86:16 Respiratory Smooth Muscle Relaxants

Theophyllines
Introduction
Theophylline, a xanthine derivative, directly relaxes smooth muscle of the respiratory tract,
producing relief of bronchospasm and increasing flow rates and vital capacity.
Uses
Bronchospasm
Theophylline is used as a bronchodilator in the symptomatic treatment of asthma and reversible
bronchospasm that may occur in association with chronic bronchitis or emphysema.
Asthma
Theophylline is used as a bronchodilator in the symptomatic treatment of asthma. The drug
relieves the primary manifestations of asthma, including shortness of breath, wheezing and
dyspnea, and improves pulmonary function as measured by increased flow rates and vital
capacity. Theophylline also suppresses exercise-induced bronchospasm and, in doses that
maintain therapeutic serum concentrations, prevents symptoms of chronic asthma.
In the stepped-care approach to antiasthmatic drug therapy, use of a selective, short-acting,
inhaled 2-adrenergic agonist on an intermittent, as-needed basis to control acute symptoms (e.g.,
cough, wheezing, dyspnea) is recommended for all patients with asthma; such use of an inhaled
short-acting 2-agonist alone generally is sufficient as initial treatment for newly diagnosed
patients with mild intermittent asthma.212, 213, 214, 215 Short-acting theophylline (provided extendedrelease theophylline is not already used) is considered by some clinicians to be one of several
less effective alternatives (e.g., including an inhaled anticholinergic agent or a short-acting oral
2-agonist) to short-acting inhaled 2-agonists for relief of acute asthma symptoms, but these
alternatives have a slower onset of action and/or a greater risk of adverse effects.212
Extended-release theophylline may be administered orally for long-term symptom control in
mild to moderate persistent asthma. While theophylline is an effective bronchodilator, the drug
generally is considered alternative therapy in asthma because of its increased risk of adverse
effects and more difficult therapeutic monitoring requirements compared with inhaled 2-agonist
and corticosteroid therapy.211, 212 Use of an extended-release oral theophylline preparation is
considered one of several alternatives (including mast-cell stabilizers [e.g., cromolyn,
nedocromil] or leukotriene modifiers [e.g., montelukast, zafirlukast, zileuton]) to low-dose
inhaled corticosteroids for adults and children older than 5 years of age with mild persistent
asthma.211, 212 Theophylline or a leukotriene modifier also are considered less-effective
alternatives to long-acting inhaled 2-adrenergic agonists for use in conjunction with inhaled
corticosteroids for long-term control of symptoms in patients with moderate persistent asthma.211,
212
Considerations favoring theophylline in combination with orally inhaled corticosteroids
include intolerance to long-acting inhaled 2-adrenergic agonists, marked preference for oral
therapy, demonstration of superior responsiveness to theophylline, and cost.211 However, in

comparative studies in patients with moderate persistent asthma, the addition of theophylline to
low-dose orally inhaled corticosteroid therapy has not been shown to be more effective than
doubling the dosage of inhaled corticosteroids alone.211 Extended-release theophylline, a
leukotriene modifier, a long-acting oral 2-agonist, and/or an oral corticosteroid are
recommended as adjunctive therapy to high dosages of orally inhaled corticosteroids and a longacting inhaled 2-adrenergic agonist in adults and children with severe persistent asthma.212
Limited evidence does not support the addition of theophylline to orally inhaled corticosteroids
and inhaled long-acting 2-adrenergic agonists in order to avoid oral corticosteroid therapy.211
In children younger than 5 years of age with mild persistent asthma, some experts consider
extended-release theophylline to be an alternative to orally inhaled corticosteroids.212 Infants
have frequent febrile illnesses, which increase theophylline concentrations and the potential for
adverse effects.211 Other experts state that extended-release theophylline may be considered as
adjunctive therapy in young children with mild or moderate persistent asthma if there are
demonstrable adverse effects with orally inhaled corticosteroids.211 If extended-release
theophylline is used as adjunctive therapy in young children, serum theophylline concentrations
should be carefully monitored.211
An IV xanthine derivative (e.g., theophylline or aminophylline) also may be used as alternative
add-on therapy in patients who are hospitalized for severe exacerbations of asthma.212 Initial
hospital management of such exacerbations includes oxygen and inhaled short-acting 2-agonist
therapy via metered-dose inhaler aerosol or nebulization.212 If therapeutic response is not
immediate, if the patient used oral corticosteroids as self-medication prior to hospitalization, or if
the episode is severe, systemic corticosteroids should be added to the regimen.212 An inhaled
anticholinergic bronchodilator also may be added for continuing moderate or severe asthma
exacerbations (peak expiratory flow [PEF] 80% or less of predicted or personal best).212 For
severe asthma exacerbations not responding to the above regimen, administration of IV
methylxanthines may be used but should be considered as alternative therapy to inhaled shortacting 2-agonist therapy because of an increased risk of adverse effects with methylxanthine
therapy.212
For more information on the stepped-care approach for drug therapy in asthma, see Asthma
under Uses: Bronchospasm, in Albuterol 12:12.
Aminophylline and dyphylline generally share the same indications as theophylline. Because of
its short half-life, some clinicians believe that dyphylline is impractical for chronic
bronchodilator therapy. Most clinicians believe that the use of special theophylline vehicles,
salts, and preparations is unnecessary and that uncoated oral theophylline tablets provide the
most efficacious and convenient formulation for chronic therapy in many patients. Reliably
absorbed extended-release preparations allow longer dosing intervals with less variation in serum
theophylline concentration and can improve compliance.
Many clinicians have questioned the routine, prolonged administration of drug combinations
containing theophylline derivatives, sympathomimetic agents (e.g., ephedrine), sedatives (e.g.,
phenobarbital), and/or expectorants to asthmatic patients. Theophylline doses in most
combination preparations are inadequate. Single-ingredient preparations are more effective,
facilitate necessary dosage adjustment, and are safer than combination preparations. Concomitant

administration of sympathomimetics and theophylline is usually no more effective than either

drug alone and synergistic toxicity may result. For example, one study in children with severe
asthma showed that a combination of ephedrine and theophylline was no more effective than
therapeutic doses of theophylline alone and that the incidence of adverse effects was greater
when the drugs were given in combination than when they were used separately. Addition of
sympathomimetics to theophylline therapy (or vice versa) may be reasonable, however, in some
patients.
Chronic Obstructive Pulmonary Disease
In the stepped-care approach to drug therapy for chronic obstructive pulmonary disease (COPD),
theophylline (as an extended-release oral preparation) may be added to or substituted for therapy
with long-acting bronchodilators (e.g., tiotropium, a selective inhaled 2-agonist) in patients with
severe COPD who require additional therapy because of inadequate response or limiting adverse
effects.216, 217, 218, 220 The role of theophylline derivatives in patients with acute exacerbations of
COPD is controversial; some clinicians do not consider them to be beneficial, and even suggest
that they may have deleterious effects, in such patients.216, 219 For information on the stepped-care
approach to drug therapy in COPD, see Chronic Obstructive Pulmonary Disease under Uses:
Bronchospasm, in Albuterol 12:12 and in Ipratropium 12:08.08.
Other Uses
IV theophylline (often as aminophylline) has been used to relieve the periodic apnea and increase
arterial blood pH in patients with Cheyne-Stokes respiration#. Oral and IV theophylline have also
been used in infants to stimulate respiration and myocardial contractility associated with apnea#
and to reduce severe bronchospasm associated with cystic fibrosis# and acute descending
respiratory infections#.
IV theophylline has been used as an adjunct in the treatment of pulmonary edema or paroxysmal
nocturnal dyspnea caused by left-sided heart failure#, but its use in these situations has been
supplanted by more effective therapy. Theophylline has been used in the prophylaxis of angina
pectoris#, but its value in this disease is controversial and its usage is not recommended.
Theophylline has also been used to increase cerebrovascular resistance in the treatment of
hypertensive headaches#, but its use has been superseded by more potent antihypertensive agents.
Theophylline should not be used in the treatment of coronary thrombosis.
Aminophylline has been used to augment the diuretic action of the thiazides and carbonic
anhydrase inhibitors#, and to relieve dyspnea, decrease venous filling pressure, and increase
cardiac output when used as an adjunct in the treatment of congestive heart failure#. However,
use of aminophylline has largely been replaced by more effective diuretics such as furosemide
and ethacrynic acid.
Dosage and Administration
General Administration
Theophyllines (e.g., theophylline, aminophylline) and dyphylline usually are administered orally.
For faster absorption, conventional oral theophylline dosage forms may be taken with a full glass
of water on an empty stomach 30-60 minutes before meals or 2 hours after meals; to minimize
local GI irritation, oral theophyllines may be taken with meals or immediately after meals, with a

full glass of liquid, or with antacids. Extended-release preparations should not be chewed or
crushed; the contents of some extended-release capsules may be mixed with soft food and taken
without chewing in patients who have difficulty swallowing solid dosage forms. Administration
of some extended-release theophylline preparations with food may affect the rate and/or extent of
absorption of the drug, and the manufacturer's recommendations for administration of specific
products should be followed. Extended-release preparations should be administered in a
consistent manner, either always with or always without food.222, 223, 224 Patients should not alter
the administration schedule of theophylline preparations without consulting their clinician.221, 222,
223, 224, 225, 226, 229

Extended-release theophylline preparations are indicated in patients with relatively continuous or

frequently recurring asthma symptoms, and may be particularly useful in patients in whom
theophylline elimination is rapid (e.g., children, adult smokers). Extended-release preparations
designed for once-daily dosing (e.g., Uniphyl tablets) should be administered at the same time
each day, either morning or evening.223 The manufacturer of Theo-24 capsules states that this
preparation should be administered at the same time each morning when given once daily; oncedaily administration at night is not recommended because the effect of circadian rhythm, food,
posture, and other factors on theophylline absorption and/or clearance rates requires additional
study.222 The manufacturer of Theo-24 capsules suggests that patients who require twice-daily
dosing should receive the second dose 10-12 hours after the morning dose and before the
evening meal.222 Patients with more rapid metabolism (e.g., young individuals, smokers, some
nonsmoking adults) may require smaller doses administered more frequently (e.g., twice daily)
to avoid breakthrough symptoms resulting from low trough concentrations.222, 223
Aminophylline and theophylline also may be administered undiluted by slow IV injection or,
preferably, in large volume parenteral fluids by slow IV infusion.227, 228 Aminophylline solutions
may be prepared by diluting an appropriate volume of a commercially available injection or
pharmacy bulk package injection in a compatible IV infusion fluid. Loading doses usually are
given over 30 minutes.227, 228 If patients experience acute adverse effects while IV loading doses
of theophylline are being infused, the infusion may be stopped for 5-10 minutes or administered
at a slower rate.228
Aminophylline has been, and dyphylline may be administered IM, but this route is rarely used;
IM injection of aminophylline causes intense local pain and is not recommended.
Dosage
Theophyllines
Theophylline has a low therapeutic index; therefore, cautious dosage determination is essential.
Because individuals metabolize theophylline at different rates, appropriate dosages must be
determined for each patient by carefully monitoring patient response and tolerance, pulmonary
function, and serum theophylline concentrations. Dosages required to achieve a therapeutic
serum theophylline concentration vary fourfold among otherwise similar patients in the absence
of factors known to alter theophylline clearance.221 Although extended-release preparations have
been formulated to release the drug at various rates suitable for dosing every 8-12, 12, or 24
hours, the actual dosing frequency for a given patient and preparation depends on the patient's
individual pharmacokinetic parameters. Dosage should be calculated on the basis of lean body
weight.

For maintenance therapy, serum theophylline concentrations should be obtained after a patient
has received a given dosage for 3 days. Peak serum concentrations can be estimated by obtaining
blood samples 30 minutes after administration of an IV loading dose,227, 228 1-2 hours after
administration of an oral solution or uncoated tablet, or 3-12 (usually 3-8) hours (depending on
the specific formulation) after administration of an extended-release preparation. Trough
concentrations of theophylline can be determined by taking blood samples just before the next
dose. When the recommended maximum dosage is exceeded, dosage adjustment should be based
on measurement of peak serum theophylline concentrations. For dosage adjustments based on
serum theophylline concentrations determined in such circumstances, it is important that dosage
in the previous 48 hours be reasonably typical of the prescribed regimen and that the patient not
have missed a dose nor taken an additional dose in this time period. Dosage adjustments based
on serum theophylline concentration when these conditions have not been fulfilled may result in
dosages that present risk of toxicity to the patient. Therapeutic serum concentrations for
bronchospastic disease generally range from 10-15 mcg/mL, although lower concentrations may
provide beneficial effects in some patients with mild asthma and may be effective for neonatal
apnea. When serum theophylline concentrations exceed 20 mcg/mL, toxicity often becomes
apparent.
Dosage of theophylline preparations may be conveniently expressed in terms of anhydrous
theophylline. The approximate anhydrous theophylline content in the various theophylline
derivatives is shown in Table 1.
Table 1. Anhydrous Theophylline Content in Theophylline Derivatives
Drug Anhydrous Theophylline Content aminophylline anhydrous 85.7% (1.7%) aminophylline
hydrous 78.9% (1.6%) theophylline monohydrate 90.7% (1.1%)
Acute Bronchospasm. For the treatment of acute bronchospasm, theophylline (or
aminophylline) is preferably administered IV.
For the treatment of acute bronchospasm in patients who have not received any theophylline in
the previous 24 hours, a theophylline loading dose of 4.6 mg/kg (approximately equivalent to 5.7
mg/kg of hydrous aminophylline) based on ideal body weight will produce an average serum
theophylline concentration of 10 mcg/mL.227, 228 In general, each 1 mg/kg (based on ideal body
weight) of theophylline given by IV infusion over 30 minutes results in an average 2-mcg/mL
increase in serum theophylline concentration.227, 228 Serum theophylline concentration should be
measured 30 minutes after administration of a loading dose to determine the need for and size of
subsequent loading doses.228 After a therapeutic serum theophylline concentration is attained,
maintenance dosage by continuous IV infusion should be adjusted depending on the patient's
age, clinical characteristics, pharmacokinetic parameters, and target serum theophylline
concentration (generally 10-15 mcg/mL).227, 228
Following a loading dose, the following dosages by continuous IV infusion are recommended:
Table 2. Initial Theophylline IV Infusion Rate Following an Appropriate Loading Dose227, 228
Patient Population Theophylline Infusion Rate Neonates, postnatal age 24 days 1 mg/kg every
12 hours Neonates, postnatal age >24 days 1.5 mg/kg every 12 hours Infants 6 weeks to 1 year of
age mg/kg per hour = (0.008)(age in weeks) + 0.21 Children 1-9 years of age 0.8 mg/kg per hour

Children 9-12 years of age 0.7 mg/kg per hour Marijuana- or cigarette-smoking adolescents 1216 0.7 mg/kg per hour years of age Nonsmoking adolescents 12-16 years of age 0.5 mg/kg per
hour (maximum 900 mg daily) Nonsmoking adolescents and adults 16-60 years of 0.4 mg/kg per
hour (maximum 900 mg daily) age Geriatric patients >60 years of age 0.3 mg/kg per hour up to
maximum 17 mg/hour Maximum daily theophylline dosage 400 mg Cardiac decompensation,
cor pulmonale, hepatic 0.2 mg/kg per hour up to a maximum infusion rate dysfunction, sepsis
with multi-organ failure, of 17 mg/hour unless serum theophylline shock concentrations are
monitored at 24-hour intervals Maximum daily theophylline dosage 400 mg
----------------------------------------------------------------------------------------------------To achieve a target theophylline concentration of 10 mcg/mL.228
Approximate aminophylline dosage = theophylline dosage/0.8.228
Use ideal body weight for obese patients. Lower initial dosage may be required for patients with
conditions or receiving drugs that decrease theophylline clearance. (See Cautions: Precautions
and Contraindications and also see Drug Interactions.)227, 228
To achieve a target theophylline concentration of 7.5 mcg/mL.227, 228
Unless serum concentration indicates need for larger dosage.227, 228
A serum theophylline concentration should be measured at 1 expected half-life after starting the
continuous IV infusion (i.e., after approximately 4 hours for children 1-9 years of age, after 8
hours for nonsmoking adults) to determine if theophylline concentrations are decreasing or
increasing from the postloading dose drug concentration.228 If theophylline concentrations are
decreasing from the postloading drug concentration, an additional loading dose may be
administered and/or the rate of infusion may be increased.228 If the theophylline concentration
after initiation of the continuous infusion is higher than the postloading drug concentration, the
infusion rate should be decreased before the theophylline concentration exceeds 20 mcg/mL.228
An additional serum theophylline concentration should be measured 12-24 hours later to
determine if dosage adjustments are required, then at 24-hour intervals, to adjust for changes in
theophylline concentrations in the initial period of theophylline administration.228
In patients who are currently receiving theophylline preparations, estimation of serum
theophylline concentration based upon patient history is unreliable, and a serum theophylline
concentration should be measured immediately to determine a loading dose.228 A loading dose
should not be given before obtaining a serum theophylline concentration if the patient has
received any theophylline in the past 24 hours.228Loading doses of theophylline are based on the
general expectation that each 0.5 mg/kg (of lean body weight) of theophylline will result in a 1mcg/mL increase in serum theophylline concentration. A loading dose in patients who are
currently receiving theophylline preparations should be determined using the following formula:
Loading dose= (desired serum concentration - measured serum concentration) volume of
distribution.228 Volume of distribution for this calculation is assumed to be approximately 0.5
L/kg.228 The desired drug concentration should be conservative (e.g., 10 mcg/mL) to allow for
variability in the volume of distribution.228

IV dosage adjustments should be based on peak serum theophylline concentrations and the
clinical response and tolerance of the patient as shown in Table 3:
Table 3. IV Dosage Adjustment Based on Serum Theophylline Concentration228
Serum Dosage Adjustment Theophylline Concentration (mcg/mL) <9.9 Increase infusion rate by
25% if symptoms are not controlled and current dosage is tolerated; recheck serum concentration
after 12 hours in pediatric patients and 24 hours in adults 10-14.9 Maintain infusion rate if
symptoms are controlled and current dosage is tolerated; recheck serum concentration after 24
hours Consider adding additional agents if symptoms are not controlled and current dosage is
tolerated 15-19.9 Consider 10% decrease in infusion rate to provide greater margin of safety
even if current dosage is tolerated 20-24.9 Decrease infusion rate by 25% even if no adverse
effects are present; recheck serum concentration after 12 hours in pediatric patients and 24 hours
in adults 25-30 Stop infusion for 12 hours in pediatric patients and 24 hours in adults;
subsequently, decrease infusion rate by 25% even if no adverse effects are present Recheck
serum concentration after 12 hours in pediatric patients and 24 hours in adults; if symptomatic,
stop infusion and consider whether treatment for overdose is indicated >30 Stop infusion and
treat overdose as indicated If therapy is resumed, decrease subsequent infusion rate by 50% and
recheck serum concentration after 12 hours in pediatric patients and 24 hours in adults
------------------------------------------------------------------------------------------------------Dose reduction and/or serum theophylline concentration measurement is indicated whenever
adverse effects are present, physiologic abnormalities that can reduce theophylline clearance
occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued.
(See Cautions: Precautions and Contraindications and see Drug Interactions.)
IV theophylline is preferred over other routes of administration for the treatment of acute
bronchospasm. Oral extended-release dosage forms should not be used for the treatment of acute
bronchospasm.222, 224 An inhaled, short-acting 2-adrenergic agonist alone or in combination with
systemic corticosteroids is the most effective treatment for acute exacerbations of reversible
airway obstruction.211, 212, 225, 226, 229 If an inhaled or parenteral 2-adrenergic agonist is not
available, a loading dose of oral theophylline using immediate-release preparations can be used
as a temporary measure.225, 226, 229 Some experts suggest initiating therapy with a theophylline
dosage of 10 mg/kg (up to 300 mg) daily in divided doses, with titration up to a usual maximum
daily dosage of 800 mg in divided doses in adults and children older than 12 years of age or a
maximum daily dosage of 16 mg/kg in divided doses in children 1-12 years of age.211 Patients
who have not received any theophylline preparations in the previous 24 hours may receive a
theophylline loading dose of 5 mg/kg using an immediate-release preparation.225, 226, 229
Following the loading dose, theophylline dosage for subsequent therapy using an immediaterelease preparation in children older than 1 year of age and adults may be titrated as follows:
Table 4. Recommended Dosage Titration Using Immediate-Release Preparations for Children 1
Year of Age and Adults225, 226, 229
Age Dosage Titration Children 1-15 years of age weighing <45 kg Initially, 12-14 mg/kg
(maximum 300 mg) daily in divided doses; after 3 days, if tolerated, increase dosage to 16 mg/kg
(maximum 400 mg) daily in divided doses; after 3 more days, if tolerated and if needed, increase
dosage to 20 mg/kg (maximum 600 mg) daily in divided doses Administer in divided doses
every 4-6 hours Children 1-15 years of age weighing >45 kg and Initially, 300 mg daily in

divided doses; after 3 days, if adults 16-60 years of age tolerated, increase dosage to 400 mg
daily in divided doses; after 3 more days, if tolerated and if needed, increase dosage to 600 mg
daily in divided doses Administer in divided doses every 6-8 hours Children 1-15 years of age
with risk factors for Initially 12-14 mg/kg (maximum 300 mg) daily in divided reduced
theophylline clearance or in whom doses; after 3 days, if tolerated, increase dosage to serum
concentrations cannot be monitored maximum 16 mg/kg (maximum 400 mg) daily in divided
doses Administer in divided doses every 4-6 hours Adults >16 years of age with risk factors for
Initially, 300 mg daily in divided doses; after 3 days, if reduced theophylline clearance or in
whom tolerated, increase dosage to maximum 400 mg daily in serum concentrations cannot be
monitored divided doses Administer in divided doses every 6-8 hours
--------------------------------------------------------------------------------------------------------------Patients with more rapid metabolism, identified clinically by higher than average dosage
requirements, may require smaller doses given more frequently to prevent breakthrough
symptoms resulting from low trough theophylline concentrations; such patients may benefit from
therapy with an extended-release preparation.
See Cautions: Precautions and Contraindications and also see Drug Interactions for information
on additional risk factors for decreased theophylline clearance.
Serum theophylline concentrations should be monitored at 24-hour intervals to adjust final
dosage.225, 226
Chronic Bronchospasm. Extended-release preparations of theophylline may be administered
every 8, 12, or 24 hours to provide therapeutic serum theophylline concentrations in patients who
have relatively continuous or recurrent symptoms. 221, 222, 223, 224 For chronic maintenance
bronchodilator therapy in patients receiving certain extended-release preparations designed to be
given every 8-12 hours, dosage titration is shown in Table 5.
Table 5. Dosage Titration Using Certain Extended-Release Preparations Every 8-12 Hours221, 224
Age Daily Dosage Children 6-15 years of age weighing <45 kg Initially, 12-14 mg/kg (maximum
300 mg) daily in divided doses; after 3 days, if tolerated, increase dosage to 16 mg/kg (maximum
400 mg) daily in divided doses; after 3 more days, if tolerated and needed, increase dosage to 20
mg/kg (maximum 600 mg) daily in divided doses Children 6-15 years of age weighing >45 kg,
Initially, 300 mg daily in divided doses; after 3 days, if adolescents 16 years of age, and adults
tolerated, increase dose to 400 mg daily in divided doses; after 3 more days, if tolerated and
needed, increase dosage to 600 mg daily in divided doses Children 6-15 years of age with risk
factors Initially, 12-14 mg/kg (maximum 300 mg) daily in divided for reduced theophylline
clearance or in whom doses; after 3 days, if tolerated, increase dosage to serum concentrations
cannot be monitored maximum 16 mg/kg (maximum 400 mg) daily in divided doses Adults 16
years of age with risk factors for Initially, 300 mg daily in divided doses; after 3 days, if reduced
theophylline clearance or in whom tolerated, increase dosage to maximum 400 mg daily in
serum concentrations cannot be monitored divided doses Geriatric patients >60 years of age
Maximum 400 mg daily unless patient continues to be symptomatic, and peak serum
concentration <10 mcg/mL Administer dosages >400 mg daily with caution
--------------------------------------------------------------------------------------------------------------Dosage given as total daily dosage. Drug should be administered in divided doses every 8 or 12
hours; manufacturer's labeling for individual preparations should be consulted for recommended

dosing intervals.221, 224 It is generally recommended that the daily dosage requirement first be
established by monitoring serum theophylline concentrations while the patient is receiving an
immediate-release dosage form before switching to therapy with an extended-release
preparation. (See text.)
Some generic extended-release preparations (e.g.,extended-release capsules from Inwood
Laboratories) are FDA-labeled for use in children 1-15 years of age.221
See Cautions: Precautions and Contraindications and also see Drug Interactions for information
on additional risk factors for decreased theophylline clearance.
Regardless of oral dosage form, dosage for the treatment of chronic bronchospasm should not
exceed the 600 mg maximum daily dosage without measurement of serum theophylline
concentration.221, 222, 223, 224, 225, 226, 229
When extended-release preparations are to be administered, it is generally recommended that the
daily dosage requirement first be established by monitoring serum theophylline concentrations
while the patient is receiving a rapidly absorbed dosage form; then, therapy with an extendedrelease preparation may be started by administering one-half of the total daily dose every 12
hours. When transferring therapy from conventional tablets or 8-12 hour extended-release
preparations to a once-daily (24-hour) extended-release preparation (i.e., Uniphyl) in patients 12
years of age and older, to substitution of Uniphyl dosage using the 400- or 600-mg tablets on a
mg-for-mg basis is recommended.223
Oral dosage adjustments may be based on peak serum theophylline concentrations and the
clinical response and tolerance of the patient as follows:
Table 6. Oral Dosage Adjustment Based on Serum Theophylline Concentration
Serum Dosage Adjustment Theophylline Concentration (mcg/mL) <9.9 If symptoms are not
controlled and current dosage is tolerated, increase dosage by 25%. Recheck serum theophylline
concentration after 3 days for further dosage adjustment. 10-14.9 If symptoms are controlled and
current dosage is tolerated, maintain dosage and recheck serum theophylline concentration at 6to 12-month intervals.* If symptoms are not controlled and current dosage is tolerated, consider
adding additional agents. 15-19.9 Consider decreasing dosage by about 10% to provide greater
margin of safety even if current dosage is tolerated. 20-24.9 Decrease dosage by 25% even if no
adverse effects are present. Recheck serum theophylline concentration after 3 days to guide
further dosage adjustment. 25-30 Skip next dose and decrease subsequent doses by at least 25%
even if no adverse effects are present. Recheck serum theophylline concentration after 3 days to
guide further dosage adjustment. If symptomatic, consider whether treatment for overdose is
indicated. (See Acute Toxicity.) >30 Treat overdose as indicated. (See Acute Toxicity.) If
theophylline is resumed, decrease subsequent doses by at least 50% and recheck serum
theophylline concentration after 3 days to guide further dosage adjustment.
-------------------------------------------------------------------------------------------------------The clinical characteristics of each patient must be considered when applying these general
dosage recommendations to individual patients. In general, dosage adjustments should not
exceed these recommendations in order to decrease the risk of potentially serious adverse effects
associated with unexpected large increases in serum theophylline concentration.

Dosage reduction and/or serum theophylline concentration measurement is indicated whenever

adverse effects are present, physiologic abnormalities that can reduce theophylline clearance
occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued.
(See Cautions: Precautions and Contraindications and see Drug Interactions.)
When adjusting dosage in this manner, it is important that dosage in the previous 48 hours be
reasonably typical of the prescribed regimen and that the patient not have missed a dose nor
taken an additional dose in this time period.
IV dosage adjustments may be based on peak serum theophylline concentrations and the clinical
response and tolerance of the patient as follows:
Table 7. IV Dosage Adjustment Based on Serum Theophylline Concentration228
Serum Dosage Adjustment Theophylline Concentration (mcg/mL) <9.9 Increase infusion rate by
25% if symptoms are not controlled and current dosage is tolerated; recheck serum concentration
after 12 hours in pediatric patients and 24 hours in adults 10-14.9 Maintain infusion rate if
symptoms are controlled and current dosage is tolerated; recheck serum concentration after 24
hours Consider adding additional agents if symptoms are not controlled and current dosage is
tolerated 15-19.9 Consider 10% decrease in infusion rate to provide greater margin of safety
even if current dosage is tolerated 20-24.9 Decrease infusion rate by 25% even if no adverse
effects are present; recheck serum concentration after 12 hours in pediatric patients and 24 hours
in adults 25-30 Stop infusion for 12 hours in pediatric patients and 24 hours in adults;
subsequently, decrease infusion rate by 25% even if no adverse effects are present Recheck
serum concentration after 12 hours in pediatric patients and 24 hours in adults; if symptomatic,
stop infusion and consider whether treatment for overdose is indicated >30 Stop infusion and
treat overdose as indicated If therapy is resumed, decrease subsequent infusion rate by 50% and
recheck serum concentration after 12 hours in pediatric patients and 24 hours in adults
------------------------------------------------------------------------------------------------------Dose reduction and/or serum theophylline concentration measurement is indicated whenever
adverse effects are present, physiologic abnormalities that can reduce theophylline clearance
occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued.
(See Cautions: Precautions and Contraindications and see Drug Interactions.)
Dosage in Children Younger than 1 Year of Age. Dosage of theophylline in children younger
than 1 year of age, particularly in premature and term neonates, must be carefully individualized.
Elimination of the drug in children younger than 1 year of age, especially in neonates, generally
appears to be reduced. Because of potential toxicity, use of the drug in children younger than 1
year of age should be carefully considered and, if used, the initial and maintenance dosages
(particularly the latter) should be conservative. Maintenance dosage should not be exceeded and
therapy with the drug should not be continued unless the drug is well tolerated and clinically
beneficial. Recommended initial maintenance dosages for neonates and infants for the treatment
of bronchospasm are shown in the following table:.
Table 8. Recommended Dosage Titration for Children <1 Year of Age using Immediate-Release
Preparations225, 226, 229
Age Dosage Titration Premature neonates <24 days Initially, 1 mg/kg every 12 hours postnatal
age Adjust dosage to maintain a peak steady-state serum concentration of 5-10 mcg/mL

Premature neonates 24 days Initially, 1.5 mg/kg every 12 hours postnatal age Adjust dosage to
maintain a peak steady-state serum concentration of 5-10 mcg/mL Full-term infants <26 weeks
of age [(0.2 x age in weeks) + 5] x body weight (kg) = total daily dosage (mg); administer in 3
equally divided doses every 8 hours Adjust dose to maintain a peak steady-state serum
concentration of 5-10 mcg/mL in neonates or 10-15 mcg/mL in older infants Infants 26-52 weeks
of age [(0.2 x age in weeks) + 5] x body weight (kg) = total daily dosage (mg); administer in 4
equally divided doses every 6 hours Adjust dosage to maintain a peak steady-state serum
concentration of 10-15 mcg/mL
Other Uses. In infants with cystic fibrosis#, daily IV theophylline (as aminophylline)
maintenance doses of 10-12 mg/kg have been given. In adults, IV bolus theophylline doses of
approximately 200-400 mg have been used to promote diuresis# and to treat Cheyne-Stokes
respiration# and paroxysmal nocturnal dyspnea#.
Dyphylline
For acute bronchospasm in adults, the usual oral dosage of dyphylline recommended by the
manufacturer is 15 mg/kg or 200-400 mg every 6 hours.230, 231 Dosage must be carefully adjusted
according to individual requirements and response. In patients with renal impairment, dosage
reduction should be considered.230 Pediatric dosage has not been established.
Cautions
GI and Nervous System Effects
Theophyllines produce GI irritation and CNS stimulation following administration by any route.
Theophyllines are all somewhat irritating to gastric mucosa; the importance of reported
differences among the individual agents is doubtful. The most common adverse GI effects (both
locally and centrally mediated) include nausea, vomiting, epigastric pain, abdominal cramps,
anorexia, and, rarely, diarrhea. Hematemesis has also occurred. Adverse CNS effects, which are
often more severe in children than in adults, include headache, irritability, restlessness,
nervousness, insomnia, dizziness, reflex hyperexcitability, and seizures. Reduction of
theophylline dosage usually reduces the incidence and severity of adverse gastric and CNS
effects; however, if these adverse effects persist, the drug may have to be withdrawn. The drugs
may be administered orally before or after meals, with a full glass of liquid, or with antacids to
minimize locally mediated GI irritation.
Cardiovascular Effects
Adverse cardiovascular effects of theophyllines include palpitation, sinus tachycardia,
extrasystoles, and increased pulse rate. These adverse cardiovascular effects are usually mild and
transient. Flushing, hypotension, circulatory failure, and ventricular arrhythmias may also occur.
Other Adverse Effects
Theophyllines may also produce transiently increased urinary frequency, dehydration, twitching
of fingers and hands, tachypnea, and elevated serum AST (SGOT) concentrations.
Hypersensitivity reactions characterized by urticaria, generalized pruritus, and angioedema have
been reported with aminophylline administration. A contact-type dermatitis, caused by
hypersensitivity to the ethylenediamine component of aminophylline, has also been reported.
Bone marrow suppression, leukopenia, thrombocytopenia, and hemorrhagic diathesis have also

been reported, but their association with theophylline therapy is questionable. Other adverse
effects of theophyllines include albuminuria, increased urinary excretion of renal tubular cells
and erythrocytes, hyperglycemia, and syndrome of inappropriate secretion of antidiuretic
hormone (SIADH).
Adverse Effects Associated with Route and Method of Administration
Rapid IV injection of aminophylline may produce dizziness, faintness, lightheadedness,
palpitation, syncope, precordial pain, flushing, profound bradycardia, premature ventricular
contractions, severe hypotension, or cardiac arrest. IM injection of aminophylline produces
intense local pain and sloughing of tissue; IM dyphylline reportedly produces little tissue
irritation. When administered rectally as suppositories (dosage form no longer commercially
available in the US), theophyllines have caused rectal irritation and inflammation.
Precautions and Contraindications
When therapeutic doses of theophylline are administered simultaneously by more than one route
or in more than one preparation, the hazard of serious toxicity is increased; theophyllines should
not be administered concomitantly with other xanthine drugs. Smokers (cigarettes and/or
marijuana) may require larger than usual or more frequent doses, since theophylline clearance
may be increased and its half-life decreased in smokers when compared with nonsmokers.
Theophylline should be administered cautiously to young children. Theophylline should be
administered cautiously to patients older than 60 years of age (particularly males and those with
chronic obstructive pulmonary disease),221, 222, 223, 224, 225, 226, 228 neonates and infants under 1 year
of age, patients receiving concomitant therapy with certain drugs (see Drug Interactions),
patients undergoing influenza immunization or who have an active influenza infection, patients
with sustained high fever, and patients who have cardiac failure from any cause, chronic
obstructive pulmonary disease, cor pulmonale, or renal (in infants younger than 3 months of
age)228 or hepatic dysfunction, since clearance of theophylline is usually decreased, often
resulting in higher and potentially toxic serum concentrations; dosage should generally be
reduced and serum theophylline concentrations should be monitored cautiously in these patients.
In addition, these patients may have markedly prolonged serum theophylline concentrations
following discontinuance of the drug.
The drugs should be used with caution in patients with peptic ulcer, hyperthyroidism, glaucoma,
diabetes mellitus, severe hypoxemia, hypertension, or in patients with compromised cardiac or
circulatory function. Theophylline preparations should be used cautiously in patients with angina
pectoris or acute myocardial injury when myocardial stimulation would be harmful. Since
theophylline may cause dysrhythmia and/or worsen preexisting arrhythmias, any substantial
change in rate and/or rhythm warrants ECG monitoring and further investigation.
Some commercially available formulations of theophyllines contain sulfites that may cause
allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic
episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the
general population is unknown but probably low; such sensitivity appears to occur more
frequently in asthmatic than in nonasthmatic individuals.
Theophyllines are contraindicated in patients who are allergic to any of the theophyllines,
caffeine, or theobromine; aminophylline should not be used in patients hypersensitive to

ethylenediamine. At least one manufacturer states that theophyllines also are contraindicated in
patients with active peptic ulcer disease and in those with underlying seizure disorders, unless
the latter patients are receiving adequate anticonvulsant therapy.
Because of their erratic and unpredictable absorption and accumulation, theophylline rectal
suppositories (no longer commercially available in the US) have been associated with toxicity
more frequently than other formulations.
Pregnancy and Lactation
Pregnancy
Animal reproduction studies have not been performed with theophyllines. It is not known
whether theophyllines can cause fetal harm when administered to pregnant women. Although
safe use of theophyllines during pregnancy has not been established relative to the potential risk
to the fetus, the drugs have been used during pregnancy without teratogenicity or other adverse
fetal effect; because of the risk of uncontrolled asthma, their safety during pregnancy when
clearly needed is generally not seriously questioned.
Lactation
Theophylline is distributed into milk and may occasionally induce irritability or other signs of
toxicity in nursing infants. The risk to the breast-fed infant must be weighed against the benefit
of nursing in lactating women who are receiving theophylline.
Drug Interactions
Theophylline increases excretion of lithium and may decrease its therapeutic effectiveness.
Higher doses of lithium may be required during concurrent administration of theophylline. The
direct stimulatory effect of theophylline on the myocardium may enhance the sensitivity and
toxic potential of the cardiac glycosides. Theophylline may exhibit synergistic toxicity with
ephedrine and other sympathomimetics and, when administered concomitantly, these agents may
further predispose the patient to the development of cardiac arrhythmias.
Theophylline may enhance the effects of the oral anticoagulants by increasing plasma
prothrombin and factor V, but therapeutic theophylline dosages will probably have little or no
effect on anticoagulant response.
Cimetidine, high-dose allopurinol (e.g., 600 mg daily), oral contraceptives, propranolol,
ciprofloxacin, erythromycin, and troleandomycin may increase serum theophylline
concentrations by decreasing theophylline's hepatic clearance. Rifampin may decrease serum
theophylline concentrations by increasing theophylline's hepatic clearance. Concomitant
theophylline and phenytoin administration can result in decreased serum concentrations of either
or both agents by increasing hepatic metabolism.
Methotrexate may decrease clearance of theophylline; plasma theophylline concentrations should
be monitored in patients receiving theophylline concomitantly with methotrexate.
There is some evidence from animal studies that concomitant administration of a -Adrenergic
agonist (e.g., isoproterenol) and a theophylline derivative (e.g., aminophylline) may produce
increased cardiotoxic effects. Although such an interaction has not been established in humans, a

few reports have suggested that such a combination may have the potential for producing cardiac
arrhythmias. Further accumulation of clinical data is needed to determine whether this potential
interaction exists in humans.
Laboratory Test Interferences
Theophylline produces false-positive elevations of serum uric acid as measured by the Bittner or
colorimetric method but will not affect serum uric acid when measured by the uricase method.
In vitro, serum theophylline concentrations, as measured by spectrophotometric methods, may be
falsely elevated by furosemide, sulfathiazole, phenylbutazone, probenecid, theobromine,
caffeine-containing beverages, chocolate, and acetaminophen. These substances do not interfere
with results when theophylline concentrations are measured by high-pressure liquid
chromatography.
Acute Toxicity
Manifestations
Theophylline has a low therapeutic index. Theophylline toxicity is most likely to occur when
serum concentrations exceed 20 mcg/mL and becomes progressively more severe at higher
serum concentrations. Tachycardia, in the absence of hypoxia, fever, or administration of
sympathomimetic drugs, may be an indication of theophylline toxicity. Anorexia, nausea and
occasional vomiting, diarrhea, insomnia, irritability, restlessness, and headache commonly occur.
The distinguishing symptoms of toxicity may include agitated maniacal behavior, frequent
vomiting, extreme thirst, slight fever, tinnitus, palpitation, and arrhythmias. Patients may
experience delirium, muscle twitching, severe dehydration, albuminuria, emesis of a "coffee
ground" material, hyperthermia, and profuse diaphoresis. Seizures may occur even without other
preceding symptoms of toxicity and often result in death.
Fatalities in adults have generally occurred during or following IV administration of large doses
of aminophylline in patients with renal, hepatic, or cardiovascular complications. In other
patients, the rapidity of the injection, rather than the dose used, appears to be the more important
factor precipitating acute hypotension, seizures, coma, cardiac standstill, ventricular fibrillation,
and death. IV aminophylline or theophylline should therefore be given slowly. In children,
fatalities usually are a result of overdosage and marked sensitivity to the CNS stimulation of
theophylline.
Treatment
Treatment of theophylline overdosage is supportive and includes withdrawal of the drug. If
seizures have not occurred following acute overdosage, the stomach should be emptied
immediately by inducing emesis or by gastric lavage, followed by administration of activated
charcoal and a cathartic (particularly when extended-release preparations have been taken). If the
patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if
an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents;
activated charcoal and/or a cathartic may be administered via a large-bore gastric lavage tube. If
the patient is having seizures, an adequate airway should first be established and maintained and
oxygen administered; seizures may be treated with IV diazepam 0.1-0.3 mg/kg up to 10 mg.

Some clinicians recommend the use of barbiturates or anesthetics to control seizures. In one
clinical report, however, theophylline-induced seizures were relatively refractory to IV
diazepam, phenytoin, and phenobarbital. Restoration of fluid and electrolyte balance is
necessary. Administration of phenothiazines for intractable hyperthermia and propranolol for
extreme tachycardia may be warranted in life-threatening situations.
In general, theophylline is metabolized rapidly and hemodialysis is not warranted. In patients
with congestive heart failure or liver disease, hemodialysis or charcoal hemoperfusion may
increase theophylline clearance by as much as 2-fold. Charcoal hemoperfusion can rapidly
remove theophylline and may be clinically indicated when the serum theophylline concentration
exceeds 50 mcg/mL, even in the absence of obvious signs of toxicity. Some clinicians
recommend that charcoal hemoperfusion generally be used for all patients whose serum
theophylline concentration 4 hours after ingestion is greater than 60 mcg/mL. When the serum
theophylline concentration is 40-50 mcg/mL, the risks of hemoperfusion (e.g., hypotension,
thrombocytopenia) must be carefully weighed against the potential benefits of the procedure;
when the serum concentration is less than 40 mcg/mL, the risks of hemoperfusion probably
outweigh any potential benefits. Some clinicians recommend that charcoal hemoperfusion be
used in patients with a serum theophylline concentration of 30 mcg/mL or greater and 3 of the
following 4 risk factors: the patient is 60 years of age or older, the patient has substantial liver
disease and/or congestive heart failure, the theophylline half-life for the patient is calculated to
be 24 hours or more, and/or the patient's serum theophylline concentration is 50 mcg/mL or
greater. If hemoperfusion is not performed, some clinicians recommend oral administration of
activated charcoal every 4 hours until the serum theophylline concentration decreases to less than
20 mcg/mL.
Pharmacology
Theophyllines and dyphylline exert identical pharmacologic actions. Theophylline competitively
inhibits phosphodiesterase, the enzyme that degrades cyclic 3,5-adenosine monophosphate
(cAMP). Increased concentrations of intracellular cAMP may mediate most of the
pharmacologic effects of the drug. The actions of theophylline on the myocardium and on
neuromuscular transmission may result from intracellular translocation of ionized calcium. The
ubiquitous nature of calcium and cAMP accounts for the diversity of theophylline's
pharmacologic actions.
Pulmonary Effects
Theophylline directly relaxes smooth muscle of the respiratory tract, producing relief of
bronchospasm and increasing flow rates and vital capacity. The bronchodilator effect of the drug
is minimal if bronchospasm is not the principal cause of respiratory distress. Theophylline also
dilates pulmonary arterioles, reduces pulmonary hypertension and alveolar carbon dioxide
tension, and increases pulmonary blood flow. Unlike sympathomimetics, tolerance to the
bronchodilator effects of theophylline rarely occurs. (See also Pharmacology: Nervous System
Effects.)
Nervous System Effects
Theophylline stimulates all levels of the CNS, but to a lesser degree than does caffeine.
Stimulation of the vasomotor and vagal centers promotes vasoconstriction and bradycardia,

respectively, but the overall effect of theophylline on heart rate and blood pressure depends on
whether CNS or peripheral effects predominate. In the medulla, theophylline also lowers the
threshold of the respiratory center to carbon dioxide, but substantial increases in rate and depth
of respiration occur only if respiration is depressed. Alleviation of neonatal apnea and the apnea
of Cheyne-Stokes respiration by these drugs may be caused by direct stimulation of the
medullary respiratory center. Theophylline constricts cerebral vasculature; in some patients, the
resultant decrease in cerebral blood flow and increase in carbon dioxide tension may result in
respiratory center stimulation. The ethylenediamine component of aminophylline reportedly
contributes to the respiratory stimulant action of theophylline; however, the importance and
validity of this action are doubtful. Therapeutic serum concentrations of theophylline may
stimulate the vomiting center while toxic serum concentrations activate all levels of the cortex
and spinal cord, often producing seizures. Tolerance of a low magnitude may develop to the
sleep-disturbing effect of theophylline.
Cardiovascular Effects
In doses larger than those required for bronchodilation, theophylline produces a positive
inotropic effect on the myocardium and a positive chronotropic effect at the sinoatrial (SA) node.
Although heart rate, force of contraction, cardiac output, and myocardial oxygen demand may be
increased transiently, theophylline rarely alters heart rate to a substantial degree with usual doses.
At high serum concentrations, however, the central vagal effects of the drug may be masked by
increased sinus rate, and acute hypotension, tachycardia, extrasystoles, or ventricular arrhythmia
may result. The ethylenediamine component of aminophylline reportedly contributes to the
positive inotropic action of theophylline; however, the importance and validity of this action are
doubtful. (See also Pharmacology: Nervous System Effects.)
Theophylline directly dilates coronary, pulmonary, renal, and general systemic arterioles and
veins, decreasing peripheral vascular resistance and venous pressure. The effect of this decrease
in peripheral resistance (and possibly that of vagal stimulation) on blood pressure is offset by
increased cardiac output (and possibly stimulation of the medullary vasomotor area); there is
generally only a slight increase in blood pressure following administration of moderate doses of
theophylline. Rapid IV injection, however, may cause transient hypotension. In a similar manner,
peripheral blood flow increases initially, but this increase is of short duration. Dilation of
coronary blood vessels may be a direct effect of theophylline or may result from increased
cardiac work. Coronary blood flow increases and, theoretically, myocardial oxygen supply is
improved by theophylline. However, some studies report an increase in myocardial oxygen
consumption resulting from increased heart work. In contrast to its peripheral vasodilation,
theophylline constricts cerebral vasculature.
Renal Effects
The diuretic effect of theophylline is more potent than that of theobromine but is of shorter
duration. Mild diuresis is produced by the combined effect of theophylline on renal
hemodynamics and on tubular reabsorption. Increased cardiac output and dilation of efferent and
afferent renal arterioles result in increased glomerular filtration rate (GFR) and renal blood flow.
In congestive heart failure, theophylline-induced changes in GFR are variable. Theophylline also
inhibits sodium and chloride reabsorption at the proximal tubule. Potassium excretion is not
markedly increased. Tolerance of a low magnitude may develop to the diuretic effect of
theophylline.

 Endocrine and Metabolic Effects

At therapeutic serum concentrations, theophylline may stimulate release of catecholamines from
the adrenal medulla and increase the urinary excretion of epinephrine. Theophylline exhibits
many of the -Adrenergic effects of epinephrine; their cardiac and hyperglycemic effects may be
synergistic. Conversely, theophylline may potentiate corticotropin and catecholamine-induced
insulin secretion. The net effect on blood glucose is variable. The lipolytic action of theophylline
requires the presence of growth hormone or glucocorticoid to produce maximum increase in
plasma free fatty acids. Theophylline may potentiate the calcemic response to parathyroid
hormone and inhibit that of calcitonin. Theophylline may also increase basal metabolic rate.
Other Effects
Theophylline relaxes smooth muscle of the biliary and GI tract, and stimulates gastric secretion.
Theophylline stimulates skeletal muscle in vitro, increasing the force of contraction and
decreasing muscular fatigue; this action of theophylline may be mediated by acetylcholine.
Pharmacokinetics
Absorption
Dissolution appears to be the rate-limiting step in the absorption of oral theophylline. Under the
acidic conditions of the stomach, the theophylline salts and compounds release free theophylline.
Dyphylline is absorbed through the gastric mucosa and appears in the plasma intact.
Microcrystalline dosage forms and oral solutions of theophyllines are absorbed more rapidly, but
not to a greater extent, than are uncoated tablets. Although the rate of absorption is slower,
extended-release preparations (capsules and tablets) of theophylline are generally absorbed to the
same extent as uncoated tablets; however, the actual rate of absorption of extended-release
preparations may differ. Extended-release preparations of theophyllines have been formulated to
release the drug at various rates suitable for dosing every 8-12, 12, or 24 hours; however, the
actual dosing frequency for a given patient depends on their individual pharmacokinetic
parameters. Since the rate and extent of absorption may differ between various extended-release
preparations and sometimes between different dosage sizes of the same preparation, patients
should generally be stabilized on a given preparation; substitution of one extended-release
preparation for another should generally only be made when the preparations have been shown to
be equivalent and/or the patient is evaluated pharmacokinetically during the transition period.
Absorption of theophyllines may also be delayed, but is generally not reduced, by the presence
of food in the GI tract; however, the effect of food on the absorption of extended-release
preparations appears to be variable, and the manufacturer's recommendations for administration
of specific preparations should be followed. When administered IM, theophylline is usually
absorbed slowly and incompletely. Rectal suppositories (no longer commercially available in the
US) are slowly and erratically absorbed, regardless of whether the suppository base is
hydrophilic or lipophilic.
Serum theophylline concentrations of about 10-20 mcg/mL are usually needed to produce
optimum bronchodilator response. Reports indicate that serum concentrations of dyphylline in
this same range produce a bronchodilator response. Some patients with mild pulmonary disease
will experience relief of bronchospasm with serum theophylline concentrations of 5 mcg/mL.
With serum concentrations ranging from 8-20 mcg/mL, a linear relationship exists between
improvement in pulmonary function and the logarithm of serum theophylline concentration. In

premature infants, serum theophylline concentrations of about 7-14 mcg/mL may be sufficient to
reverse apnea. Serum theophylline concentrations of about 10 mcg/mL produce a transient
diuretic response. Adverse reactions to theophylline often occur when serum concentrations
exceed 20 mcg/mL.
IV theophylline produces the highest and most rapid serum theophylline concentration.
Following a single IV dose of theophylline (as aminophylline) of about 5 mg/kg over 30 minutes
to healthy adults, mean peak serum theophylline concentrations of about 10 mcg/mL are reached.
Slightly lower or equal peak serum concentrations are reached after oral administration of equal
amounts of theophylline in uncoated tablet, capsule, or liquid formulations. Following oral
administration of theophylline capsules or uncoated tablets, peak serum concentrations are
usually reached in 1-2 hours. Peak serum theophylline concentrations are usually obtained after
about 1 hour when theophylline oral solutions or microcrystalline tablets are administered.
Enteric-coated theophylline tablets produce variable serum concentrations which usually peak at
about 5 hours. Single doses of extended-release theophylline capsules or tablets usually produce
peak serum concentrations after 4 hours, but commercial products vary in their rates and
completeness of absorption. Extended-release theophylline preparations are generally associated
with relatively small fluctuations in steady-state peak and trough serum concentration; however,
clinically important steady-state peak-trough differences may occur in individuals who rapidly
eliminate theophylline. Theophylline retention enemas usually produce peak serum
concentrations in 1-2 hours. Serum theophylline concentrations generally have been apparent 3-5
hours after administration of the drug as rectal suppositories (no longer commercially available
in the US).
Distribution
Theophylline is rapidly distributed throughout extracellular fluids and body tissues with
distribution equilibrium being reached 1 hour after an IV loading dose. The drug partially
penetrates erythrocytes and readily crosses the placenta.
The drug is also distributed into milk in concentrations about 70% those in serum.
The apparent volume of distribution of theophylline ranges from 0.3-0.7 L/kg and averages about
0.45 L/kg in children and adults. In premature infants, theophylline's apparent volume of
distribution is generally almost 2 times that in adults. At serum concentrations of 17 mcg/mL,
approximately 56% of theophylline in adults and children, and 36% of that in premature infants,
is bound to plasma proteins. Although saliva concentrations of theophylline have been reported
to be 50% of serum concentrations in relatively healthy patients, saliva concentrations ranged
from 50-100% of serum concentrations in one study in severely ill patients.
Elimination
In maintenance-dose theophylline schedules, serum concentrations among patients vary at least
6-fold and serum half-lives (t 1/2) exhibit wide interpatient variation because of differences in rate
of metabolism. Serum t 1/2 ranges from about 3-12.8 (average 7-9) hours in otherwise healthy,
nonsmoking asthmatic adults, from about 1.5-9.5 hours in children, and from about 15-58 hours
in premature infants. Theophylline clearances (mean standard deviation) have been reported to
be 1.45 0.58 mL/kg per minute in children older than 6 months of age and 0.65 0.19 mL/kg
per hour in otherwise healthy, nonsmoking asthmatic adults. In adults, a shorter serum t 1/2 of

about 2 hours has been demonstrated for dyphylline. When compared with that of otherwise
healthy, nonsmoking asthmatic adults, the serum t 1/2 of theophylline may be increased and total
body clearance decreased in patients with congestive heart failure, chronic obstructive
pulmonary disease, cor pulmonale, or liver disease, and in geriatric patients. In cigarette and/or
marijuana smokers, theophylline serum t 1/2 averages 4-5 hours and total body clearance is
increased compared with nonsmokers.
Theophylline is metabolized by the liver to 1,3-dimethyluric acid, 1-methyluric acid, and 3methylxanthine. The metabolism of dyphylline has not been fully elucidated, but the drug is not
metabolized to theophylline. Individuals metabolize theophylline at different rates; however,
individual metabolism of the drug is generally reproducible. Theophylline and its metabolites are
excreted mainly by the kidneys. Renal clearance of the drug, however, contributes only 8-12% of
the overall plasma clearance of theophylline. Small amounts of theophylline are excreted in feces
unchanged.
Chemistry
Theophylline
Like caffeine and theobromine, theophylline may be structurally classified as a xanthine
derivative. Theophylline occurs naturally in tea, but it is prepared synthetically for commercial
use. The drug may contain one molecule of water or be anhydrous. At physiologic pH,
theophylline functions as a weak base (pKb 13-14). Tautomeric shift of the hydrogen from the
unsubstituted 7 nitrogen is possible at high pH, creating a weak organic acid (pKa 8.79) that
reacts with alkali salts of weak organic acids and certain organic amines. Theophylline occurs as
a white, odorless, crystalline powder having a bitter taste and is sparingly soluble in alcohol. The
drug is only slightly soluble in water at pH 7; the water solubility increases with increases in pH.
Aminophylline
Aminophylline is a water-soluble theophylline compound with ethylenediamine and occurs as
white or slightly yellowish granules or powder having a slight ammoniacal odor and a bitter
taste. Aminophylline is soluble in water and insoluble in alcohol. Aminophylline has a pKa of 5.
Aminophylline may be anhydrous or may contain not more than 2 molecules of water of
hydration. Upon exposure to air, aminophylline and aminophylline solutions gradually lose
ethylenediamine, absorb carbon dioxide, and liberate free theophylline; aminophylline solutions
should not be used if they contain crystals. Aminophylline injection has a pH of 8.6-9 and should
be stored in single-dose containers from which carbon dioxide has been excluded.
Aminophylline injections reportedly are not stable in solutions having a pH substantially less
than 8; however, the drug appears to be relatively stable in large volume parenteral solutions over
a wide pH range (3.5-8.6) if aminophylline concentrations do not exceed 40 mg (31.6 mg of
anhydrous theophylline) per mL. The activity of alkali-sensitive drugs will be reduced by
aminophylline; these drugs should not be added to IV fluids containing aminophylline. Published
data on specific incompatibilities of aminophylline are varied and/or limited; specialized
references should be consulted for specific compatibility information.
Dyphylline

Dyphylline, which is a distinct chemical entity, is structurally and pharmacologically similar to

theophylline but has a 2,3-dihydroxypropyl radical at position 7. Dyphylline is not metabolized
to theophylline in vivo. Dyphylline occurs as a white, odorless, amorphous or crystalline solid
having an extremely bitter taste. Dyphylline is freely soluble in water and sparingly soluble in
alcohol. Dyphylline injection has a pH of 6.4-7.4 and should be protected from light.
Oxtriphylline
Oxtriphylline (no longer commercially available in the US), the choline salt of theophylline,
occurs as a white, crystalline powder having an amine-like odor and a slightly saline taste.
Oxtriphylline is freely soluble in water and in alcohol.
Preparations
* available generically
Aminophylline (Hydrous)
Routes Dosage Strengths Brand Names Manufacturer Forms Oral Tablets 100 mg (78.9 mg of
anhydrous Aminophylline West-ward theophylline)* Tablets 200 mg (157.8 mg of anhydrous
Aminophylline West-ward theophylline)* Tablets Parenteral Injection 25 mg (19.7 mg of
anhydrous Aminophylline American theophylline) per mL* Injection Regent, Hospira
* available generically
Aminophylline (Anhydrous)
Routes Dosage Strengths Brand Names Manufacturer Forms Oral Solution 105 mg (90 mg of
Aminophylline DF (dye-free) Actavis anhydrous theophylline) per 5 mL* Aminophylline Oral
Solution Roxane
Dyphylline
Routes Dosage Strengths Brand Names Manufacturer Forms Oral Solution 33 mg/5 mL Dylix
Elixir (with alcohol 20%) Lunsco Lufyllin Elixir (with alcohol 20%) MedPointe Tablets 200
mg Dilor (with povidone; scored) Savage Lufyllin (scored) MedPointe 400 mg Dilor (with
povidone; scored) Savage Lufyllin (scored) MedPointe
Dyphylline and Guaifenesin
Routes Dosage Strengths Brand Names Manufacturer Forms Oral Solution 33.3 mg/5 mL
Dyphylline Dyphylline GG (with alcohol Actavis, and Guaifenesin 33.3 mg/ 17%) Cypress 5
mL Lufyllin-GG Elixir (with MedPointe alcohol 17%) 100 mg/5 mL Dyphylline and Dilor-G
(with parabens) Savage Guaifenesin 100 mg/5 mL Dy-G (alcohol-free, dye-free) Cypress
Dyline-GG Seatrace Tablets 200 mg Dyphylline and Dilor-G (with povidone; Savage
Guaifenesin 200 mg scored) Dyflex-G EconoMed Dyline-GG (scored) Seatrace DyphyllineGG United Research Lufyllin-GG (scored) MedPointe
Dyphylline Combinations
Routes Dosage Strengths Brand Names Manufacturer Forms Oral Tablets 100 mg with
Ephedrine Hydrochloride 16 Lufyllin-EPG MedPointe mg, Guaifenesin 200 mg, and
Phenobarbital 16 mg

* available generically
Theophylline (Anhydrous)
Routes Dosage Strengths Brand Names Manufacturer Forms Bulk Powder* Oral Capsules, 100
mg Theo-24 (24 hours) UCB extended- release 125 mg Theophylline Extended-Release
Capsules (12 Inwood hours) 200 mg Theo-24 (24 hours) UCB Theophylline Extended-Release
Capsules (12 Inwood hours) 300 mg Theo-24 (24 hours) UCB Theophylline Extended-Release
Capsules (12 Inwood hours) 400 mg Theo-24 (24 hours) UCB Solution 27 mg/5 mL*
Elixophyllin Elixir (with alcohol 20%) Forest Theophylline Solution Actavis, Roxane Tablets
125 mg Theolair (scored) 3M 250 mg Theolair (scored) 3M 300 mg Quibron-T (scored)
Monarch Tablets, 100 mg* Theochron (12 hours, scored) Forest extended- release
Theophylline Extended-Release Tablets (12 hours) Inwood 200 mg* Theochron (12 hours,
scored) Forest Theophylline Extended-Release Tablets (12 hours) Inwood 300 mg* QuibronT/SR (12 hours, scored) Monarch Theochron (12 hours, scored) Forest Theophylline
Extended-Release Tablets (12 hours) Inwood 400 mg Uniphyl Unicontin (24 hours, scored;
with Purdue povidone) Frederick 600 mg Uniphyl Unicontin (24 hours, scored; with Purdue
providone) Frederick
Theophylline (Anhydrous) in Dextrose
Routes Dosage Forms Strengths Brand Names Manufacturer Parenteral Injection, 0.4 mg/mL
(400 mg) Theophylline Theophylline and 5% Dextrose Injection Various for IV (anhydrous) in
5% Dextrose (Viaflex [Baxter]) Manufacturers infusion 0.8 mg/mL (400 and 800 mg)
Theophylline Theophylline and 5% Dextrose Injection Various (anhydrous) in 5% Dextrose
(LifeCare [Hospira], Excel [Braun], Manufacturers Viaflex [Baxter]) 1.6 mg/mL (400 and
800 mg) Theophylline Theophylline and 5% Dextrose Injection Various (anhydrous) in 5%
Dextrose (LifeCare [Hospira], Excel [Braun], Manufacturers Viaflex [Baxter]) 2 mg/mL (200
mg) Theophylline (anhydrous) Theophylline and 5% Dextrose Injection Various in 5% Dextrose
(LifeCare [Hospira], Viaflex [Baxter]) Manufacturers 3.2 mg/mL (800 mg) Theophylline
Theophylline and 5% Dextrose Injection Various (anhydrous) in 5% Dextrose (LifeCare
[Hospira], Viaflex [Baxter]) Manufacturers 4 mg/mL (200 and 400 mg) Theophylline
Theophylline and 5% Dextrose Injection Various (anhydrous) in 5% Dextrose (LifeCare
[Hospira], Viaflex [Baxter]) Manufacturers
Theophylline and Guaifenesin
Routes Dosage Strengths Brand Names Manufacturer Forms Oral Capsules, 150 mg
Theophylline (anhydrous) and Quibron Monarch liquid- Guaifenesin 90 mg filled 300 mg
Theophylline (anhydrous) and Quibron Monarch Guaifenesin 180 mg Solution 33.3 mg/5 mL
Theophylline Elixophyllin GG Forest (anhydrous) and Guaifenesin 33.3 (with parabens and
mg/5 mL propylene glycol)
Comparative Pricing
Pricing information provided by drugstore.com.
Elixophyllin 80MG/15ML ELIX (FOREST): 480/$97.01 or 1440/$280.94
Quibron 90-150MG CAPS (MONARCH PHARMACEUTICALS): 30/$21.83 or 90/$59.26

Theo-24 200MG CP24 (UCB PHARMA): 60/$48.99 or 180/$130.97

Theo-24 300MG CP24 (UCB PHARMA): 60/$62.99 or 180/$174.96
Theo-24 400MG CP24 (UCB PHARMA): 60/$79.99 or 180/$222.97
Theochron 200MG TB12 (FOREST): 60/$30.7 or 180/$88.72
Theophylline CR 100MG TB12 (PLIVA): 60/$10.69 or 180/$25.67
Theophylline CR 125MG CP12 (QUALITEST): 60/$43.57 or 180/$105.1
Theophylline CR 200MG CP12 (INWOOD LABS): 60/$29.99 or 180/$81.68
Theophylline CR 200MG TB12 (INWOOD LABS): 60/$23.74 or 180/$57.49
Theophylline CR 300MG CP12 (INWOOD LABS): 60/$49.99 or 180/$135.95
Theophylline CR 300MG TB12 (INWOOD LABS): 60/$18.99 or 180/$36.97
Theophylline CR 450MG TB12 (PLIVA): 60/$32.99 or 180/$84.98
Uniphyl 600MG TB24 (PURDUE PHARMACEUTICAL PRODUCTS): 60/$106.3 or
180/$306.22
AHFS Drug Information. Copyright, 1959-2008, Selected Revisions January 2007. American
Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
#

Use is not currently included in the labeling approved by the US Food and Drug
Administration.
References
Only references cited for selected revisions after 1984 are available electronically.
211. National Asthma Education and Prevention Program. Expert panel report: guidelines for the
diagnosis and management of asthma-update on selected topics 2002. Bethesda, Md: National
Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program
Coordinating Committee; 2003 Jun. Available from National Heart, Lung, and Blood Institute
Information Center, NIH Publication No. 02-5074. Also available at
http://www.nhlbi.nih.gov/guidelines/asthma/asthmafullrpt.pdf. Accessed 2004 Sep. 15.
212. National Institutes of Health, National Heart, Lung, and Blood Institute. Global Initiative
for asthma: global strategy for asthma management and prevention NHLBI/WHO Workshop
Report. Bethesda, MD: National Institutes of Health. 2005 Oct. NIH/NHLBI Publication No. 023659. Available at: http://www.ginasthma.com. Accessed Mar. 09, 2006.
213. National Asthma Education and Prevention Program. Expert panel report II: guidelines for
the diagnosis and management of asthma. 1997 Jul.

214. National Asthma Education Program. Executive summary: guidelines for the diagnosis and
management of asthma. NIH Publ. No.94-3042A. Washington, DC: US Government Printing
Office; 1994 Jul.
215. British Thoracic Society. Guidelines on the management of asthma. Thorax. 2003; 58(1
Suppl):i1-94.
216. O'Donnell DE, Aaron S, Bourbeau J et al. State of the art compendium: Canadian Thoracic
Society recommendations for management of chronic obstructive pulmonary disease. Can
Respir J. 2004; 11 (Suppl. B):7B-59B. [PubMed 15340581]
217. Celli BR, Macnee W. Standard for the diagnosis and treatment of patients with COPD: a
summary of the ATS/ERS position paper. Eur Respir J. 2004; 23:932-46. [PubMed 15219010]
218. ATS/ERS Standards for the diagnosis and management of patients with COPD. New York,
NY: American Thoracic Society, European Respiratory Society; 2004. Available at
http://www.thoracic.org/COPD/. Accessed Dec. 8, 2004.
219. Snow V, Lascher S, Mottur-Pilson C for the Joint Expert Panel of Chronic Obstructive
Pulmonary Disease of the American College of Chest Physicians and the American College of
Physicians-American Society of Internal Medicine. Evidence base for management of acute
exacerbations of chronic obstructive pulmonary disease. Clinical Practice Guideline, pt.1. Ann
Intern Med. 2001; 134:595-9. [PubMed 11281744]
220. National Heart, Lung, and Blood Institute/World Health Organization. Global strategy for
the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Bethesda,
MD: National Heart, Lung, and Blood Institute, Global Initiative for Chronic Obstructive Lung
Disease, World Health Organization; 2005 Sep. Available at: http://www.goldcopd.com.
Accessed Oct. 5, 2005.
221. Inwood Laboratories. Theophylline extended-release capsules prescribing information.
Inwood, NY; 2005 Mar.
222. UCB Pharma. Theo-24 (theophylline anhydrous) extended-release capsules prescribing
information. Smyrna, GA: 2005 Apr.
223. Purdue Pharmaceutical Products. Uniphyl (theophylline anhydrous) tablets prescribing
information. Stamford, CT; 2004 Mar 17.
224. Monarch Pharmaceuticals. Quibron-T/SR (theophylline anhydrous) accudose tablets
prescribing information. Bristol, TN; 1999 Aug.
225. Monarch Pharmaceuticals. Quibron-T (theophylline) tablets prescribing information.
Bristol, TN; 1999 Aug.
226. 3M Pharmaceuticals. Theolair (theophylline) tablets prescribing information. Northridge,
CA; 1998 May.

227. American Regent Laboratories, Inc. Aminophylline injection, USP prescribing information.
Shirley, NY; 1999 June.
228. B. Braun Medical Inc. Theophylline in 5% dextrose injections USP prescribing information.
Irvine, CA; 2003 Aug.
229. Forest Pharmaceuticals, Inc. Elixophyllin(theophylline anhydrous) elixir prescribing
information. St. Louis, MO; 1999 May.
230. Lunsco, Inc. Dylix (dyphylline elixir, USP) prescribing information. Puluski, VA; not
dated.
231. MedPointe Pharmaceuticals. Lufyllin(dyphylline tablets, USP) prescribing information.
Somerset, NJ; 2004 Feb.
Copyright 2008 by the American Society of Health-System Pharmacists, Inc. All rights
reserved.
(+/-) Show / Hide Bibliography
Electronic Reference Style Guide

Copyright:
o Copyright 2008 by the American Society of Health-System Pharmacists, Inc.
All rights reserved.

Database Title:
o STAT!Ref Online Electronic Medical Library

Editor:
o Gerald K. McEvoy, Pharm.D.

ISBN:
o 978-1-58528-206-7

ISSN:
o 8756-6028

Publication City:
o Bethesda, MD

Publication Year:

o 2008

Publisher:
o American Society of Health-System Pharmacists, Inc.

Title:
o AHFS Drug Information (2008)

Date Posted:
o 11/17/2008 2:49:05 PM PST (GMT -08:00)

Electronic Address:
o http://online.statref.com/document.aspx?fxid=1&docid=1206

Date Accessed:
o 11/27/2008 1:26:14 PM PST (GMT -08:00)

Location In Title:
o AHFS DRUG INFORMATION (2008)
86:00 Smooth Muscle Relaxants
86:16 Respiratory Smooth Muscle Relaxants

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