 ®
(theo phylline anhydro us )
Extended-releas e caps ules 10 0 , 20 0 , 3 0 0 , & 4 0 0 mg
Rx Only
DESCRIPT ION
Theophylline
T heo phylline is structurally classified as a methylxanthine. It o ccurs as a white, o do rless,
crystalline po wder with a bitter taste. Anhydro us theo phylline has the chemical name 1H-Purine-2,
6 -dio ne, 3, 7- dihydro -1, 3-dimethyl-, and is represented by the fo llo wing structural fo rmula:
T he mo lecular fo rmula o f anhydro us theo phylline is C 7 H8 N4 O2 with a mo lecular weig ht o f 18 0
.17. T heo -24 is available as capsules intended fo r o ral administratio n, co ntaining 10 0 mg , 20 0 mg ,
30 0 mg , o r 4 0 0 mg o f anhydro us theo phylline per capsule, in an extended-release fo rmulatio n
which allo ws a 24 -ho ur do sing interval fo r appro priate patients.
Inactive ing redients are edible ink (which co ntains synthetic black iro n o xide, FD&C Blue No . 1,
FD&C Blue No . 2, FD&C Yello w No . 6 , D&C Yello w No . 10 , FD&C Red No . 4 0 ), ethylcellulo se,
g elatin, pharmaceutical g laze, co llo idal silico n dio xide, starch, sucro se, talc, titanium dio xide, and co
lo ring ag ents: 10 0 mg - includes FD&C Yello w No . 6 ; 20 0 mg - FD&C Red No . 3 and D&C Yello w
No . 10 ; 30 0 mg - FD&C Blue No . 1 and FD&C Red No . 4 0 ; 4 0 0 mg - FD&C Red No . 4 0 and D&C
Red No 28 .
T heo -24 Extended-release capsules meet Drug Release T est 6 as published in the current USP
monograph fo r T heo phylline Extended-release Capsules.
CLINICAL
PHARMACOLOGY
Mechanis m o f Actio n:
T heo phylline has two distinct actio ns in the airways o f patients with reversible o bstruction:
smoothmuscle relaxation (i.e., bro ncho dilatio n) and suppressio n o f the response o f the airways to
stimuli (i.e., no n-bro ncho dilato r pro phylactic effects). While the mechanisms o f actio n o f
theophylline are no t kno wn with certainty, studies in animals sug g est that bro ncho dilatio n is
mediated by the inhibition o f two iso zymes o f pho spho diesterase (PDE III and, to a lesser extent,
PDE IV) while no n-bro ncho dilato r pro phylactic actio ns are pro bably mediated thro ug h o ne o r mo re
different mo lecular mechanisms that do no t invo lve inhibitio n o f PDE III o r antag o nism o f adeno sine
recepto rs. So me o f the adverse effects asso ciated with theo phylline appear to be mediated by
inhibitio n o f PDE III (e.g, hypo tensio n, tachycardia, headache, and emesis) and adeno sine recepto r
antag o nism (e.g ., alteration ns in cerebral blo o d flo w).
T heo phylline increases the fo rce o f co ntractio n o f diaphrag matic muscles. T his actio n appears to
be due to enhancement o f calcium uptake thro ug h an adeno sine-mediated channel.
Serum Co ncentratio n-Effect Relatio ns hip:
Bro ncho dilatio n o ccurs o ver the serum theo phylline co ncentratio n rang e o f 5 - 20 mcg /mL.
Clinically impo rtant impro vement in sympto m co ntro l has been fo und in mo st studies to require peak
serum theo phylline co ncentratio ns >10 mcg /mL, but patients with mild disease may benefit fro m
lower co ncentratio ns. At serum theo phylline co ncentratio ns >20 mcg /mL, bo th the frequency and
severity o f adverse reactio ns increase. In g eneral, maintaining peak serum theo phylline
concentrations between 10 and 15 mcg /mL will achieve mo st o f the drug 's po tential therapeutic
benefit while minimizing the risk o f serio us adverse events.
Pharmacokinetics :
Overview T heo phylline is rapidly and co mpletely abso rbed after o ral administratio n in so lutio n o r
immediate-release so lid o ral do sag e fo rm. T heo phylline do es no t underg o any appreciable presystemic eliminatio n, distributes freely into fat-free tissues and is extensively metabo lized in the
liver.
T he pharmaco kinetics o f theo phylline vary widely amo ng similar patients and canno t be predicted by
ag e, sex, bo dy weig ht o r o ther demo g raphic characteristics. In additio n, certain co ncurrent illnesses
and alteratio ns in no rmal physio lo g y (see T able I) and co -administratio n o f o ther drug s (see T able II)
can sig nificantly alter the pharmaco kinetic characteristics o f theo phylline. Within-subject variability
in metabo lism has also been repo rted in so me studies, especially in acutely ill patients. It is, therefore,
reco mmended that serum theo phylline co ncentratio ns be measured frequently in acutely illpatients (e.g,
at 24-hr intervals) and perio dically in patients receiving lo ng -term therapy, e.g , at 6 -12 mo nth
intervals. Mo re frequent measurements sho uld be made in the presence o f any co nditio n that may sig
nificantly alter theo phylline clearance (see PRECAUT IONS, Labo rato ry T ests).
Abs o rptio n T heo phylline is rapidly and co mpletely abso rbed after o ral administratio n in so lutio n o r
immediate-release so lid o ral do sag e fo rm. After a sing le immediate-release do se o f 5 mg /kg in
adults, a mean peak serum co ncentratio n o f abo ut 10 mcg /mL (rang e 5 - 15 mcg /mL) can be expected
1-2 hr after do se. Co -administratio n o f theo phylline with fo o d o r antacids do es no t cause clinically
sig nificant chang es in the abso rptio n o f theo phylline fro m immediate-release do sag e fo rms.
T heo -24 ® capsules co ntain hundreds o f co ated beads o f theo phylline. Each bead is an individual
extended-release delivery system. After disso lutio n o f the capsules these beads are released and
distributed in the g astro intestinal tract, thus minimizing the pro bability o f hig h lo cal co ncentratio ns o f
theo phylline at any particular site.
In a 6 -day multiple-do se study invo lving 18 subjects (with theo phylline clearance rates between 0.57
and 1.0 2 mL/kg /min) who had fasted o vernig ht and 2 ho urs after mo rning do sing, T heo -24 ® g iven
once daily in a do se o f 150 0 mg pro duced serum theo phylline levels that rang ed between 5.7 mcg
/mL and 22 mcg /mL. T he mean minimum and maximum values were 11.6 mcg /mL and 18 .1 mcg /mL,
respectively, with an averag e peak-tro ug h difference o f 6 .5 mcg /mL. T he mean percent fluctuatio n
[(C max –C min /C min ) × 10 0 ] equals 8 0 %. A 24 -ho ur sing le-do se study demo nstrated an
approximately pro po rtio nal increase in serum levels as the do se was increased fro m 6 0 0 to 150 0 mg
.
T aking T heo -24 ® with a hig h-fat-co ntent meal may result in a sig nificant increase in the peak
serum level and in the extent o f abso rptio n o f theo phylline as co mpared to administratio n in the
fasted state (see PRECAUT IONS, Drug /Fo o d Interactio ns).
Fo llo wing the sing le-do se administratio n (8 mg /kg ) o f T heo -24 ® to 20 no rmal subjects who had
fasted o vernig ht and 2 ho urs after mo rning do sing , peak serum theo phylline co ncentratio ns o f 4 .8 ±
1.5 (SD) mcg /mL were o btained at 13.3 ± 4 .7 (SD) ho urs. T he amo unt o f the do se abso rbed was
appro ximately 13% at 3 ho urs, 31% at 6 ho urs, 55% at 12 ho urs, 70 % at 16 ho urs, and 8 8 % at 24
hours. T he extent o f theophylline bio availability fro m T heo -24 ® was co mparable to the mo st
widely used 12-ho ur extended- release pro duct when bo th pro ducts were administered every 12
hours.
Dis tributio n Once theo phylline enters the systemic circulatio n, abo ut 4 0 % is bo und to plasma
protein, primarily albumin. Unbo und theo phylline distributes thro ug ho ut bo dy water, but distributes
po o rly into bo dy fat. T he apparent vo lume o f distributio n o f theo phylline is appro ximately 0.45 L/kg
(rang e 0 .3 - 0 .7 L/kg ) based o n ideal bo dy weig ht. T heo phylline passes freely acro ss the placenta,
into breast milk and into the cerebro spinal fluid (CSF). Saliva theo phylline co ncentratio ns appro
ximate unbo und serum co ncentratio ns, but are no t reliable fo r ro utine o r therapeutic momitoring
unless special techniques are used. An increase in the vo lume o f distributio n o f theophylline,
primarily due to reductio n in plasma pro tein binding , o ccurs in premature neo nates, patients with
hepatic cirrho sis, unco rrected acidemia, the elderly and in wo men during the third trimester o f preg
nancy. In such cases, the patient may sho w sig ns o f to xicity at to tal (bound+unbound) serum co
ncentratio ns o f theo phylline in the therapeutic rang e (10 - 20 mcg /mL) due to elevated co ncentratio
ns o f the pharmaco lo g ically active unbo und drug . Similarly, a patient with decreased theo phylline
binding may have a sub-therapeutic to tal drug co ncentratio n while the pharmaco lo g ically active
unbo und co ncentratio n is in the therapeutic rang e. If o nly to tal serum theophylline co ncentratio n is
measured, this may lead to an unnecessary and po tentially dang ero us do se increase. In patients with
reduced pro tein binding , measurement o f unbo und serum theophylline co ncentratio n pro vides a mo
re reliable means o f do sag e adjustment than measurement o f to tal serum theo phylline co ncentratio n.
Generally, co ncentratio ns o f unbo und theo phylline should be maintained in the rang e o f 6 - 12 mcg
/mL.
Metabo lis m Fo llo wing o ral do sing , theo phylline do es no t underg o any measurable first-pass
eliminatio n. In adults and children beyo nd o ne year o f ag e, appro ximately 9 0 % o f the do se is
metabolized in the liver. Bio transfo rmatio n takes place thro ug h demethylatio n to 1-methylxanthine and
3- methylxanthine and hydro xylatio n to 1,3-dimethyluric acid. 1-methylxanthine is further
hydroxylated, by xanthine o xidase, to 1-methyluric acid. Abo ut 6 % o f a theo phylline do se is Nmethylated to caffeine. T heo phylline demethylatio n to 3-methylxanthine is catalyzed by cyto chro me
P-4 50 1A2, while cyto chro mes P-4 50 2E1 and P-4 50 3A3 catalyze the hydro xylatio n to 1,3dimethyluric acid. Demethylatio n to 1-methylxanthine appears to be catalyzed either by cyto chro me
P-4 50 1A2 o r a clo sely related cyto chro me. In neo nates, the N-demethylatio n pathway is absent while
the functio n o f the hydro xylatio n pathway is markedly deficient. T he activity o f these pathways slo
wly increases to maximal levels by o ne year o f ag e.
Caffeine and 3-methylxanthine are the o nly theo phylline metabo lites with pharmaco lo g ic activity. 3methylxanthine has appro ximately o ne tenth the pharmaco lo g ic activity o f theo phylline and serum
concentratio ns in adults with no rmal renal functio n are <1 mcg /mL. In patients with end-stag e renal
disease, 3-methylxanthine may accumulate to co ncentratio ns that appro ximate the unmetabo lized
theophylline co ncentratio n. Caffeine co ncentratio ns are usually undetectable in adults reg ardless o f
renal functio n. In neo nates, caffeine may accumulate to co ncentratio ns that appro ximate the
unmetabolized theo phylline co ncentratio n and thus, exert a pharmaco lo g ic effect.
Bo th the N-demethylatio n and hydro xylatio n pathways o f theo phylline bio transfo rmatio n are capacitylimited. Due to the wide intersubject variability o f the rate o f theo phylline metabo lism, no n-linearity o f
eliminatio n may beg in in so me patients at serum theo phylline co ncentratio ns <10 mcg /mL. Since this
non-linearity results in mo re than pro po rtio nal chang es in serum theo phylline co ncentratio ns with
changes in do se, it is advisable to make increases o r decreases in do se in small increments in o rder to
achieve desired chang es in serum theo phylline co ncentratio ns (see DOSAGE AND
ADMINISTRATION, Table VI). Accurate predictio n o f do se-dependency o f theo phylline metabo lism
in patients a priori is no t po ssible, but patients with very hig h initial clearance rates (i.e., lo w steady
state serum theo phylline co ncentratio ns at abo ve averag e do ses) have the g reatest likelihood of
experiencing larg e chang es in serum theo phylline co ncentratio n in respo nse to do sag e chang es.
Excretio n In neo nates, appro ximately 50 % o f the theo phylline do se is excreted unchang ed in the
urine. Beyo nd the first three mo nths o f life, appro ximately 10 % o f the theo phylline do se is excreted
unchang ed in the urine. T he remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35 - 4
0 %), 1-methyluric acid (20 - 25%) and 3-methylxanthine (15 - 20 %). Since little theophylline is
excreted unchang ed in the urine and since active metabo lites o f theo phylline (i.e., caffeine, 3methylxanthine) do no t accumulate to clinically sig nificant levels even in the face o f end-stag e renal
disease, no do sag e adjustment fo r renal insufficiency is necessary in adults and children >3 mo nths o
f ag e. In co ntrast, the larg e fractio n o f the theo phylline do se excreted in the urine as unchang ed theo
phylline and caffeine in neo nates requires careful attentio n to do se reduction and frequent mo nito ring
o f serum theo phylline co ncentratio ns in neo nates with reduced renal functio n (see WARNINGS).
Serum Co ncentratio ns at Steady State After multiple do ses o f theo phylline, steady state is reached
in 30 – 6 5 ho urs (averag e 4 0 ho urs) in adults. At steady state, o n a do sag e reg imen with 6 -ho ur
intervals, the expected mean tro ug h co ncentratio n is appro ximately 6 0 % o f the mean peak
concentration, assuming a mean theo phylline half-life o f 8 ho urs. T he difference between peak and
troug h co ncentratio ns is larg er in patients with mo re rapid theo phylline clearance. In patients with high
theo phylline clearance and half-lives o f abo ut 4 -5 ho urs, such as children ag e 1 to 9 years, the tro ug h
serum theo phylline co ncentratio n may be o nly 30 % o f peak with a 6 -ho ur do sing interval. In these
patients a slo w release fo rmulatio n wo uld allo w a lo ng er do sing interval (8 - 12 ho urs) with a smaller
peak/tro ug h difference.
Special Populations (See Table I for mean clearance and half-life values)
Geriatric T he clearance o f theo phylline is decreased by an averag e o f 30 % in healthy elderly adults
(>6 0 yrs) co mpared to healthy yo ung adults. Careful attentio n to do se reductio n and frequent
monitoring o f serum theo phylline co ncentratio ns are required in elderly patients (see WARNINGS).
Pediatrics T he clearance o f theo phylline is very lo w in neo nates (see WARNINGS). T heo phylline
clearance reaches maximal values by o ne year o f ag e, remains relatively co nstant until abo ut 9 years
o f ag e and then slo wly decreases by appro ximately 50 % to adult values at abo ut ag e 16 . Renal
excretio n o f unchang ed theo phylline in neo nates amo unts to abo ut 50 % o f the do se, co mpared to
about 10 % in children o lder than three mo nths and in adults. Careful attentio n to do sag e selectio n and
mo nito ring o f serum theo phylline co ncentratio ns are required in pediatric patients (see WARNINGS
and DOSAGE AND ADMINIST RAT ION).
Gender Gender differences in theo phylline clearance are relatively small and unlikely to be o f
clinical sig nificance. Sig nificant reductio n in theo phylline clearance, ho wever, has been repo rted in
wo men o n the 20 th day o f the menstrual cycle and during the third trimester o f preg nancy.
Race Pharmaco kinetic differences in theo phylline clearance due to race have no t been studied.
Renal Insufficiency Only a small fractio n, e.g ., abo ut 10 %, o f the administered theo phylline do se
is excreted unchang ed in the urine o f children g reater than three mo nths o f ag e and adults. Since
little theo phylline is excreted unchang ed in the urine and since active metabo lites o f theophylline
(i.e., caffeine, 3-methylxanthine) do no t accumulate to clinically sig nificant levels even in the
face o f end- stag e renal disease, no do sag e adjustment fo r renal insufficiency is necessary in
adults and children >3 mo nths o f ag e. In co ntrast, appro ximately 50 % o f the administered theo
phylline do se is excreted unchang ed in the urine in neo nates. Careful attentio n to do se reductio n
and frequent mo nito ring o f serum theo phylline co ncentratio ns are required in neo nates with
decreased renal functio n (see WARNINGS).
Hepatic Insufficiency T heo phylline clearance is decreased by 50 % o r mo re in patients with hepatic
insufficiency (e.g ., cirrho sis, acute hepatitis, cho lestasis). Careful attentio n to do se reductio n and
frequent mo nito ring o f serum theo phylline co ncentratio ns are required in patients with reduced
hepatic functio n (see WARNINGS).
Co ng estive Heart Failure (CHF) T heo phylline clearance is decreased by 50 % o r mo re in patients
with CHF. T he extent o f reductio n in theo phylline clearance in patients with CHF appears to be
directly co rrelated to the severity o f the cardiac disease. Since theo phylline clearance is
independent o f liver blo o d flo w, the reductio n in clearance appears to be due to impaired hepatocyte
functio n rather than reduced perfusio n. Careful attentio n to do se reductio n and frequent monitoring o
f serum theo phylline co ncentratio ns are required in patients with CHF (see WARNINGS).
Smo kers T o bacco and marijuana smo king appears to increase the clearance o f theo phylline by
inductio n o f metabo lic pathways. T heo phylline clearance has been sho wn to increase by
approximately 50 % in yo ung adult to bacco smo kers and by appro ximately 8 0 % in elderly to bacco
smo kers co mpared to no n- smo king subjects. Passive smo ke expo sure has also been sho wn to
increase theo phylline clearance by up to 50 %. Abstinence fro m to bacco smo king fo r o ne week
causes a reductio n o f appro ximately 4 0 % in theo phylline clearance. Careful attentio n to do se
reductio n and frequent mo nito ring o f serum theo phylline co ncentratio ns are required in patients who
sto p smo king (see WARNINGS). Use o f nico tine g um has been sho wn to have no effect o n
theophylline clearance.
Fever Fever, reg ardless o f its underlying cause, can decrease the clearance o f theo phylline. T he
mag nitude and duratio n o f the fever appear to be directly co rrelated to the deg ree o f decrease o f
theo phylline clearance. Precise data are lacking , but a temperature o f 39 ° C (10 2° F) fo r at least 24
ho urs is pro bably required to pro duce a clinically sig nificant increase in serum theo phylline
concentratio ns. Children with rapid rates o f theo phylline clearance (i.e., tho se who require a do se
that is substantially larg er than averag e [e.g ., >22 mg /kg /day] to achieve a therapeutic peak serum
theo phylline co ncentratio n when afebrile) may be at g reater risk o f to xic effects fro m decreased
clearance during sustained fever. Careful attentio n to do se reductio n and frequent mo nito ring o f
serum theo phylline co ncentratio ns are required in patients with sustained fever (see WARNINGS).
Miscellaneo us
Other facto rs asso ciated with decreased theo phylline clearance include the third trimester o f
pregnancy, sepsis with multiple o rg an failure, and hypo thyro idism. Careful attentio n to do se
reductio n and frequent mo nito ring o f serum theo phylline co ncentratio ns are required in patients
with any o f these co nditio ns (see WARNINGS). Other facto rs asso ciated with increased
theophylline clearance include hyperthyro idism and cystic fibro sis.
Clinical Studies:
In patients with chro nic asthma, including patients with severe asthma requiring inhaled co rtico
steroids o r alternate-day o ral co rtico stero ids, many clinical studies have sho wn that theo phylline
decreases the frequency and severity o f sympto ms, including no cturnal exacerbatio ns, and
decreases the "as needed" use o f inhaled beta2 ag o nists. T heo phylline has also been sho wn to
reduce the need fo r sho rt co urses o f daily o ral predniso ne to relieve exacerbatio ns o f airway
obstructio n that are unrespo nsive to bro ncho dilato rs in asthmatics.
In patients with chro nic o bstructive pulmo nary disease (COPD), clinical studies have sho wn that
theophylline decreases dyspnea, air trapping , the wo rk o f breathing , and impro ves contractility o f
diaphrag matic muscles with little o r no impro vement in pulmo nary functio n measurements.
INDICATIONS AND USAGE
T heo phylline is indicated fo r the treatment o f the sympto ms and reversible airflo w obstructio n
associated with chro nic asthma and o ther chro nic lung diseases, e.g ., emphysema and chro nic
bronchitis.
CONTRAINDICATIONS
T heo -24 is co ntraindicated in patients with a histo ry o f hypersensitivity to theo phylline o r
other co mpo nents in the pro duct.
WARNINGS Concurrent Illness:
T heo phylline sho uld be used with extreme cautio n in patients with the fo llo wing clinical co nditio ns
due to the increased risk o f exacerbatio n o f the co ncurrent co nditio n:
Active peptic ulcer disease
Seizure diso rders
Cardiac arrhythmias (no t including bradyarrhythmias)
Co nditio ns T hat Reduce T heo phylline Clearance
T here are several readily identifiable causes o f reduced theo phylline clearance. If the total daily
dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal
theophylline toxicity can occur. Careful co nsideratio n must be g iven to the benefits and risks o f
theophylline use and the need fo r mo re intensive mo nito ring o f serum theo phylline co ncentratio ns in
patients with the fo llo wing risk facto rs:
Age
Neonates (term and premature)
Children <1 year
Elderly (>6 0 years)
Concurrent Diseases
Acute pulmo nary edema
Co ng estive heart failure
Cor-pulmo nale
Fever; ≥10 2°F fo r 24 ho urs o r mo re; o r lesser temperature elevatio ns fo r lo ng er perio ds
Hypo thyro idism
Liver disease; cirrho sis, acute hepatitis
Reduced renal functio n in infants <3 mo nths o f ag e
Sepsis with multi-o rg an failure
Sho ck
Ces sation of Smoking
Drug Interactio ns Adding a drug that inhibits theo phylline metabo lism (e.g ., cimetidine,
erythromycin, tacrine) o r sto pping a co ncurrently administered drug that enhances theo phylline
metabolism (e.g ., carbamazepine, rifampin) (see PRECAUT IONS, Drug Interactio ns, T able II).
When Sig ns o r Sympto ms o f T heo phylline T o xicity Are Pres ent: Whenever a patient receiving
theophylline develops nausea or vomiting, particularly repetitive vomiting, or other s igns or sympto
ms cons is tent with theophylline to xicity (even if another caus e may be s us pected), additional dos es
of theophylline s hould be withheld and a s erum theophylline concentration meas ured immediately.
Patients sho uld be instructed no t to co ntinue any do sag e that causes adverse effects and to withho ld
subsequent do ses until the sympto ms have reso lved, at which time the healthcare pro fessio nal may
instruct the patient to resume the drug at a lo wer do sag e (see DOSAGE AND ADMINIST RAT ION,
Do sing Guidelines, T able VI).
Dosage Increases:
Increases in the do se o f theo phylline sho uld no t be made in respo nse to an acute exacerbatio n o f
sympto ms o f chro nic lung disease since theo phylline pro vides little added benefit to inhaled beta2selective ag o nists and systemically administered co rtico stero ids in this circumstance and increases
the risk o f adverse effects. A peak steady-state serum theo phylline co ncentratio n sho uld be measured
befo re increasing the do se in respo nse to persistent chro nic sympto ms to ascertain whether an
increase in do se is safe. Befo re increasing the theo phylline do se o n the basis o f a lo w serum co
ncentratio n, the healthcare pro fessio nal sho uld co nsider whether the blo o d sample was obtained at an
appro priate time in relatio nship to the do se and whether the patient has adhered to the prescribed reg
imen (see PRECAUT IONS, Labo rato ry T ests).
As the rate o f theo phylline clearance may be do se-dependent (i.e., steady-state serum
concentrations may increase dispro po rtio nately to the increase in do se), an increase in do se based
upo n a sub- therapeutic serum co ncentratio n measurement sho uld be co nservative. In g eneral,
limiting do se increases to abo ut 25% o f the previo us to tal daily do se will reduce the risk o f
unintended excessive increases in serum theo phylline co ncentratio n (see DOSAGE AND
ADMINIST RAT ION, T able VI).
PRECAUTIONS
General:
Careful co nsideratio n o f the vario us interacting drug s and physio lo g ic co nditio ns that can alter
theophylline clearance and require do sag e adjustment sho uld o ccur prio r to initiatio n o f theo phylline
therapy, prio r to increases in theo phylline do se, and during fo llo w up (see WARNINGS). T he do se o
f theo phylline selected fo r initiatio n o f therapy sho uld be lo w and, if tolerated, increased slo wly over
a perio d o f a week o r lo ng er with the final do se g uided by mo nito ring serum theo phylline
concentratio ns and the patient's clinical respo nse (see DOSAGE AND ADMINIST RAT ION, T able
V).
Monitoring Serum Theophylline Co ncentrations:
Serum theophylline co ncentratio n measurements are readily available and sho uld be used to determine
whether the do sag e is appro priate. Specifically, the serum theophylline co ncentratio n sho uld be
measured as follo ws:
1. When initiating therapy to g uide final dosag e adjustment after titratio n.
2. Befo re making a do se increase to determine whether the serum co ncentratio n is sub-therapeutic
in a patient who co ntinues to be sympto matic.
3. Whenever sig ns o r sympto ms o f theophylline to xicity are present.
4 . Whenever there is a new illness, wo rsening o f a chro nic illness o r a chang e in the patient's
treatment reg imen that may alter theo phylline clearance (e.g ., fever >10 2° F sustained fo r ≥24 ho urs,
hepatitis, o r drug s listed in T able II are added o r disco ntinued).
T o g uide a do se increase, the blo o d sample sho uld be o btained at the time o f the expected peak
serum theo phylline co ncentratio n; 12 ho urs after a do se at steady-state (expected peak serum
theophylline co ncentratio n rang e is between 5 –15 mcg /mL). Fo r mo st patients, steady-state will be
reached after 3 days o f do sing when no do ses have been missed, no extra do ses have been added, and
no ne o f the do ses have been taken at unequal intervals. A tro ug h co ncentratio n (i.e., at the end o f the
do sing interval) pro vides no additio nal useful info rmatio n and may lead to an inappro priate do se
increase since the peak serum theo phylline co ncentratio n can be two o r mo re times g reater than the
tro ug h co ncentratio n with an extended-release fo rmulatio n. If the serum sample is drawn mo re o r less
than twelve (12) ho urs after the do se, the results must be interpreted with cautio n since the
concentratio n may no t be reflective o f the peak co ncentratio n. In co ntrast, when sig ns o r sympto ms o f
theo phylline to xicity are present, the serum sample sho uld be o btained as so o n as po ssible, analyzed
immediately, and the result repo rted to the healthcare pro fessio nal witho ut delay. In patients in who m
decreased serum pro tein binding is suspected (e.g ., cirrho sis, wo men during the third trimester o f
preg nancy), the co ncentratio n o f unbo und theo phylline sho uld be measured and the do sag e adjusted to
achieve an unbo und co ncentratio n o f 6 - 12 mcg /mL.
Saliva co ncentratio ns o f theo phylline canno t be used reliably to adjust do sag e witho ut special
techniques.
Effects o n Labo rato ry T es ts:
As a result o f its pharmaco lo g ical effects, theo phylline at serum co ncentratio ns within the 10 - 20
mcg /mL rang e mo destly increases plasma g luco se (fro m a mean o f 8 8 mg % to 9 8 mg %), uric acid
(fro m a mean o f 4 mg /dL to 6 mg /dL), free fatty acids (fro m a mean o f 4 51 µEq/L to 8 0 0 µEq/L, to tal
cho lestero l (fro m a mean o f 14 0 vs 16 0 mg /dL), HDL (fro m a mean o f 36 to 50 mg /dL), HDL/LDL
ratio (fro m a mean o f 0 .5 to 0 .7), and urinary free co rtiso l excretio n (fro m a mean o f 4 4 to 6 3 mcg /24
hr). T heo phylline at serum co ncentratio ns within the 10 - 20 mcg /mL rang e may also transiently
decrease serum co ncentratio ns o f tri-io do thyro nine (14 4 befo re, 131 after o ne week and 14 2 ng /dL
after 4 weeks o f theo phylline). T he clinical impo rtance o f these chang es sho uld be weig hed ag ainst
the po tential therapeutic benefit o f theo phylline in individual patients.
Info rmatio n fo r Patients :
T he patient (o r parent/care g iver) sho uld be instructed to seek medical advice whenever nausea,
vomiting , persistent headache, inso mnia o r rapid heart beat o ccurs during treatment with
theophylline, even if ano ther cause is suspected. T he patient sho uld be instructed to co ntact their
healthcare pro fessio nal if they develo p a new illness, especially if acco mpanied by a persistent
fever, if they experience wo rsening o f a chro nic illness, if they start o r sto p smo king cig arettes o r
marijuana, o r if ano ther healthcare pro fessio nal adds a new medicatio n o r disco ntinues a previo usly
prescribed medicatio n. Patients sho uld be info rmed that theo phylline interacts with a wide variety of
drug s (see T able II). T he dietary supplement St. Jo hn's Wo rt (Hypericum perfo ratum) sho uld no t be
taken at the same time as theo phylline, since it may result in decreased theo phylline levels. If
patients are already taking St. Jo hn's Wo rt and theo phylline to g ether, they sho uld co nsult their
healthcare pro fessio nal befo re sto pping the St. Jo hn's Wo rt, since their theo phylline co ncentrations
may rise when this is do ne, resulting in to xicity. Patients sho uld be instructed to info rm all
healthcare pro fessio nals invo lved in their care that they are taking theo phylline, especially when a
medicatio n is being added o r deleted fro m their treatment. Patients sho uld be instructed to no t alter
the do se, timing o f the do se, o r frequency o f administratio n witho ut first co nsulting their healthcare
pro fessio nal. If a do se is missed, the patient sho uld be instructed to take the next do se at the usually
scheduled time and to no t attempt to make up fo r the missed do se.
Patients sho uld be instructed to take this medicatio n each mo rning at appro ximately the same time
and no t to exceed the prescribed do se.
Patients who require a relatively hig h do se o f theo phylline sho uld be info rmed o f impo rtant
consideratio ns relating to time o f drug administratio n and meal co ntent (see PRECAUT IONS, Drug
/Food Interactions; and DOSAGE AND ADMINISTRATION).
Drug Interactions:
Drug /Drug Interactio ns T heo phylline interacts with a wide variety o f drug s. T he interactio n may
be pharmaco dynamic, i.e., alteratio ns in the therapeutic respo nse to theo phylline o r ano ther drug o r
o ccurrence o f adverse effects witho ut a chang e in serum theo phylline co ncentratio n. Mo re
frequently, ho wever, the interactio n is pharmaco kinetic, i.e., the rate o f theo phylline clearance is
altered by ano ther drug resulting in increased o r decreased serum theo phylline co ncentratio ns.
Theo phylline o nly rarely alters the pharmaco kinetics o f o ther drug s.
T he drug s listed in T able II have the po tential to pro duce clinically sig nificant pharmaco dynamic
or pharmaco kinetic interactio ns with theo phylline. T he info rmatio n in the "Effect" co lumn o f Table
II assumes that the interacting drug is being added to a steady-state theo phylline reg imen. If theo
phylline is being initiated in a patient who is already taking a drug that inhibits theo phylline
clearance (e.g ., cimetidine, erythro mycin), the do se o f theo phylline required to achieve a
therapeutic serum theo phylline co ncentratio n will be smaller. Co nversely, if theo phylline is being
initiated in a patient who is already taking a drug that enhances theo phylline clearance (e.g.,
rifampin), the do se o f theo phylline required to achieve a therapeutic serum theo phylline
concentratio n will be larg er. Disco ntinuatio n o f a co nco mitant drug that increases theo phylline
clearance will result in accumulatio n o f theo phylline to po tentially to xic levels, unless the
theophylline do se is appro priately reduced. Disco ntinuatio n o f a co nco mitant drug that inhibits
theo phylline clearance will result in decreased serum theo phylline co ncentratio ns, unless the
theophylline do se is appro priately increased.
T he drug s listed in T able III have either been do cumented no t to interact with theo phylline o r
do no t pro duce a clinically sig nificant interactio n (i.e., <15% chang e in theo phylline clearance).
T he listing o f drug s in T able II is current as o f June 20 0 4 . T he listing o f drug s in T able III is
current as o f January 2, 19 9 6 . New interactio ns are co ntinuo usly being repo rted fo r theo phylline,
especially with new chemical entities. T he healthcare pro fessio nal sho uld no t assume that a drug do es
not interact with theo phylline if it is no t listed in T able II. Befo re additio n o f a newly available drug in a
patient receiving theo phylline, the packag e insert o f the new drug and/o r the medical literature
should be co nsulted to determine if an interactio n between the new drug and theo phylline has been
repo rted.
Drug/Food Interactions T aking T heo -24 ® less than o ne ho ur befo re a hig h-fat-co ntent meal, such as
8 o z who le milk, 2 fried eg g s, 2 baco n strips, 2 o z hashed bro wn po tato es, and 2 slices o f buttered to
ast (abo ut 9 8 5 calo ries, including appro ximately 71 g o f fat) may result in a sig nificant increase in
peak serum level and in the extent o f abso rptio n o f theo phylline as co mpared to administratio n in the
fasted state. In so me cases (especially with do ses o f 9 0 0 mg o r mo re taken less than o ne ho ur befo re
a hig h-fat-co ntent meal) serum theo phylline levels may exceed the 20 mcg /mL level, abo ve which
theo phylline to xicity is mo re likely to o ccur.
T he Effect o f Other Drug s o n T heo phylline Serum Co ncentratio n Meas urements : Mo st serum
theo phylline assays in clinical use are immuno assays which are specific fo r theo phylline. Other
xanthines such as caffeine, dyphylline, and pento xifylline are no t detected by these assays. So me
drug s (e.g ., cefazo lin, cephalo thin), ho wever, may interfere with certain HPLC techniques. Caffeine
and xanthine metabo lites in neo nates o r patients with renal dysfunctio n may cause the reading fro m
some dry reag ent o ffice metho ds to be hig her than the actual serum theo phylline co ncentratio n.
Carcino g enes is , Mutag enes is , and Impairment o f Fertility:
Lo ng term carcino g enicity studies have been carried o ut in mice (o ral do ses 30 - 150 mg /kg ) and rats
(o ral do ses 5 - 75 mg /kg ). Results are pending .
T heo phylline has been studied in Ames salmo nella, in vivo and in vitro cyto g enetics, micro nucleus and
Chinese hamster o vary test systems and has no t been sho wn to be g eno to xic.
In a 14 week co ntinuo us breeding study, theo phylline, administered to mating pairs o f B6 C3F1 mice
at o ral do ses o f 120 , 270 and 50 0 mg /kg (appro ximately 1.0 - 3.0 times the human do se o n a mg /m2
basis) impaired fertility, as evidenced by decreases in the number o f live pups per litter, decreases in
the mean number o f litters per fertile pair, and increases in the g estatio n perio d at the hig h do se as
well as decreases in the pro po rtio n o f pups bo rn alive at the mid and hig h do se. In 13 week to xicity
studies, theo phylline was administered to F34 4 rats and B6 C3F1 mice at o ral do ses o f 4 0 - 30 0 mg
/kg (appro ximately 2.0 times the human do se o n a mg /m2 basis). At the hig h do se, systemic to xicity
was o bserved in bo th species including decreases in testicular weig ht.
Pregnancy
CAT EGORY C:
In studies in which preg nant mice, rats and rabbits were do sed during the perio d o f o rg ano
genesis, theo phylline pro duced terato g enic effects.
In studies with mice, a sing le intraperito neal do se at and abo ve 10 0 mg /kg (appro ximately equal to
the maximum reco mmended o ral do se fo r adults o n a mg /m2 basis) during o rg ano g enesis pro duced
cleft palate and dig ital abno rmalities. Micro melia, micro g nathia, clubfo o t, subcutaneo us hematoma,
o pen eyelids, and embryo lethality were o bserved at do ses that are appro ximately 2 times the
maximum reco mmended o ral do se fo r adults o n a mg /m2 basis.
In a study with rats do sed fro m co nceptio n thro ug h o rg ano g enesis, an o ral do se o f 150 mg /kg
/day (appro ximately 2 times the maximum reco mmended o ral do se fo r adults o n a mg /m2 basis)
pro duced dig ital abno rmalities. Embryo lethality was o bserved with a subcutaneo us do se o f 20 0
mg /kg /day (appro ximately 4 times the maximum reco mmended o ral do se fo r adults o n a mg /m2
basis).
In a study in which preg nant rabbits were do sed thro ug ho ut o rg ano g enesis, an intraveno us do se o f
6 0 mg /kg /day (appro ximately 2 times the maximum reco mmended o ral do se fo r adults o n a mg /m2
basis), which caused the death o f o ne do e and clinical sig ns in o thers, pro duced cleft palate and
was embryo lethal. Do ses at and abo ve 15 mg /kg /day (less than the maximum reco mmended o ral do
se fo r adults o n a mg /m2 basis) increased the incidence o f skeletal variatio ns.
T here are no adequate and well-co ntro lled studies in preg nant wo men. T heo phylline sho uld be
used during preg nancy o nly if the po tential benefit justifies the po tential risk to the fetus.
Nurs ing Mo thers :
T heo phylline is excreted into breast milk and may cause irritability o r o ther sig ns o f mild to xicity in
nursing human infants. T he co ncentratio n o f theo phylline in breast milk is abo ut equivalent to the
maternal serum co ncentratio n. An infant ing esting a liter o f breast milk co ntaining 10 - 20 mcg /mL o f
theo phylline per day is likely to receive 10 - 20 mg o f theo phylline per day. Serio us adverse effects
in the infant are unlikely unless the mo ther has to xic serum theo phylline co ncentratio ns.
Pediatric Us e:
T heo phylline is safe and effective fo r the appro ved indicatio ns in pediatric patients (see
INDICATIONS AND USAGE). T he maintenance do se o f theo phylline must be selected with cautio n
in pediatric patients since the rate o f theo phylline clearance is hig hly variable acro ss the ag e rang e
of neo nates to ado lescents (see CLINICAL PHARMACOLOGY, T able I, WARNINGS, and
DOSAGE AND ADMINIST RAT ION, T able V). Due to the immaturity o f theo phylline metabo lic
pathways in infants under the ag e o f o ne year, particular attentio n to do sag e selectio n and frequent mo
nito ring o f serum theo phylline co ncentratio ns are required when theo phylline is prescribed to
pediatric patients in this ag e g ro up.
Geriatric Us e:
Elderly patients are at a sig nificantly g reater risk o f experiencing serio us to xicity fro m theo phylline
than yo ung er patients due to pharmaco kinetic and pharmaco dynamic chang es asso ciated with ag ing .
The clearance o f theo phylline is decreased by an averag e o f 30 % in healthy elderly adults (>6 0 yrs)
co mpared to healthy yo ung adults. T heo phylline clearance may be further reduced by co nco mitant
diseases prevalent in the elderly, which further impair clearance o f this drug and have the po tential to
increase serum levels and po tential to xicity. T hese co nditio ns include impaired renal functio n,
chronic o bstructive pulmo nary disease, co ng estive heart failure, hepatic disease and an increased
prevalence o f use o f certain medicatio ns (see PRECAUT IONS: Drug Interactio ns) with the po tential
fo r pharmaco kinetic and pharmaco dynamic interactio n. Pro tein binding may be decreased in the
elderly resulting in an increased pro po rtio n o f the to tal serum theo phylline co ncentratio n in the
pharmaco lo g ically active unbo und fo rm. Elderly patients also appear to be mo re sensitive to the to xic
effects o f theo phylline after chro nic o verdo sag e than yo ung er patients. Careful attentio n to do se
reductio n and frequent mo nito ring o f serum theo phylline co ncentratio ns are required in elderly
patients (see PRECAUT IONS, Mo nito ring Serum T heo phylline Co ncentratio ns, and DOSAGE AND
ADMINIST RAT ION). T he maximum daily do se o f theo phylline in patients g reater than 6 0 years o f
ag e o rdinarily sho uld no t exceed 4 0 0 mg /day unless the patient co ntinues to be sympto matic and the
peak steady-state serum theo phylline co ncentratio n is <10 mcg /mL (see DOSAGE AND ADMINIST
RAT ION). T heo phylline do ses g reater than 4 0 0 mg /d sho uld be prescribed with cautio n in elderly
patients.
ADVERSE REACT IONS
Adverse reactio ns asso ciated with theo phylline are g enerally mild when peak serum theo phylline
concentratio ns are <20 mcg /mL and mainly co nsist o f transient caffeine-like adverse effects such as
nausea, vo miting , headache, and inso mnia. When peak serum theo phylline co ncentratio ns exceed 20
mcg /mL, ho wever, theo phylline pro duces a wide rang e o f adverse reactio ns including persistent
vomiting , cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE).
The transient caffeine-like adverse reactio ns o ccur in abo ut 50 % o f patients when theo phylline
therapy is initiated at do ses hig her than reco mmended initial do ses (e.g ., >30 0 mg /day in adults and
>12 mg /kg /day in children beyo nd 1 year o f ag e). During the initiatio n o f theo phylline therapy,
caffeine-like adverse effects may transiently alter patient behavio r, especially in scho o l ag e
children, but this respo nse rarely persists. Initiatio n o f theo phylline therapy at a lo w do se with
subsequent slo w titratio n to a predetermined ag e-related maximum do se will sig nificantly reduce the
frequency o f these transient adverse effects (see DOSAGE AND ADMINIST RAT ION, T able V).
In a small percentag e o f patients (<3% o f children and <10 % o f adults) the caffeine-like adverse
effects persist during maintenance therapy, even at peak serum theo phylline co ncentratio ns within the
therapeutic rang e (i.e., 10 - 20 mcg /mL). Do sag e reductio n may alleviate the caffeine-like adverse
effects in these patients, ho wever, persistent adverse effects sho uld result in a reevaluatio n o f the
need fo r co ntinued theo phylline therapy and the po tential therapeutic benefit o f alternative treatment.
Other adverse reactio ns that have been repo rted at serum theo phylline co ncentratio ns <20 mcg /mL
include diarrhea, irritability, restlessness, fine skeletal muscle tremo rs, and transient diuresis. In
patients with hypo xia seco ndary to COPD, multifo cal atrial tachycardia and flutter have been
reported at serum theo phylline co ncentratio ns ≥15 mcg /mL. T here have been a few iso lated repo rts o
f seizures at serum theo phylline co ncentratio ns <20 mcg /mL in patients with an underlying
neurological disease o r in elderly patients. T he o ccurrence o f seizures in elderly patients with
serum theo phylline co ncentratio ns <20 mcg /mL may be seco ndary to decreased pro tein binding
resulting in a larg er pro po rtio n o f the to tal serum theo phylline co ncentratio n in the pharmacologically
active unbo und fo rm. T he clinical characteristics o f the seizures repo rted in patients with serum theo
phylline co ncentratio ns <20 mcg /mL have g enerally been milder than seizures asso ciated with
excessive serum theo phylline co ncentratio ns resulting fro m an o verdo se (i.e., they have g enerally
been transient, o ften sto pped witho ut antico nvulsant therapy, and did no t result in neuro lo g ical
residua).
OVERDOSAGE
General:
T he chro nicity and pattern o f theo phylline o verdo sag e sig nificantly influences clinical manifestations
o f to xicity, manag ement and o utco me. T here are two co mmo n presentatio ns: (1) acute overdose, i.e.,
ing estio n o f a sing le larg e excessive do se (>10 mg /kg ) as o ccurs in the co ntext o f an attempted
suicide o r iso lated medicatio n erro r, and (2) chronic overdosage, i.e., ing estio n o f repeated do ses that
are excessive fo r the patient's rate o f theo phylline clearance. T he mo st co mmo n causes o f chro nic
theo phylline o verdo sag e include patient o r care g iver erro r in do sing , healthcare pro fessio nal
prescribing o f an excessive do se o r a no rmal do se in the presence o f facto rs kno wn to decrease the
rate o f theo phylline clearance, and increasing the do se in respo nse to an exacerbatio n o f sympto ms
witho ut first measuring the serum theo phylline co ncentratio n to determine whether a do se increase is
safe.
Severe to xicity fro m theo phylline o verdo se is a relatively rare event. In o ne health maintenance
organizatio n, the frequency o f ho spital admissio ns fo r chro nic o verdo sag e o f theo phylline was about
1 per 10 0 0 perso n-years expo sure. In ano ther study, amo ng 6 0 0 0 blo o d samples o btained fo r
measurement o f serum theo phylline co ncentratio n, fo r any reaso n, fro m patients treated in an emerg
ency department, 7% were in the 20 -30 mcg /mL rang e and 3% were >30 mcg /mL. Appro ximately two
-thirds o f the patients with serum theo phylline co ncentratio ns in the 20 -30 mcg /mL rang e had o ne o r
mo re manifestatio ns o f to xicity while >9 0 % o f patients with serum theo phylline co ncentratio ns >30
mcg /mL were clinically into xicated. Similarly, in o ther repo rts, serio us to xicity from theophylline is
seen principally at serum co ncentratio ns >30 mcg /mL.
Several studies have described the clinical manifestatio ns o f theo phylline o verdo se and attempted to
determine the facto rs that predict life-threatening to xicity. In g eneral, patients who experience an
acute o verdo se are less likely to experience seizures than patients who have experienced a chro nic
o verdo sag e, unless the peak serum theo phylline co ncentratio n is >10 0 mcg /mL. After a chro nic
overdo sag e, g eneralized seizures, life-threatening cardiac arrhythmias, and death may o ccur at
serum theo phylline co ncentratio ns >30 mcg /mL. T he severity o f to xicity after chro nic o verdo sag e
is mo re stro ng ly co rrelated with the patient's ag e than the peak serum theo phylline co ncentratio n;
patients >6 0 years are at the g reatest risk fo r severe to xicity and mo rtality after a chro nic
overdosage. Pre-existing o r co ncurrent disease may also sig nificantly increase the susceptibility o f
a patient to a particular to xic manifestatio n, e.g ., patients with neuro lo g ic diso rders have an
increased risk o f seizures and patients with cardiac disease have an increased risk o f cardiac
arrhythmias fo r a g iven serum theo phylline co ncentratio n co mpared to patients without the
underlying disease.
T he frequency o f vario us repo rted manifestatio ns o f theo phylline o verdo se acco rding to the mo de
o f o verdo se are listed in T able IV.
Other manifestatio ns o f theo phylline to xicity include increases in serum calcium, creatine
kinase, myo g lo bin and leuko cyte co unt, decreases in serum pho sphate and mag nesium, acute
myo cardial infarctio n, and urinary retentio n in men with o bstructive uro pathy.
Seizures asso ciated with serum theo phylline co ncentratio ns >30 mcg /mL are o ften resistant to antico
nvulsant therapy and may result in irreversible brain injury if no t rapidly co ntro lled. Death fro m
theophylline to xicity is mo st o ften seco ndary to cardio respirato ry arrest and/o r hypo xic
encephalopathy fo llo wing pro lo ng ed g eneralized seizures o r intractable cardiac arrhythmias causing
hemo dynamic co mpro mise.
Overdo s e Manag ement: General Reco mmendatio ns fo r Patients with Sympto ms o f
Theophylline Overdo s e o r Serum T heo phylline Co ncentratio ns >3 0 mcg /mL (No te: Serum
theo phylline co ncentratio ns may co ntinue to increas e after pres entatio n o f the patient fo r
medical care.)
1.
While simultaneo usly instituting treatment, co ntact a reg io nal po iso n center to o btain
updated info rmatio n and advice o n individualizing the reco mmendatio ns that fo llo w.
2.
Institute suppo rtive care, including establishment o f intraveno us access, maintenance o f the
airway, and electro cardio g raphic mo nito ring .
3. T reatment o f seizures Because o f the hig h mo rbidity and mo rtality asso ciated with theo phylline-
induced seizures, treatment sho uld be rapid and ag g ressive. Antico nvulsant therapy sho uld be
initiated with an intraveno us benzo diazepine, e.g ., diazepam, in increments o f 0 .1 - 0 .2 mg /kg every 1 3 minutes until seizures are terminated. Repetitive seizures sho uld be treated with a lo ading do se o f
pheno barbital (20 mg /kg infused o ver 30 - 6 0 minutes). Case repo rts o f theo phylline o verdo se in
humans and animal studies sug g est that phenyto in is ineffective in terminating theo phylline-induced
seizures. T he do ses o f benzo diazepines and pheno barbital required to terminate theo phyllineinduced seizures are clo se to the do ses that may cause severe respirato ry depressio n o r respirato ry
arrest; the healthcare pro fessio nal sho uld therefo re be prepared to pro vide assisted ventilatio n.
Elderly patients and patients with COPD may be mo re susceptible to the respirato ry depressant
effects o f antico nvulsants. Barbiturate-induced co ma o r administratio n o f g eneral anesthesia may be
required to terminate repetitive seizures o r status epilepticus. General anesthesia sho uld be used
with cautio n in patients with theo phylline o verdo se because fluo rinated vo latile anesthetics may
sensitize the myo cardium to endo g eno us catecho lamines released by theo phylline. Enflurane appears
less likely to be asso ciated with this effect than halo thane and may, therefo re, be safer.
Neuromuscular blo cking ag ents alo ne sho uld no t be used to terminate seizures since they abo lish the
musculo skeletal manifestatio ns witho ut terminating seizure activity in the brain.
4. Anticipate need fo r antico nvulsants In patients with theo phylline o verdo se who are at hig h risk fo r
theo phylline-induced seizures, e.g ., patients with acute o verdo ses and serum theo phylline
concentratio ns >10 0 mcg /mL o r chro nic o verdo sag e in patients >6 0 years o f ag e with serum
theophylline co ncentratio ns >30 mcg /mL, the need fo r antico nvulsant therapy sho uld be anticipated.
A benzo diazepine such as diazepam sho uld be drawn into a syring e and kept at the patient's bedside
and medical perso nnel qualified to treat seizures sho uld be immediately available. In selected
patients at hig h risk fo r theo phylline-induced seizures, co nsideratio n sho uld be g iven to the
administratio n o f pro phylactic antico nvulsant therapy. Situatio ns where pro phylactic antico nvulsant
therapy sho uld be co nsidered in hig h risk patients include anticipated delays in instituting metho ds fo
r extraco rpo real remo val o f theo phylline (e.g ., transfer o f a hig h risk patient fro m o ne health care
facility to ano ther fo r extraco rpo real remo val) and clinical circumstances that sig nificantly interfere
with effo rts to enhance theo phylline clearance (e.g ., a neo nate where dialysis may no t be technically
feasible o r a patient with vo miting unrespo nsive to antiemetics who is unable to to lerate multiple- do
se o ral activated charco al). In animal studies, pro phylactic administratio n o f phenobarbital, but no t
phenyto in, has been sho wn to delay the o nset o f theo phylline-induced generalized seizures and to
increase the do se o f theo phylline required to induce seizures (i.e., markedly increases the LD 50 ).
Altho ug h there are no co ntro lled studies in humans, a lo ading do se of intraveno us pheno barbital (20
mg /kg infused o ver 6 0 minutes) may delay o r prevent life-threatening seizures in hig h risk patients
while effo rts to enhance theo phylline clearance are continued. Pheno barbital may cause respirato ry
depressio n, particularly in elderly patients and patients with COPD.
5. T reatment o f cardiac arrhythmias Sinus tachycardia and simple ventricular premature beats are no t
harbing ers o f life-threatening arrhythmias, they do no t require treatment in the absence o f
hemodynamic co mpro mise, and they reso lve with declining serum theo phylline co ncentratio ns. Other
arrhythmias, especially tho se asso ciated with hemo dynamic co mpro mise, sho uld be treated with
antiarrhythmic therapy appro priate fo r the type o f arrhythmia.
6 . Gastro intestinal deco ntaminatio n Oral activated charco al (0 .5 g /kg up to 20 g and repeat at least
once 1 - 2 ho urs after the first do se) is extremely effective in blo cking the abso rptio n o f theo phylline
thro ug ho ut the g astro intestinal tract, even when administered several ho urs after ing estio n. If the
patient is vo miting , the charco al sho uld be administered thro ug h a naso g astric tube o r after
administratio n o f an antiemetic. Pheno thiazine antiemetics such as pro chlo rperazine o r perphenazine
sho uld be avo ided since they can lo wer the seizure thresho ld and frequently cause dysto nic reactions.
A sing le do se o f so rbito l may be used to pro mo te sto o ling to facilitate remo val o f theo phylline bound
to charco al fro m the g astro intestinal tract. So rbito l, ho wever, sho uld be do sed with cautio n since it is
a po tent purg ative which can cause pro fo und fluid and electro lyte abno rmalities, particularly after
multiple do ses. Co mmercially available fixed co mbinatio ns o f liquid charco al and so rbito l sho uld be
avo ided in yo ung children and after the first do se in ado lescents and adults since they do no t allo w fo r
individualizatio n o f charco al and so rbito l do sing . Ipecac syrup sho uld be avoided in theo phylline o
verdo ses. Altho ug h ipecac induces emesis, it do es no t reduce the absorption o f theo phylline unless
administered within 5 minutes o f ing estio n and even then is less effective than o ral activated charco al.
Mo reo ver, ipecac induced emesis may persist fo r several hours after a sing le do se and sig nificantly
decrease the retentio n and the effectiveness o f o ral activated charco al.
7. Serum theo phylline co ncentratio n mo nito ring T he serum theo phylline co ncentratio n sho uld be
measured immediately upo n presentatio n, 2 - 4 ho urs later, and then at sufficient intervals, e.g ., every
4 ho urs, to g uide treatment decisio ns and to assess the effectiveness o f therapy. Serum theo phylline
co ncentratio ns may co ntinue to increase after presentatio n o f the patient fo r medical care as a result
of co ntinued abso rptio n o f theo phylline fro m the g astro intestinal tract. Serial mo nito ring o f serum
theo phylline co ncentratio ns sho uld be co ntinued until it is clear that the co ncentratio n is no lo ng er
rising and has returned to no n-to xic levels.
8 . General mo nito ring pro cedures Electro cardio g raphic mo nito ring sho uld be initiated o n presentatio
n and co ntinued until the serum theo phylline level has returned to a no n-to xic level. Serum electro
lytes and g luco se sho uld be measured o n presentatio n and at appro priate intervals indicated by
clinical circumstances. Fluid and electro lyte abno rmalities sho uld be pro mptly corrected. Mo nito
ring and treatment s ho uld be co ntinued until the s erum co ncentratio n decreas es belo w 20 mcg
/mL.
9 . Enhance clearance o f theo phylline Multiple-do se o ral activated charco al (e.g ., 0 .5 g /kg up to 20 g ,
every two ho urs) increases the clearance o f theo phylline at least two fo ld by adso rptio n o f
theophylline secreted into g astro intestinal fluids. Charco al must be retained in, and pass thro ug h, the
g astro intestinal tract to be effective; emesis sho uld therefo re be co ntro lled by administratio n o f
appro priate antiemetics. Alternatively, the charco al can be administered co ntinuo usly thro ug h a nasog
astric tube in co njunctio n with appro priate antiemetics. A sing le do se o f so rbito l may be administered
with the activated charco al to pro mo te sto o ling to facilitate clearance o f the adso rbed theo phylline
fro m the g astro intestinal tract. So rbito l alo ne do es no t enhance clearance o f theo phylline and sho uld
be do sed with cautio n to prevent excessive sto o ling which can result in severe fluid and electro lyte
imbalances. Co mmercially available fixed co mbinatio ns o f liquid charco al and so rbito l sho uld be
avoided in yo ung children and after the first do se in ado lescents and adults since they do no t allo w
for individualizatio n o f charco al and so rbito l do sing . In patients with intractable vo miting , extraco
rporeal metho ds o f theo phylline remo val sho uld be instituted (see OVERDOSAGE, Extraco rpo real
Removal).
Specific Reco mmendatio ns:
Acute Overdose
A. SerumCo ncentratio n>20 <30 mcg /mL
1. Administer a sing le do se o f o ral activated charco al.
2. Mo nito r the patient and o btain a serum theo phylline co ncentratio n in 2 - 4 ho urs to insure that the
co ncentratio n is no t increasing.
B. SerumCo ncentratio n>30 <10 0 mcg /mL
1. Administer multiple do se o ral activated charco al and measures to co ntro l emesis.
2. Mo nito r the patient and o btain serial theo phylline co ncentratio ns every 2 - 4 ho urs to g aug e the
effectiveness o f therapy and to g uide further treatment decisio ns.
3. Institute extraco rpo real remo val if emesis, seizures, o r cardiac arrhythmias canno t be adequately
co ntro lled (see OVERDOSAGE, Extraco rpo real Remo val).
C. SerumCo ncentratio n>10 0 mcg /mL
1. Co nsider pro phylactic antico nvulsant therapy.
2. Administer multiple-do se o ral activated charco al and measures to co ntro l emesis.
3. Co nsider extraco rpo real remo val, even if the patient has no t experienced a seizure (see
OVERDOSAGE, Extraco rpo real Remo val).
4 . Mo nito r the patient and o btain serial theo phylline co ncentratio ns every 2 - 4 ho urs to g aug e the
effectiveness o f therapy and to g uide further treatment decisio ns.
Chronic Overdosage
A. SerumCo ncentratio n>20 <30 mcg /mL(withmanifestatio ns o f theo phylline to xicity)
1. Administer a sing le do se o f o ral activated charco al.
2. Mo nito r the patient and o btain a serum theo phylline co ncentratio n in 2 - 4 ho urs to insure that the
co ncentratio n is no t increasing.
B. SerumCo ncentratio n>30 mcg /mLinpatients <6 0 years o f ag e
1. Administer multiple-do se o ral activated charco al and measures to co ntro l emesis.
2. Mo nito r the patient and o btain serial theo phylline co ncentratio ns every 2 - 4 ho urs to g aug e the
effectiveness o f therapy and to g uide further treatment decisio ns.
3. Institute extraco rpo real remo val if emesis, seizures, o r cardiac arrhythmias canno t be adequately
co ntro lled (see OVERDOSAGE, Extraco rpo real Remo val).
C. SerumCo ncentratio n>30 mcg /mLinpatients ≥6 0 years o f ag e.
1. Co nsider pro phylactic antico nvulsant therapy.
2. Administer multiple-do se o ral activated charco al and measures to co ntro l emesis.
3. Co nsider extraco rpo real remo val even if the patient has no t experienced a seizure (see
OVERDOSAGE, Extraco rpo real Remo val).
4 . Mo nito r the patient and o btain serial theo phylline co ncentratio ns every 2 - 4 ho urs to g aug e the
effectiveness o f therapy and to g uide further treatment decisio ns.
Extraco rpo real Remo val:
Increasing the rate o f theo phylline clearance by extraco rpo real metho ds may rapidly decrease serum
co ncentratio ns, but the risks o f the pro cedure must be weig hed ag ainst the po tential benefit. Charco al
hemo perfusio n is the mo st effective metho d o f extraco rpo real remo val, increasing theo phylline
clearance up to six fo ld, but serio us co mplicatio ns, including hypo tensio n, hypo calcemia, platelet
consumptio n and bleeding diatheses may o ccur. Hemo dialysis is abo ut as efficient as multiple-do se
oral activated charco al and has a lo wer risk o f serio us co mplicatio ns than charco al hemo perfusio n.
Hemo dialysis sho uld be co nsidered as an alternative when charco al hemo perfusio n is no t feasible
and multiple-do se o ral charco al is ineffective because o f intractable emesis. Serum theo phylline
concentratio ns may rebo und 5 - 10 mcg /mL after disco ntinuatio n o f charco al hemo perfusio n o r
hemodialysis due to redistributio n o f theo phylline fro m the tissue co mpartment. Perito neal dialysis is
ineffective fo r theo phylline remo val; exchang e transfusio ns in neo nates have been minimally
effective.
DOSAGE AND ADMINIST RAT ION General Co ns ideratio ns:
T heo -24 , like o ther extended-release theo phylline pro ducts, is intended fo r patients with relatively
co ntinuo us o r recurring sympto ms who have a need to maintain therapeutic serum levels o f
theophylline. It is no t intended fo r patients experiencing an acute episo de o f bro ncho spasm
(associated with asthma, chro nic bro nchitis, o r emphysema). Such patients require rapid relief o f
sympto ms and sho uld be treated with an immediate-release o r intraveno us theo phylline preparatio n
(o r o ther bro ncho dilato rs) and no t with extended-release pro ducts.
Patients who metabo lize theo phylline at a no rmal o r slo w rate are reaso nable candidates fo r o ncedaily do sing with T heo -24 . Patients who metabo lize theo phylline rapidly (e.g ., the yo ung , smo kers,
and so me no nsmo king adults) and who have sympto ms repeatedly at the end o f a do sing interval, will
require either increased do ses g iven o nce a day o r preferably, are likely to be better co ntro lled by a
schedule o f twice-daily do sing . T ho se patients who require increased daily do ses are mo re likely to
experience relatively wide peak-tro ug h differences and may be candidates fo r twice-a-day do sing
with T heo -24.
Patients sho uld be instructed to take this medicatio n each mo rning at appro ximately the same time and
no t to exceed the prescribed do se.
Recent studies sug g est that do sing o f extended-release theo phylline pro ducts at nig ht (after the
evening meal) results in serum co ncentratio ns o f theo phylline which are no t identical to tho se
recorded during waking ho urs and may be characterized by early tro ug h and delayed peak levels.
This appears to o ccur whether the drug is g iven as an immediate-release, extended-release, o r
intraveno us pro duct. T o avo id this pheno meno n when two do ses per day are prescribed, it is
recommended that the seco nd do se be g iven 10 to 12 ho urs after the mo rning do se and befo re the
evening meal.
Fo o d and po sture, alo ng with chang es asso ciated with circadian rhythm, may influence the rate o f
abso rptio n and/o r clearance rates o f theo phylline fro m extended-release do sag e fo rms administered
at nig ht. T he exact relatio nship o f these and o ther facto rs to nig httime serum co ncentratio ns and the
clinical sig nificance o f such finding s require additio nal study. T herefo re, it is no t reco mmended
that T heo -24 (when used as a o nce-a-day pro duct) be administered at nig ht.
Patients who require a relatively hig h do se o f theo phylline (i.e., a do se equal to o r g reater than 9 0 0
mg o r 13 mg /kg , whichever is less) sho uld no t take T heo -24 less than 1 ho ur befo re a hig h-fatcontent meal since this may result in a sig nificant increase in peak serum level and in the extent o f
absorptio n o f theo phylline as co mpared to administratio n in the fasted state (see PRECAUT IONS,
Drug /Fo o d Interactio ns).
T he steady-state peak serum theo phylline co ncentratio n is a functio n o f the do se, the do sing
interval, and the rate o f theo phylline abso rptio n and clearance in the individual patient. Because o f
marked individual differences in the rate o f theo phylline clearance, the do se required to achieve a
peak serum theo phylline co ncentratio n in the 10 - 20 mcg /mL rang e varies fo urfo ld amo ng
otherwise similar patients in the absence o f facto rs kno wn to alter theo phylline clearance (e.g ., 4 0 0
- 16 0 0 mg /day in adults <6 0 years o ld and 10 - 36 mg /kg /day in children 1 - 9 years o ld). Fo r a
given po pulatio n there is no sing le theo phylline do se that will pro vide bo th safe and effective
serum co ncentratio ns fo r all patients. Administratio n o f the median theo phylline do se required to
achieve a therapeutic serum theo phylline co ncentratio n in a g iven po pulatio n may result in either
sub-therapeutic o r po tentially to xic serum theo phylline co ncentratio ns in individual patients. Fo r
example, at a do se o f 9 0 0 mg /day in adults <6 0 years o r 22 mg /kg /day in children 1-9 years, the
steady-state peak serum theo phylline co ncentratio n will be <10 mcg /mL in abo ut 30 % o f patients, 10
- 20 mcg /mL in abo ut 50 % and 20 - 30 mcg /mL in abo ut 20 % o f patients. T he do s e o f theo phylline
mus t be individualized o n the bas is o f peak s erum theo phylline co ncentratio n meas urements in
order to achieve a dose that will provide maximum
po tential benefit with minimal ris k o f
adverse effects.
T ransient caffeine-like adverse effects and excessive serum co ncentratio ns in slo w metabo lizers
can be avo ided in mo st patients by starting with a sufficiently lo w do se and slo wly increasing the do
se, if judg ed to be clinicallyindicated, in small increments (See T able V). Do se increases sho uld o nly
be made if the previo us do sag e is well to lerated and at intervals o f no less than 3 days to allo w
serum theo phylline co ncentratio ns to reach the new steady state. Do sag e adjustment sho uld be g
uided by serum theo phylline co ncentratio n measurement (see PRECAUT IONS, Labo rato ry T ests
and DOSAGE AND ADMINIST RAT ION, T able VI). Health care pro viders sho uld instruct patients
and care g ivers to disco ntinue any do sag e that causes adverse effects, to withho ld the medicatio n
until these sympto ms are g o ne and to then resume therapy at a lo wer, previo usly to lerated do sag e
(see WARNINGS).
If the patient's sympto ms are well co ntro lled, there are no apparent adverse effects, and no
intervening facto rs that mig ht alter do sag e requirements (see WARNINGS and PRECAUT IONS),
serum theo phylline co ncentratio ns sho uld be mo nito red at 6 mo nth intervals fo r rapidly g ro wing
children and at yearly intervals fo r all o thers. In acutely ill patients, serum theo phylline
concentrations sho uld be mo nito red at frequent intervals, e.g ., every 24 ho urs.
T heo phylline distributes po o rly into bo dy fat, therefo re, mg /kg do se sho uld be calculated o n the
basis o f ideal bo dy weig ht.
T able V co ntains theo phylline do sing titratio n schema reco mmended fo r patients in vario us ag e
groups and clinical circumstances. T able VI co ntains reco mmendatio ns fo r theo phylline do sag e
adjustment based upo n serum theo phylline co ncentratio ns. Applicatio n o f thes e g eneral do s ing
recommendatio ns to individual patients mus t take into acco unt the unique clinical characteris
tics of each patient. In general, thes e recommendations s hould s erve as the upper limit for dos age
adjustments in o rder to decreas e the ris k o f po tentially s erio us advers e events as s o ciated with
unexpected large increases in s erum theophylline concentration.
1 If caffeine-like adverse effects o ccur, then co nsideratio n sho uld be g iven to a
lo wer
do se and titrating the do se mo re slo wly (see ADVERSE REACT IONS).
B. Patients with ris k facto rs fo r impaired clearance, the elderly (>6 0 Years ), and
those in who m it is no t feas ible to mo nito r s erum theo phylline co ncentratio ns : In
children 12-15 years o f ag e, the final theo phylline do se sho uld no t exceed 16 mg
/kg /day up to a maximum o f 4 0 0 mg /day in the presence o f risk facto rs fo r reduced
theo phylline clearance (see WARNINGS) o r if it is no t feasible to mo nito r serum
theo phylline co ncentratio ns.
In ado lescents ≥16 years and adults, including the elderly, the final theo phylline
do se sho uld no t exceed 4 0 0 mg /day in the presence o f risk facto rs fo r reduced
theo phylline clearance (see WARNINGS) o r if it is no t feasible to mo nito r
serum theo phylline co ncentratio ns.
* Patients with mo re rapid metabo lism, clinically identified by hig her than averag e do se
requirements, sho uld receive a smaller do se mo re frequently to prevent breakthro ug h sympto ms
resulting fro m lo w tro ug h co ncentratio ns befo re the next do se. A reliably abso rbed slo w-release fo
rmulatio n will decrease fluctuatio ns and permit lo ng er do sing intervals.
HOW SUPPLIED
T heo -24 (theo phylline anhydro us) is supplied in extended-release capsules co ntaining 10 0 , 20 0 , 30
0 o r 4 0 0 mg o f anhydro us theo phylline.
T heo -24 10 0 mg capsules are o rang e o paque and natural, with marking s T heo -24 , 10 0 mg , AP, and 28
32, supplied as:
NDC Number
5224 4 -10 0 -10
Size
bo ttle o f 10 0
T heo -24 20 0 mg capsules are o rang e o paque and clear, with marking s T heo -24 , 20 0 mg ,
AP, and 28 4 2, supplied as:
NDC Number
Size
5224 4 -20 0 -10
bo ttle o f 10 0 T heo -24 30 0 mg capsules are Swedish o rang e and natural, with
marking s T heo -24 , 30 0 mg , AP, and 28 52, supplied as:
NDC Number
5224 4 -30 0 -10
Size
bo ttle o f 10 0
T heo -24 4 0 0 mg capsules are pink o paque and natural, with marking s T heo -24 , 4 0 0 mg , AP, and 29
0 2, supplied as:
NDC Number
5224 4 -4 0 0 -10
Size
bo ttle o f 10 0
ST ORAGE
Sto re belo w 77° F (25° C).
FOR MEDICAL INFORMAT ION
Co ntact: Auxilium Drug Info rmatio n
Pho ne: 1-8 77-6 6 3-0 4 12
Manufactured fo r:
Actient Pharmaceuticals LLC
Chesterbro o k, PA 19087
by: Neo lpharma, Inc. Cag uas, PR 00725
Revised 10 /20 13
PL-0 9 13-0 0 5.a