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Theophyllines (Monograph)

Brand names: Dy-G, Dylix, Dyphylline-GG, Elixophyllin, Lufyllin, ... show all 9 brands
Drug class: Respiratory Smooth Muscle Relaxants
ATC class: R03DA01
VA class: RE104
CAS number: 317-34-0

Introduction

Xanthine derivative; respiratory smooth muscle relaxant, bronchodilator.221 222 223 226 227 228 229 230 231 a d e f g h i k l m n

Uses for Theophyllines

Symptomatic management or prevention of asthma and reversible bronchospasm associated with COPD, including chronic bronchitis and emphysema.211 212 221 222 223 226 229 230 231 a d e f g h i j m n

Aminophylline and dyphylline generally share the same indications as theophylline.a d h i

Bronchospasm in Asthma

Symptomatic management or prevention of bronchospasm in patients with reversible, obstructive airway disease (e.g., asthma).211 212 221 222 223 226 227 228 229 230 231 a d e f g h i k l m n

In the stepped-care approach recommended in current asthma management guidelines,m n a selective, short-acting, inhaled β2-adrenergic agonist is used as needed to control acute asthma symptoms in all patients; use of such a β2-adrenergic agonist alone generally sufficient for patients with intermittent asthma.211 212 213 214 215 m n

Consider short-acting theophylline (if extended-release theophylline not already used) as less-effective alternative to short-acting inhaled β2-agonist for relief of acute asthma symptoms (i.e., as temporary measure if inhaled or parenteral β2-agonist not available); theophylline has slower onset of action and greater risk of adverse effects.212 226 229 f i n

Consider extended-release theophylline as less-effective alternative to low-dose inhaled corticosteroid for long-term control and prevention of symptoms in adults and children ≥5 years of age with mild persistent asthma.211 212 m n Also consider extended-release theophylline as less-effective alternative to long-acting inhaled β2-adrenergic agonist for use as adjunct to inhaled corticosteroid therapy in adults and children ≥5 years of age with moderate persistent asthma.211 212 f i m n Some clinicians do not recommend use of extended-release theophylline as alternative or add-on long-term control therapy in children <5 years of age with mild persistent asthma.211 m (See Pediatric Use under Cautions.)

Consider extended-release theophylline as add-on therapy in adults and children ≥5 years of age with severe persistent asthma inadequately controlled by high dosages of an orally inhaled corticosteroid and a long-acting inhaled β2-adrenergic agonist.212 m n

IV theophylline and aminophylline are FDA-labeled for use as an adjunct to inhaled β2-adrenergic agonists and systemic corticosteroids in the treatment of acute asthma exacerbations.227 228 k l However, some experts do not recommend theophylline derivatives for treatment of severe, acute asthma exacerbations because such therapy does not appear to provide additional benefit to optimal therapy with inhaled short-acting β2-adrenergic agonists and is associated with an increased risk of adverse effects.m Other experts suggest consideration of IV theophylline or aminophylline as add-on therapy for treatment of severe, acute exacerbations of asthma in hospitalized patients not responding adequately to oxygen, inhaled short-acting β2-adrenergic agonists, and systemic corticosteroids.212

Dyphylline not indicated for the management of status asthmaticus.230 231 d e h

Bronchospasm in COPD

Management of symptoms and reversible airflow obstruction in patients with COPD.221 222 223 226 227 228 230 231 d e f g h i

Consider extended-release theophylline in patients with stable COPD as less-preferred alternative to inhaled bronchodilators (e.g., long-acting β2-adrenergic agonist, long-acting anticholinergic agent [e.g., tiotropium]) depending on individual response/tolerance and availability.j

Some experts consider extended-release theophylline as add-on therapy in patients with severe symptoms of COPD inadequately controlled with other therapy (long-acting β2-adrenergic agonist, long-acting anticholinergic bronchodilator [e.g., tiotropium], and inhaled corticosteroid).q

IV theophylline and aminophylline are FDA-labeled for use as an adjunct to inhaled β2-adrenergic agonists and systemic corticosteroids for acute exacerbations of COPD.227 228 k l However, such use considered controversial by some experts because of modest/inconsistent response and frequent adverse effects;219 j q use suggested in patients with severe exacerbations who have inadequate response to short-acting bronchodilators (e.g., inhaled β2-adrenergic agonist).k l j

Other Uses

Has been used to relieve periodic apnea and increase arterial blood pH in patients with Cheyne-Stokes respiration [off-label].a o r

Has been used to stimulate respiration and myocardial contractility associated with apnea in infants [off-label].a p

Not for treatment of coronary thrombosis.a

Theophyllines Dosage and Administration

General

Monitoring Serum Theophylline Concentrations

Administration

Usually, administer theophyllines (e.g., theophylline, aminophylline) and dyphylline orally as a tablet, capsule, or solution;221 222 223 226 229 230 231 d e f g h i may also administer theophylline or aminophylline by slow IV injection or slow IV infusion.227 228 a k l (See IV Administration under Dosage and Administration.)

Aminophylline has been administered by IM injection [off-label]; however, IM administration may cause intense local pain and is not recommended.a

Oral Administration

Immediate-Release Preparations

Administer conventional oral preparations with a full glass of water on an empty stomach 30–60 minutes before meals or 2 hours after meals for faster absorption and to minimize GI irritation.a

Food or antacids do not cause clinically important changes in the absorption of theophylline from immediate-release dosage forms.222 f

Extended-Release Preparations

Administration of some extended-release preparations with food may affect the rate and/or extent of drug absorption.221 222 223 a g Administer extended-release preparations in a consistent manner, either always with or always without food; follow manufacturer’s recommendations for specific preparations.222 223 a g

Administer extended-release preparations every 8, 12, or 24 hours (depending on particular preparations; consult manufacturer's labeling) to provide therapeutic serum theophylline concentrations in patients who have relatively continuous or recurrent symptoms.222 223 a g

Do notcrush or chew extended-release preparations; patients who have difficulty swallowing solid dosage forms may mix contents of some extended-release capsules with soft food and swallow without chewing.222 223 a g May split scored, extended-release tablets of Uniphyl for once-daily dosing.223 May also split scored, extended-release Theochron tablets for twice-daily dosing but not for once-daily dosing.g

Administer extended-release (Theo-24) capsules at same time in the morning when given once daily; evening administration not recommended.222 In patients who require twice-daily dosing, administer second dose 10–12 hours after morning dose and before evening meal.222 In patients with more rapid metabolism (e.g., young individuals, smokers, some nonsmoking adults), administer smaller doses more frequently (e.g., twice daily) to avoid breakthrough symptoms resulting from low trough concentrations.222 223

Administer extended-release (Uniphyl) tablets at same time each day, either morning or evening.223 Consider that peak and trough serum theophylline concentrations produced by once-daily dosing may vary from those produced by the previous product and/or regimen.223

NG Tubing Administration

May pour contents of extended-release capsules down feeding tube; however, do not crush drug pellets.b

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer aminophylline and theophylline solutions undiluted by slow IV injection or, preferably, diluted in large-volume parenteral fluids by slow IV infusion.227 228 k l

For single-dose administration; solutions do not contain bacteriostatic or antimicrobial agents.k l Discard unused portions.k l

Dilution

Prepare aminophylline solutions for IV infusion by diluting an appropriate volume of a commercially available aminophylline injection or pharmacy bulk package injection in a compatible IV infusion fluid.a l

Rate of Administration

Administer slowly IV over 30 minutes (≤20 mg/minute);227 228 if acute adverse effects occur during infusion, stop infusion for 5–10 minutes or administer at a slower rate.228 a

After therapeutic serum theophylline concentration is attained, administer maintenance dosage by continuous IV infusion; infusion rate depends on patient's age, clinical characteristics, pharmacokinetic parameters, and target serum theophylline concentration (generally 10 mcg/mL).227 228

In patients with cardiac decompensation, cor pulmonale, liver dysfunction, sepsis with multi-organ failure, shock, or those taking drugs that markedly reduce theophylline clearance, do not exceed a maximum rate of 17 mg/hour unless serum concentrations are monitored at 24-hour intervals.227 228

Dosage

Available as aminophylline anhydrous, aminophylline hydrous, and theophylline monohydrate; dosage of theophylline and aminophylline preparations is expressed in terms of anhydrous theophylline.a i

Anhydrous Theophylline Content in Theophylline Derivativesa

Drug

Anhydrous Theophylline Content

Aminophylline anhydrous

85.7% (±1.7%)

Aminophylline hydrous

78.9% (±1.6%)

Theophylline monohydrate

90.7% (±1.1%)

Also available as dyphylline; dosage expressed in terms of dyphylline.a

Low therapeutic index; cautious dosage determination essential.a Do not exceed recommended dosage adjustments; risk of potentially serious adverse effects associated with large increases in serum theophylline concentration.222 223 226 227 228 229 a f g i k l

Dosage required to achieve therapeutic serum concentration varies fourfold among otherwise similar patients in absence of factors known to affect theophylline clearance.221 222 223 226 227 228 229 a f g i k l Adjust dosage carefully according to individual requirements and response, pulmonary function, and serum theophylline concentrations.221 222 223 226 227 228 229 a f g i k l

Calculate dosage based on ideal body weight.221 222 223 226 227 228 229 a f g i k l

Adjust dosage based on peak serum theophylline concentration.221 222 223 226 227 228 229 a f g i k l

Pediatric Patients

Carefully consider use and individualize dosage of the drug in children <1 year of age, particularly premature and term neonates; if used, administer conservative initial and maintenance dosages (particularly the latter).a Do not exceed recommended maintenance dosage and do not continue use of the drug unless well tolerated and clinically beneficial.a

Asthma
Acute Bronchospasm
Oral

Oral solutions, immediate-release tablets, extended-release tablets, and capsules: For acute exacerbations of reversible airway obstruction (when an inhaled, short-acting β2-adrenergic agonist or systemic corticosteroids not available),226 229 f i n may administer a loading dose of 5 mg/kg (in patients who have not received any theophylline in the previous 24 hours) using an immediate-release preparation to produce an average peak serum concentration of 10 mcg/mL (range 5–15 mcg/mL).226 229 f

Some experts suggest initiating therapy with a theophylline dosage of 10 mg/kg (up to 300 mg in adolescents ≥12 years of age) daily in divided doses, with titration up to a usual maximum dosage of 16 mg/kg daily in divided doses in children 1–11 years of age or 800 mg daily in divided doses in adolescents ≥12 years of age.m

Following loading dose, titrate theophylline dosage for subsequent therapy in pediatric patients using an immediate-release preparation as follows:

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 Warnings/Precautions under Cautions and also see Interactions for information on risk factors for decreased theophylline clearance.

Table 1. Recommended Dosage Titration in Pediatric Patients Using Immediate-Release Preparations226229fim

Age

Dosage Titration

Premature neonates <24 days postnatal age

Initially, 1 mg/kg every 12 hours

Adjust dosage to maintain a peak steady-state serum concentration of 5–10 mcg/mL

Premature neonates ≥24 days postnatal age

Initially, 1.5 mg/kg every 12 hours

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) = initial total daily dosage (mg); administer in 3 equally divided doses every 8 hours

Adjust dosage 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) = initial 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

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 and adolescents ≥1 year of age weighing >45 kg

Initially, 300 mg daily in divided doses; after 3 days, if 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 and adolescents 1–15 years of age with risk factors for reduced theophylline clearance or in whom serum concentrations cannot be monitored

Theophylline: Initially, 12–14 mg/kg (maximum 300 mg) daily in divided doses; after 3 days, if tolerated, increase dosage to maximum 16 mg/kg (maximum 400 mg) daily in divided doses

Administer in divided doses every 4–6 hours

Monitor serum theophylline concentrations at 24-hour intervals to adjust final dosage.226 f

For final dosage titration, see Table 2.

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 Warnings/Precautions under Cautions and also see Interactions.)

Table 2. Oral Dosage Adjustment in Pediatric Patients Based on Serum Theophylline Concentrationfi

Serum Theophylline Concentration (mcg/mL)

Dosage Adjustment

<9.9

Increase dose by 25% if symptoms are not controlled and current dosage is tolerated; recheck serum concentration after 3 days for further adjustment

10–14.9

Maintain dosage if symptoms are controlled and current dosage is tolerated; recheck serum concentration at 6- to 12-month intervals.

Consider adding additional agents if symptoms are not controlled and current dosage is tolerated

15–19.9

Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated

20–24.9

Decrease dose by 25% even if no adverse effects are present; recheck serum concentration after 3 days

25–30

Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present

Recheck serum concentration after 3 days; if symptomatic, consider whether treatment for overdose is indicated

>30

Stop drug and treat overdose as indicated

If therapy is resumed, decrease subsequent dosage by ≥50% and recheck serum concentration after 3 days

Dyphylline (tablet or solution): In children ≥6 years of age, 100–200 mg given 3 or 4 times daily.d h Adjust dosage carefully according to individual requirements and response.a d e h

Dyphylline (solution): At least one manufacturer suggests dosage of approximately 0.9–1.4 mg/kg (2–3 mg/pound) daily in divided doses for children ≥6 years of age.e

IV

For acute bronchodilation, administer IV to achieve a therapeutic serum theophylline concentration (i.e., 10–15 mcg/mL).227 228 k l

Generally, 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 k l

In patients who have not received any theophylline in the previous 24 hours, administer a loading dose of 4.6 mg/kg of theophylline (approximately equivalent to 5.7 mg/kg of hydrous aminophylline) based on ideal body weight to achieve an average serum theophylline concentration of 10 mcg/mL.227 228 k l

For acute bronchodilation in patients who are currently receiving theophylline preparations, measure serum theophylline concentration immediately to determine loading dose; estimation of serum theophylline concentration based upon patient history is unreliable.227 228 k l Do not administer loading dose before obtaining serum theophylline concentration if patient has received any theophylline in past 24 hours.227 228 k l

Determine loading dose in patients currently receiving theophylline preparations using following formula:227 228 k l

Loading dose= (desired serum concentration – measured serum concentration) × volume of distribution

Assume volume of distribution of 0.5 L/kg for this calculation.228 k l Ensure that desired drug concentration is conservative (e.g., 10 mcg/mL) to allow for variability in volume of distribution.227 228 k l

Measure serum theophylline concentration 30 minutes after administration of loading dose to determine need for and size of subsequent loading doses.227 228 k l After therapeutic serum theophylline concentration attained, adjust maintenance dosage by continuous IV infusion depending on patient's age, clinical characteristics, pharmacokinetic parameters, and target serum theophylline concentration (generally 10–15 mcg/mL).227 228 k l

Following loading dose, initiate continuous IV infusion as shown in Table 3.

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 Warnings/Precautions under Cautions and also see 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

Table 3. Initial Theophylline IV Infusion Rate in Pediatric Patients Following Appropriate Loading Dose227228kl

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 12–16 years of age

0.7 mg/kg per hour

Nonsmoking adolescents 12–16 years of age

0.5 mg/kg per hour (maximum 900 mg daily)

Measure serum theophylline concentration at 1 expected half-life after starting continuous IV infusion (i.e., after approximately 4 hours for children 1–9 years of age; see Half-life under Pharmacokinetics) to determine if theophylline concentrations are decreasing or increasing from post-loading dose drug concentration.228 If theophylline concentrations decreasing, administer additional loading dose and/or increase infusion rate.228 If theophylline concentration after initiation of continuous IV infusion is higher than post-loading drug concentration, decrease infusion rate before theophylline concentration >20 mcg/mL.228 Measure additional serum theophylline concentration 12–24 hours later to determine if dosage adjustments are required, then measure again at 24-hour intervals to adjust for changes in theophylline concentrations during the initial period of theophylline administration.228

Base IV dosage adjustments on peak serum theophylline concentrations and the clinical response and tolerance of patient as shown in Table 4:

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 Warning/Precautions under Cautions and see Interactions.)

Table 4. IV Dosage Adjustment in Pediatric Patients Based on Serum Theophylline Concentration227228kl

Serum Theophylline Concentration (mcg/mL)

Dosage Adjustment

<9.9

If symptoms are not controlled and current dosage is tolerated, increase infusion rate by 25%. Recheck serum concentration after 12 hours for further dosage adjustment

10–14.9

If symptoms are controlled and current dosage is tolerated, maintain infusion rate and recheck serum concentration at 24-hour intervals. If symptoms are not controlled and current dosage is tolerated, consider adding additional agents to treatment regimen

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 to guide further dosage adjustment

25–30

Stop infusion for 12 hours and decrease infusion rate by ≥25% even if no adverse effects are present. Recheck serum concentration after 12 hours to guide further dosage adjustment. If patient symptomatic, stop infusion and consider whether treatment for overdose is indicated

>30

Stop infusion and treat overdose as indicated. If theophylline therapy is resumed, decrease subsequent infusion rate by ≥50% and recheck serum concentration after 12 hours to guide further dosage adjustment

Switching to Extended-release Preparations
Oral

With extended-release preparations, establish daily dosage requirement first by monitoring serum theophylline concentrations while patient is receiving immediate-release dosage form; then, initiate therapy with extended-release preparation by administering half of total daily dose every 12 hours.a

In adolescents ≥12 years of age: May transfer patients stabilized on an immediate-release or 8- to 12-hour extended-release theophylline preparation to once-daily (every 24 hours) administration using 400- or 600-mg tablets of Uniphyl on a mg-for-mg basis.223

Chronic Bronchospasm
Oral

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.

Some generic extended-release preparations (e.g., extended-release capsules from Inwood Laboratories) are FDA-labeled for use in children and adolescents 1–15 years of age.221

Administer in divided doses every 8 or 12 hours; consult manufacturer's labeling for specific recommended dosing intervals for individual preparations.221 Generally recommended that daily dosage requirement first be established by monitoring serum theophylline concentrations while patient is receiving an immediate-release dosage form before switching to therapy with an extended-release preparation. (See text.)

Patients with more rapid metabolism, clinically identified by higher than average dosage requirements, should receive a smaller dosage more frequently to prevent breakthrough symptoms resulting from low trough concentrations before the next dose. A reliably absorbed slow-release formulation will decrease fluctuations and permit longer dosing intervals.

See Warning/Precautions under Cautions and also see Interactions for information on risk factors for decreased theophylline clearance.

Table 5. Dosage Titration in Pediatric Patients Using Certain Extended-Release Preparations 221g

Age

Daily Dosage

Children and adolescents 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 and adolescents 6–15 years of age weighing >45 kg

Initially, 300 mg daily in divided doses; after 3 days, if tolerated, increase dosage 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 and adolescents 6–15 years of age with risk factors for reduced theophylline clearance or in whom serum concentrations cannot be monitored

Initially, 12–14 mg/kg (maximum 300 mg) daily in divided doses; after 3 days, if tolerated, increase dosage to maximum 16 mg/kg (maximum 400 mg) daily in divided doses

Adjust dosage based on peak serum theophylline concentrations and clinical response and tolerance of patient as follows:a

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.a

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 Warning/Precautions under Cautions and see Interactions.)

Table 6. Oral Dosage Adjustment in Pediatric Patients Based on Serum Theophylline Concentrationgi

Serum Theophylline Concentration (mcg/mL)

Dosage Adjustment

<9.9

If symptoms are not controlled and current dosage is tolerated, increase dosage by 25%. Recheck serum concentration after 3 days for further adjustment

10–14.9

If symptoms are controlled and current dosage is tolerated, maintain dosage and recheck serum theophylline concentration at 6- to 12-month intervals. If symptoms are not controlled and current dosage is tolerated, consider adding additional agents to treatment regimen

15–19.9

Consider 10% decrease in dosage 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 concentration after 3 days to guide further dosage adjustment

25–30

Skip next dose and decrease subsequent dosage by at least 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment; if patient symptomatic, consider whether treatment for overdose is indicated

>30

Stop drug and treat overdose as indicated. If therapy is resumed, decrease subsequent dosage by ≥50% and recheck serum concentration after 3 days to guide further dosage adjustment

When adjusting dosage in this manner, ensure that dosage in previous 48 hours was reasonably typical of prescribed regimen and that patient did not miss a dose or take an additional dose in this time period.a

Adults

Asthma
Acute Bronchospasm
Oral

For acute exacerbations of reversible airway obstruction (when an inhaled, short-acting β2-adrenergic agonist or systemic corticosteroids not available),226 229 f i n may administer a loading dose of 5 mg/kg (in patients who have not received any theophylline in the previous 24 hours) using an immediate-release preparation to produce an average peak serum concentration of 10 mcg/mL (range 5–15 mcg/mL).226 229 f

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 dosage of 800 mg daily in divided doses.211 m

Following the loading dose, titrate theophylline dosage for subsequent therapy in adults using an immediate-release preparation as follows:

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 Warning/Precautions under Cautions and also see Interactions for information on risk factors for decreased theophylline clearance.

Table 7. Recommended Dosage Titration Using Immediate-Release Preparations for Adults226229fi

Age

Dosage Titration

Adults ≥16 years of age (weighing >45 kg) without risk factors for reduced theophylline clearance

Initially, 300 mg daily in divided doses; after 3 days, if 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

Adults ≥16 years of age with risk factors for reduced theophylline clearance, including patients >60 years of age and those in whom serum concentrations cannot be monitored

Initially, 300 mg daily in divided doses; after 3 days, if tolerated, increase dosage to maximum 400 mg daily in divided doses; do not exceed 400 mg/day in the presence of risk factors for reduced theophylline clearance

Administer in divided doses every 6–8 hours

Monitor serum theophylline concentrations at 24-hour intervals to adjust final dosage.226 f For final dosage titration based on serum theophylline concentration, see Table 8:

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 Warning/Precautions under Cautions and see Interactions.)

Table 8. Oral Dosage Adjustment Based on Serum Theophylline Concentrationfi

Serum Theophylline Concentration (mcg/mL)

Dosage Adjustment

<9.9

Increase dose by 25% if symptoms are not controlled and current dosage is tolerated; recheck serum concentration after 3 days for further adjustment

10–14.9

Maintain dosage if symptoms are controlled and current dosage is tolerated; recheck serum concentration at 6- to 12-month intervals

Consider adding additional agents if symptoms are not controlled and current dosage is tolerated

15–19.9

Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated

20–24.9

Decrease dose by 25% even if no adverse effects are present; recheck serum concentration after 3 days

25–30

Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present

Recheck serum concentration after 3 days; if symptomatic, consider whether treatment for overdose is indicated

>30

Stop drug and treat overdose as indicated

If therapy is resumed, decrease subsequent dosage by ≥50% and recheck serum concentration after 3 days

Dyphylline (tablet or solution): Usually, 15 mg/kg or 100–200 mg every 6 hours;231 d e h one manufacturer recommends a dosage of 200–400 mg every 6 hours in adults.230 Adjust dosage carefully according to individual requirements and response.a d e h

IV

For acute bronchodilation, therapeutic serum theophylline concentration (i.e., 10–15 mcg/mL) best achieved with IV loading dose(s).227 228 k l

Generally, 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 k l

In patients who have not received any theophylline in the previous 24 hours, administer loading dose of 4.6 mg/kg of theophylline (approximately equivalent to 5.7 mg/kg of hydrous aminophylline) based on ideal body weight to achieve an average serum theophylline concentration of 10 mcg/mL.227 228 k l

For acute bronchodilation in patients who are currently receiving theophylline preparations, measure serum theophylline concentration immediately to determine loading dose; estimation of serum theophylline concentration based upon patient history unreliable.227 228 k l Do not administer loading dose before obtaining serum theophylline concentration if patient has received any theophylline in past 24 hours.227 228 k l

Determine loading dose in patients who are currently receiving theophylline preparations using following formula:227 228 k l

Loading dose = (desired serum concentration - measured serum concentration) × volume of distribution

Assume volume of distribution of approximately 0.5 L/kg for use in this formula.227 228 k l Ensure that desired drug concentration is conservative (e.g., 10 mcg/mL) to allow for variability in volume of distribution.227 228 k l

Measure serum theophylline concentration 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, adjust maintenance dosage depending on the patient's age, clinical characteristics, pharmacokinetic parameters, and target serum theophylline concentration (generally 10–15 mcg/mL).227 228

Following loading dose, initiate continuous IV infusion as shown in Table 9:

To achieve 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 Warning/Precautions under Cautions and also see Interactions.)227 228

Unless serum concentration indicates need for larger dosage.227 228

Table 9. Initial Theophylline IV Infusion Rate Following Appropriate Loading Dose227228kl

Patient Population

Initial Theophylline Infusion Rate

Adults 16–60 years of age

0.4 mg/kg per hour (maximum 900 mg daily)

Patients >60 years of age

0.3 mg/kg per hour up to maximum 17 mg/hour (maximum 400 mg daily)

Patients with cardiac decompensation, cor pulmonale, hepatic dysfunction, sepsis with multi-organ failure, shock

0.2 mg/kg per hour up to a maximum 17 mg/hour (maximum 400 mg daily) unless serum theophylline concentrations are monitored at 24-hour intervals

Measure serum theophylline concentration at 1 expected half-life after starting continuous IV infusion (i.e., after 8 hours for nonsmoking adults; see Half-life under Pharmacokinetics) to determine if theophylline concentrations are decreasing or increasing from post-loading dose drug concentration.228 If theophylline concentrations are decreasing, administer additional loading dose and/or increase infusion rate.228 If theophylline concentration after initiation of continuous IV infusion is higher than post-loading drug concentration, decrease infusion rate before theophylline concentration >20 mcg/mL.228 Measure additional serum theophylline concentration 12–24 hours later to determine if dosage adjustments are required, then measure again at 24-hour intervals to adjust for changes in theophylline concentrations during the initial period of theophylline administration.228

Base IV dosage adjustments on peak serum theophylline concentrations and clinical response and tolerance of patient as shown in Table 10:

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 Warning/Precautions under Cautions and see Interactions.)

Table 10. IV Dosage Adjustment Based on Serum Theophylline Concentration228kl

Serum Theophylline Concentration (mcg/mL)

Dosage Adjustment

<9.9

Increase infusion rate by 25% if symptoms are not controlled and current dosage is tolerated; recheck serum concentration after 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 24 hours in adults

25–30

Stop infusion for 24 hours in adults; subsequently, decrease infusion rate by ≥25% even if no adverse effects are present

Recheck serum concentration after 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 24 hours in adults

Switching to Extended-release Preparations
Oral

With extended-release preparations, establish daily dosage requirement first by monitoring serum theophylline concentrations while patient is receiving immediate-release dosage form; then, initiate therapy with extended-release preparation by administering half of total daily dose every 12 hours.a

May transfer patients stabilized on an immediate-release or 8- to 12-hour controlled-release theophylline preparation to once-daily (every 24 hours) administration using 400- or 600-mg tablets of Uniphyl on a mg-for-mg basis.223

Chronic Bronchospasm
Oral

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 11.

Some generic extended-release preparations (e.g., extended-release capsules from Inwood Laboratories) are FDA-labeled for use in children and adolescents 1–15 years of age.221

Administer in divided doses every 8 or 12 hours; consult manufacturer's labeling for specific recommended dosing intervals for individual preparations.221 Generally recommended that daily dosage requirement first be established by monitoring serum theophylline concentrations while patient is receiving an immediate-release dosage form before switching to therapy with an extended-release preparation. (See text.)

See Warning/Precautions under Cautions and also see Interactions for information on risk factors for decreased theophylline clearance.

Table 11. Dosage Titration Using Certain Extended-Release Preparations Every 8–12 Hours221

Age

Daily Dosage

Adults (≥16 years of age) with risk factors for reduced theophylline clearance or in whom serum concentrations cannot be monitored

Initially, 300 mg daily in divided doses; after 3 days, if tolerated, increase dosage to maximum 400 mg daily in divided doses

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

Adjust dosage based on peak serum theophylline concentrations and clinical response and tolerance of patient as follows:a

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 Warning/Precautions under Cautions and see Interactions.)

Table 12. Oral Dosage Adjustment Based on Serum Theophylline Concentrationa

Serum Theophylline Concentration (mcg/mL)

Dosage Adjustment

<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 6- to 12-month intervals. If symptoms are not controlled and current dosage is tolerated, consider adding additional agents to treatment regimen

15–19.9

Consider 10% decrease in dosage 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 dosage by at least 25% even if no adverse effects are present. Recheck serum theophylline concentration after 3 days to guide further dosage adjustment. If patient symptomatic, consider whether treatment for overdose is indicated

>30

Stop drug and treat overdose as indicated. If theophylline therapy is resumed, decrease subsequent dosage by ≥50% and recheck serum concentration after 3 days to guide further dosage adjustment

When adjusting dosage in this manner, ensure that dosage in previous 48 hours was reasonably typical of prescribed regimen and that patient did not miss a dose or take an additional dose in this time period.a

Prescribing Limits

Pediatric Patients

Asthma
Oral

Children and adolescents 1–15 years of age without risk factors for reduced theophylline clearance: Maximum of 20 mg/kg (up to 600 mg) daily recommended after at least 6 days of dosage titration.226 229 (See Table 1 under Dosage and Administration.)

Children and adolescents 1–15 years of age with risk factors for reduced theophylline clearance or in whom serum concentrations cannot be monitored: Maximum of 16 mg/kg (up to 400 mg) daily recommended after at least 3 days of dosage titration.226 229 (See Table 1 under Dosage and Administration.)

Regardless of oral preparation, dosage should not exceed the 600 mg maximum daily dosage without measurement of serum theophylline concentration.221 222 223 226 229

IV

Nonsmoking adolescents 12–16 years of age: 0.5 mg/kg per hour up to maximum of 900 mg daily (unless serum concentrations indicate need for larger dosage) following administration of appropriate loading dose.227 228 k l

Adults

Asthma and COPD
Oral

Patients without risk factors for reduced theophylline clearance: Maximum 600 mg daily.226 229

Regardless of oral preparation, do not exceed 600 mg daily without measurement of serum theophylline concentration.221 222 223 226 229

Patients with risk factors for reduced theophylline clearance or in whom serum concentrations cannot be monitored: Maximum 400 mg daily.226 229

Geriatric patients: Maximum 400 mg daily.226 229 f g i

IV

In patients who have not received theophylline in previous 24 hours: Maximum 900 mg daily (unless serum concentrations indicate need for larger dosage) following administration of loading dose.227 228 k l

In geriatric patients, patients with cardiac decompensation, cor pulmonale, hepatic dysfunction, sepsis with multi-organ failure, shock, or those taking drugs that markedly reduce theophylline clearance: Maximum initial infusion rate: 17 mg/hour (unless serum concentrations monitored at 24-hour intervals).227 228 k l

Special Populations

Hepatic Impairment

Possible increased risk of toxicity in patients with hepatic impairment; monitor serum theophylline concentrations and adjust dosage accordingly because of decreased clearance.223 226 228

In patients with suspected decreased serum protein binding (e.g., cirrhosis, third trimester of pregnancy), maintain concentrations of unbound (free) theophylline in range of 6–12 mcg/mL.222 228 f i k

Initial infusion rate following appropriate loading dose: 0.2 mg/kg per hour.228

Maximum daily dosage 400 mg unless serum concentration indicates need for larger dosage.228

Renal Impairment

Monitor serum theophylline concentrations and adjust dosage accordingly for neonates and infants ≤3 months of age with renal impairment.228 f

Dosage adjustment not required in adults and children >3 months of age.228 f

Dyphylline: Consider dosage reduction in patients with renal impairment.230 231

Geriatric Patients

Select dosage with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function, concomitant disease, and drug therapy.221 222 223 226 227 228 229 f g i k l Theophylline clearance decreased in healthy adults >60 years of age.221 222 223 226 227 228 229 f g i k l (See Elimination: Special Populations under Pharmacokinetics.) Reduced dosage and frequent monitoring of serum theophylline concentrations required in geriatric patients.221 222 223 226 227 228 229 f g i k l

Administer oral dosages >400 mg daily with caution.223 226 g

Initial IV infusion rate following appropriate loading dose: 0.3 mg/kg per hour.228

Patients with Cardiac Decompensation, Cor Pulmonale, Sepsis with Multi-organ Failure, or Shock

Initial infusion rate following appropriate loading dose: 0.2 mg/kg per hour.228 Maximum initial infusion rate: 17 mg/hour unless serum theophylline concentrations monitored at 24-hour intervals.228 k

Maximum daily dosage: 400 mg daily unless serum concentration indicates need for larger dosage.228

Smokers

May require larger than usual or more frequent doses in patients that smoke (cigarettes and/or marijuana).a

Careful attention to dose and frequent monitoring of serum theophylline concentrations required in patients who stop smoking.g (See Elimination: Special Populations under Pharmacokinetics.)

Cautions for Theophyllines

Contraindications

Warnings/Precautions

Warnings

Concurrent Diseases or Conditions

Risk of exacerbation of active peptic ulcer disease, seizures, and cardiac arrhythmias (excluding bradyarrhythmias).221 222 223 226 227 228 229 f g h i k l Use extreme caution in patients with such concurrent conditions.221 222 223 226 227 228 229 h i f g k l

Dyphylline: Do not use for status asthmaticus.230 231 d e h

Dyphylline: Relationship between plasma concentrations and appearance of toxicity not known, but excessive doses associated with increased risk of adverse effects.230 231 d e h

Conditions or Factors that Reduce Theophylline Clearance

Clearance reduced in neonates (term and premature), children <1 year of age, and patients >60 years of age; patients with acute pulmonary edema, CHF, cor pulmonale, fever ≥39°C for ≥24 hours or lesser temperature elevations for more prolonged periods, hypothyroidism, liver disease (cirrhosis, acute hepatitis), sepsis with multi-organ failure, or shock; in infants <3 months of age with reduced renal function; during the third trimester of pregnancy; and following cessation of smoking.221 222 223 226 227 228 229 i f g k l

Consider benefits and risks of use in patients with diseases or factors associated with reduction in theophylline clearance; select dosage carefully and closely monitor serum theophylline concentrations.221 222 223 226 227 228 229 i f g k l (See Elimination: Special Populations under Pharmacokinetics.)

Drug Interactions

When adding drug that inhibits theophylline metabolism or discontinuing drug that enhances metabolism, select dosages carefully and closely monitor serum theophylline concentrations.221 222 223 226 227 228 229 f g h i k l (See Interactions.)

Sensitivity Reactions

Hypersensitivity Effects

Hypersensitivity reactions characterized by urticaria, generalized pruritus, and angioedema reported with aminophylline therapy.a

Contact-type dermatitis caused by hypersensitivity to ethylenediamine component of aminophylline also reported.a

Sulfite Sensitivity

Some commercially available formulations of theophyllines contain sulfites that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes.a

General Precautions

Use with caution in patients with hyperthyroidism or cystic fibrosis; (see Elimination: Special Populations under Pharmacokinetics) those with glaucoma, diabetes mellitus, severe hypoxemia, hypertension, or compromised cardiac or circulatory function; and in patients with angina pectoris or acute myocardial injury when myocardial stimulation would be harmful.a

Since theophylline may cause dysrhythmia and/or worsen preexisting arrhythmias, any substantial change in rate and/or rhythm warrants ECG monitoring and further investigation.a e f g i k

Clinical Monitoring

Wide interpatient variability in theophylline metabolic clearance; therefore, routine serum theophylline level monitoring is essential.m Measure serum theophylline concentrations frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy (e.g., at 6–12 month intervals).222 f g l More frequent measurements recommended in the presence of any condition that may substantially alter theophylline clearance.222 f g k l (See Elimination: Special Populations under Pharmacokinetics.)

Measure serum concentrations when initiating therapy to guide final dosage adjustments after titration; before increasing dosage in patients with persistent symptoms; if signs and symptoms of toxicity occur; and if new or worsening illness or a change in treatment regimen that alters theophylline clearance occurs (e.g., sustained fever, hepatitis, interacting drugs are added or discontinued).223 228 f k l

Use of Fixed Combinations

When theophylline or dyphylline are used in fixed combination, consider the cautions, precautions, and contraindications associated with the concomitant agent(s).d e

Specific Populations

Pregnancy

Theophylline: Category C.228 f g i k l

Dyphylline: Category C.d e h

Careful dosage selection and frequent serum theophylline concentration monitoring required in patients in third trimester of pregnancy.f i (See Elimination: Special Populations under Pharmacokinetics.)

Lactation

Distributed into milk;228 d e f g h i k l may cause irritability or mild toxicity in nursing infants.i k l Use caution in nursing women.d e h

Pediatric Use

Safety and efficacy established in pediatric patients;228 f i k l however, administer with caution.f i k l

Dyphylline: Safety and efficacy in pediatric patients <6 years of age not established.d e h

Careful dosage selection and frequent monitoring of serum theophylline concentrations are required when theophylline is prescribed to pediatric patients <1 year of age.222 228 l

Use caution when determining dosage for neonates with decreased renal function; monitor serum theophylline concentrations frequently because of potential theophylline toxicity.223 f

Not recommended by some experts for children <5 years of age with persistent asthma because of its erratic metabolism during viral infections and febrile illness, higher risk of adverse effects, and need to closely monitor and control serum concentrations.211 m Children with high theophylline clearance rates (i.e., those who require a substantially larger than average dosage [e.g., >22 mg/kg daily] when afebrile) may be at greater risk of toxic effects from decreased clearance during sustained fever.221 222 223 226 227 228 229 f g i k l

Since xanthine derivatives have diuretic effects, use particular caution to avoid dehydration and acidosis in pediatric patients.e

Geriatric Use

Cautious dosage selection; monitor serum theophylline concentrations frequently in elderly patients.i

Use caution in patients >60 years of age because of age-related decreases in hepatic, renal and/or cardiac function, COPD, concomitant disease and drug therapy.223 a g i Elderly patients also appear to be more sensitive to the toxic effects of theophylline after chronic overdosage than younger patients.f g i

Hepatic Impairment

Careful attention to dosage reduction and frequent monitoring of serum theophylline concentrations are required in patients with reduced hepatic function (e.g., cirrhosis, acute hepatitis, cholestasis).222 223 (See Elimination: Special Populations under Pharmacokinetics.)

Renal Impairment

Careful attention to dosage reduction and frequent monitoring of serum theophylline concentrations are required in neonates with decreased renal function.222

No dosage adjustment required for adults and children >3 months of age with renal insufficiency.222 223

Common Adverse Effects

Nausea,221 222 223 226 227 228 229 f g i k l vomiting,221 222 223 226 227 228 229 f g i k l headache,221 222 223 226 227 228 229 a f g i k l insomnia,221 222 223 226 227 228 229 a f g i k l epigastric pain,a abdominal cramps,221 222 223 226 227 228 229 f g i k l anorexia,a palpitations,a sinus tachycardia,a extrasystoles,a diarrhea,221 222 223 226 227 228 229 f g i k l irritability,221 222 223 226 227 228 229 a f g i k l restlessness,221 222 223 226 227 228 229 a f g i k l fine skeletal muscle tremors,221 222 223 226 227 228 229 f g i k l transient diuresis.221 222 223 226 227 228 229 f g i k l

IV infusion (related to solution or administration technique): Febrile response, infection at injection site, venous thrombosis or phlebitis extending from injection site, extravasation, hypervolemia.228

Oral (dyphylline): Nausea, headache, cardiac palpitations, CNS stimulation.d e h

Rapid IV injection (aminophylline): Dizziness, faintness, lightheadedness, palpitation, syncope, precordial pain, flushing, profound bradycardia, premature ventricular contractions, severe hypotension, cardiac arrest.a

IM injection (aminophylline; IM injection not recommended): Intense local pain, sloughing of tissue.a

Rectal suppositories (dosage form no longer commercially available in the US): Rectal irritation, rectal inflammation.a

Drug Interactions

Metabolized by CYP isoenzymes; theophylline clearance decreases when used concomitantly with medications that inhibit CYP1A2 and CYP3A3.222 223 226 227 228 229 a f g i

Specific Drugs and Tests

Drugs and Tests

Interaction

Comments

Adenosine

Theophylline blocks adenosine receptor222 f

Higher adenosine doses may be required to achieve desired effect222 f

Alcohol

Large single dose (3 mL/kg) may decrease theophylline clearance for up to 24 hours 222 f

Warn patients of concomitant interaction222 f

Allopurinol

Decreased theophylline clearance at allopurinol dosages ≥600 mg daily222 f

Monitor theophylline concentrations and adjust dosage accordingly 222 f

Aminoglutethimide

Increased theophylline clearance by induction of microsomal enzyme activity; possible 25% decrease in serum theophylline concentrations222 f

Monitor theophylline concentrations and adjust dosage accordingly 222 f

Anticoagulants, oral

May enhance effects of oral anticoagulants by increasing plasma prothrombin and factor Va

Probably little or no effect on anticoagulant responsea

Benzodiazepines (diazepam, flurazepam, lorazepam, midazolam)

Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant; theophylline blocks adenosine receptors222 f

May require larger diazepam dosagesf

If theophylline discontinued without reduction of diazepam dose, respiratory depression may result222 f

Carbamazepine

Increased theophylline clearance by induction of microsomal enzyme activity; possible 30% decrease in serum theophylline concentrations222 f g

Monitor theophylline concentrations and adjust dosage accordingly 222 f

Cardiac glycosides

May enhance sensitivity and toxic potential of cardiac glycosidesa

Cimetidine

May decrease hepatic clearance and increase serum theophylline concentrations (e.g., by 70%)a g m

Use alternative H2 blocker (e.g., famotidine, ranitidine)m

Disulfiram

Decreased theophylline clearance by inhibiting hydroxylation and demethylation222 f

Monitor theophylline concentrations and adjust dosage accordingly 222

Estrogen (oral contraceptives)

Possible decrease in theophylline clearance in dose-dependent fashion222 f

Adjust theophylline dosage accordingly 222

Fluoroquinolones (ciprofloxacin, enoxacin)

May decrease hepatic clearance and increase theophylline concentrations (e.g., by 40% with ciprofloxacin or 300% with enoxacin)221 222 223 226 227 228 229 a f g i m

Use alternative antibiotic or adjust theophylline dosem

Fluvoxamine

May decrease hepatic clearance and increase serum theophylline concentrations222

Monitor theophylline concentrations and adjust dosage accordingly 222

Halothane

Myocardial sensitization, possible increased risk of ventricular arrhythmias 222

Consider risk if used concomitantly222

Interferon, human recombinant α-A

Decreases theophylline clearance; possible 100% increase in serum theophylline concentrations222

Monitor serum theophylline concentrations and adjust dosage accordingly; may require decrease in theophylline dosage (See Dosage and Administration.)222

Isoproterenol

Increases theophylline clearance; possible 20% decrease in serum theophylline concentrations222 f

Monitor theophylline concentrations and adjust dosage accordingly 222 f

Ketamine

May lower theophylline seizure threshold221 222 223 226 227 228 229 f g i k l

Lithium

Possible increase in renal lithium clearance222 f

If used concomitantly, monitor lithium levels and adjust dosages accordingly222

Macrolides (clarithromycin, erythromycin, troleandomycin)

May increase serum theophylline concentrations (e.g., 25% with clarithromycin, 35% with erythromycin, 33–100% with troleandomycin depending on troleandomycin dosage)a g m

Use alternative macrolide antibiotic, azithromycin, or another antibiotic or adjust theophylline dosem

Methotrexate (MTX)

Possible decrease in theophylline clearance.222 a f Possible 20% increase in serum theophylline concentration with low-dose MTX222 f

Monitor theophylline concentrations and adjust dosage accordingly; higher dose MTX may have an even greater effect 222 f

Methylxanthines (e.g., theophylline, dyphylline)

Possible synergistic effects230 231 d e h

Increased risk of serious toxicity when administered simultaneously by more than one route or in more than one preparationa

Do not administer concomitantlya

Mexiletine

Decreased theophylline clearance by inhibiting hydroxylation and demethylation; possible 80% increase in serum theophylline concentrations222 f

Monitor theophylline concentrations and adjust dosage accordingly 222

Moricizine

Increases theophylline clearance; possible 25% decrease in serum theophylline concentrations222

Monitor theophylline concentrations and adjust dosage accordingly 222

Nicotine

Tobacco and marijuana smoking increases theophylline clearance223 a f g m

Careful attention to dosage reduction and frequent monitoring of serum theophylline concentrations are required in patients who stop smokingg

Advise patient to stop smoking, then increase theophylline dosage according to serum concentrationm

Nicotine gum does not appear to affect theophylline clearancef g

Pancuronium

Possible pharmacokinetic interaction222 f

May require larger dose of pancuronium to achieve neuromuscular blockade 222 f

Pentoxifylline

Decreases theophylline clearance; possible 30% increase in serum theophylline concentrations222

Monitor theophylline concentrations and adjust dosage accordingly 222

Phenobarbital

Increased theophylline clearance by induction of microsomal enzyme activity; possible 25% decrease in serum theophylline concentrations after 2 weeks of phenobarbital therapy222 f

Monitor theophylline concentrations and adjust dosage accordingly 222

Phenytoin

Possible increase in theophylline clearance 221 222 223 226 227 228 229 a f g i

Theophylline decreases phenytoin absorption221 222 223 226 227 228 229 f g i

Monitor serum theophylline and phenytoin concentrations and adjust dosages accordingly221 222 223 226 227 228 229 f g i

Probenecid

May increase half-life of dyphylline230 231 d e h

Propafenone

Decreases theophylline clearance; possible 40% increase in serum theophylline concentrations222

β-blocking effect may reduce theophylline efficacy222

Monitor theophylline concentrations and adjust dosages accordingly222

Propranolol

May decrease hepatic clearance and increase serum theophylline concentrations221 222 223 226 227 228 229 a f g i

β2-blocking effect may reduce theophylline efficacy221 222 223 226 227 228 229 f g i

Rifampin

May increase theophylline clearance; possible 20–40% decrease in serum theophylline concentrations222 a g m

Monitor theophylline concentrations and adjust dosage accordingly222 m

St. John's wort (hypericum perforatum)

Possible decrease in theophylline plasma concentrations222

Monitor theophylline concentrations and adjust dosage accordingly; stopping St. John's wort without theophylline dosage adjustment may result in theophylline toxicity222

Sympathomimetics (e.g., ephedrine)

Synergistic CNS effects (e.g., increased nausea, nervousness, insomnia)221 222 223 226 227 228 229 230 231 a d e f g h i

May increase risk of cardiac arrhythmiasa

Dyphylline: Concomitant use contraindicated in pediatric patientse (See Contraindications)

If used concomitantly, monitor closely for theophylline toxicitya

Sulfinpyrazone

Increases theophylline clearance by increasing demethylation and hydroxylation.222 Decreases renal clearance of theophylline222

Monitor theophylline concentrations and adjust dosage accordingly222

Tests, cholesterol

Pharmacologic effects may increase total cholesterol, HDL, and HDL/LDL ratio222 k

Test, glucose

Pharmacologic effects may modestly increase plasma glucose222 k

Tests for serum uric acid (Bittner or colorimetric method)

Pharmacologic effects may slightly increase serum uric acid222 f k

Possible false-positive elevation of serum uric acida

Use uricase methoda

Thiabendazole

Decreases theophylline clearance; possible 190% increase in serum theophylline concentrations222

Monitor theophylline concentrations and adjust dosage accordingly222

Ticlopidine

Decrease in theophylline clearance; possible 60% increase in serum theophylline concentrations222 f

Monitor theophylline concentrations and adjust dosage accordingly222

Verapamil

Decreased theophylline clearance by inhibiting hydroxylation and demethylation; possible 20% increase in serum theophylline concentrations222 f

Monitor theophylline concentrations and adjust dosage accordingly 222

Theophyllines Pharmacokinetics

Pharmacokinetics vary widely among similar patients and cannot be predicted by age, sex, body weight, or other demographic characteristics.221 222 223 226 227 228 229 f g i k l

Absorption

Bioavailability

Theophylline and dyphylline rapidly and completely absorbed after oral administration.221 222 223 226 229 230 231 a d e f g h i

Following oral administration of immediate-release theophylline preparations in adults, mean peak serum concentration occurs after 1–2 hours.221 222 226 229 a f g i

Following oral administration of dyphylline tablets and solution, mean peak serum concentration occurs after 45 minutes.230 231 d e h

When administered IM (not recommended), absorption of theophylline usually slow and incomplete.a

Serum theophylline concentrations generally have been apparent 3–5 hours after administration of aminophylline rectal suppositories (no longer commercially available in the US); absorption slow and erratic.a

Food

Food may delay but generally does not reduce theophylline absorption;221 222 226 229 f g i however, administration of extended-release preparations with food (especially with high fat content) may increase peak serum theophylline concentrations221 222 223 and, with some preparations, extent of absorption.222 223

Plasma Concentrations

Theophylline: Bronchodilation generally occurs with total (i.e., protein bound and free) serum concentrations in range of 5–20 mcg/mL.221 222 223 226 227 228 229 f g i k l

Serum theophylline concentrations of about 7–14 mcg/mL may be sufficient to reverse apnea in premature infants. a

Theophylline: Toxicity often associated with total serum concentrations >20 mcg/mL.222 a f k

Dyphylline: Plasma concentrations dose-related and generally predictable.230 231 d e h Range at which effective bronchodilation occurs not established.230 231 d e h

Distribution

Extent

Theophylline: Rapidly throughout extracellular fluids and body tissue.221 222 223 226 227 228 229 f g k

Theophylline: Partially penetrates erythrocytes and readily crosses placenta.a k

Theophylline: Distributed into milk (about 70% of serum concentration) and CSF.222 a f g k

Plasma Protein Binding

Theophylline: 40%, principally to albumin.221 222 223 226 227 228 229 f g i k l

Special Populations

Theophylline: Measure unbound serum concentration in patients with reduced protein binding to provide more reliable means of dosage adjustment.221 222 223 226 227 228 229 f g i k l Non-protein bound (free) concentrations generally considered to be therapeutic in range of 6–12 mcg/mL.221 222 223 226 227 228 229 f g i k l

Elimination

Metabolism

Theophylline: Extensively in liver to 1-methylxanthine, 3-methylxanthine, and 1,3-dimethyluric acid.221 222 223 226 227 228 229 a f g i k l

Elimination Route

Theophylline: Mainly in urine and small amounts in feces.a

Dyphylline: Not metabolized to theophylline.230 231 a d e h Excreted largely unchanged (88% of single oral dose) by kidneys.230 231 d e h

Theophylline: In neonates, 50% of dose excreted unchanged in urine.221 222 223 226 227 228 229 f g i k l

Theophylline: In adults and children >3 months of age, 10% of dose excreted unchanged in urine.221 222 223 226 227 228 229 f g i k l

Half-life

Theophylline: Highly variable.221 222 223 226 227 228 f g i l Consult manufacturer's labeling for half-lives in specific populations (e.g., about 4 hours for children 1–9 years of age, about 8 hours in nonsmoking adults).221 222 223 226 227 228 g i l

Dyphylline: 1.8–2.1 hours.230 231 d e h

Special Populations

Theophylline clearance very low in neonates.221 222 223 226 227 228 a f g i l Clearance reaches maximal values by 1 year of age, remains relatively constant until about 9 years of age, then slowly decreases by approximately 50% to adult values at about 16 years of age.221 222 223 226 227 228 f g i l

Clearance decreased by average of 30% in patients >60 years of age compared with younger healthy adults.221 222 223 226 227 228 229 a f g i k l m

Clearance decreased by ≥50% in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis).221 222 223 226 227 228 229 a f g i k l

In patients with end-stage renal disease, active metabolite (3-methylxanthine) may accumulate to concentrations that approximate unmetabolized theophylline concentration.222

Clearance decreased by ≥50% in patients with CHF.221 222 223 226 227 228 229 a f g i k l

Clearance also decreased in patients in third trimester of pregnancy,221 222 223 226 227 228 229 f g i k l those undergoing influenza immunization or who have active influenza infection,a those with sustained high fever (>39°C for ≥24 hours) or lesser temperature elevations for longer periods,221 222 223 226 227 228 229 f g i k l sepsis with multiple organ failure,221 222 223 226 227 228 229 f g i k l or hypothyroidism.221 222 223 226 227 228 229 f g i k l

Clearance increased in patients with hyperthyroidism or cystic fibrosis.221 222 223 226 227 228 229 f g i

Clearance increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef; clearance decreased and half-life prolonged with a high carbohydrate/low protein diet.226 f i l

Clearance increased in tobacco and marijuana smokers.221 222 223 226 227 228 229 a f g i k l Clearance increased by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared with non-smoking subjects.221 222 223 226 227 228 229 f g i k l Clearance also increased by up to 50% by passive exposure to smoke.221 222 223 226 227 228 229 f g i k l Abstinence from tobacco smoking for one week may cause reduction of approximately 40% in theophylline clearance.221 222 223 226 227 228 229 f g i k l Use of nicotine gum does not affect theophylline clearance.221 222 223 226 227 228 229 f g i k l

Dyphylline: Half-life increased threefold to fourfold in anuric patients.d e h

Stability

Storage

Oral

Capsules and Tablets

Conventional and extended-release tablets (Theo-24): <25°C.222

Controlled-release (Uniphyl) tablets: Tight, light-resistant containers at 25°C; excursions permitted to 15–30°C.223

Dyphylline and guaifenesin tablets: Tight containers at 20–25°C.h Protect from moisture.h

Aminophylline: Tight, light-resistant containers at 20–25°C.i Protect from light and moisture.i

Solution

Dyphylline and guaifenesin: Tight containers at 20–25°C; excursions permitted to 15–30°C.d e h

Theophylline: Tight containers at 15–30°C.229

Parenteral

Solution

Injection in 5% dextrose: 25°C.k Avoid excessive heat.k Do not freeze.k

Aminophylline ampules/vials: 15–30°C; protect from light.227 l Keep vials in carton until time of use.227 l

Compatibility

Not recommended in combination with enteric products (Ensure, Ensure Plus, and Osmolite) for nasogastric administration.c

Parenteral

Solution Compatibility (for Aminophylline)HID

Compatible

Amino acids 4.25%, dextrose 25%

Dextrose-Ringer’s injection combinations

Dextrose-Ringer’s injection, lactated, combinations

Dextrose 5% in Ringer’s injection, lactated

Dextrose-saline combinations

Dextrose 5% in sodium chloride 0.2 or 0.9%

Dextrose 2.5, 5, 10, or 20% in water

Ionosol products

Ringer’s injection

Ringer’s injection, lactated

Sodium chloride 0.45 or 0.9%

Sodium lactate (1/6) M

Variable

Fat emulsion 10%, IV

Drug Compatibility (for Aminophylline)
Admixture Compatibility (for Aminophylline)HID

Compatible

Calcium gluconate

Chloramphenicol sodium succinate

Dexamethasone sodium phosphate

Diphenhydramine HCl

Dopamine HCl

Erythromycin lactobionate

Esmolol HCl

Flumazenil

Furosemide

Heparin sodium

Hydrocortisone sodium succinate

Lidocaine HCl

Meropenem

Methyldopate HCl

Nitroglycerin

Pentobarbital sodium

Phenobarbital sodium

Potassium chloride

Ranitidine HCl

Sodium bicarbonate

Terbutaline sulfate

Incompatible

Atracurium besylate

Bleomycin sulfate

Cefepime HCl

Ceftazidime

Ceftriaxone sodium

Chlorpromazine HCl

Ciprofloxacin

Clindamycin phosphate

Dobutamine HCl

Doxorubicin HCl

Epinephrine HCl

Hydralazine HCl

Hydroxyzine HCl

Isoproterenol HCl

Norepinephrine bitartrate

Penicillin G potassium

Pentazocine lactate

Prochlorperazine edisylate

Promethazine HCl

Verapamil HCl

Variable

Amikacin sulfate

Ascorbic acid injection

Dimenhydrinate

Methylprednisolone sodium succinate

Midazolam HCl

Nafcillin sodium

Vancomycin HCl

Y-Site Compatibility (for Aminophylline)HID

Compatible

Allopurinol sodium

Amifostine

Amphotericin B cholesteryl sulfate complex

Anidulafungin

Aztreonam

Bivalirudin

Ceftaroline fosamil

Ceftazidime

Cladribine

Clonidine HCl

Dexmedetomidine HCl

Docetaxel

Doripenem

Doxorubicin HCl liposome injection

Enalaprilat

Esmolol HCl

Etoposide phosphate

Famotidine

Filgrastim

Fluconazole

Fludarabine phosphate

Foscarnet sodium

Gallium nitrate

Gemcitabine HCl

Granisetron HCl

Heparin sodium with hydrocortisone sodium succinate

Hetastarch in lactated electrolyte injection (Hextend)

Labetalol HCl

Levofloxacin

Linezolid

Melphalan HCl

Meropenem

Micafungin sodium

Morphine sulfate

Nicardipine HCl

Paclitaxel

Pancuronium bromide

Pemetrexed disodium

Piperacillin sodium-tazobactam sodium

Potassium chloride

Propofol

Ranitidine HCl

Remifentanil HCl

Sargramostim

Tacrolimus

Teniposide

Thiotepa

Vecuronium bromide

Incompatible

Amiodarone HCl

Ciprofloxacin

Clarithromycin

Dobutamine HCl

Fenoldopam mesylate

Hydralazine HCl

Ondansetron HCl

Vinorelbine tartrate

Warfarin sodium

Variable

Cisatracurium besylate

Diltiazem HCl

Drug Compatibility for Theophylline
Admixture Compatibility (for Theophylline)HID

Compatible

Cefepime HCl

Chlorpromazine HCl

Fluconazole

Furosemide

Lidocaine HCl

Methylprednisolone sodium succinate

Papaverine HCl

Verapamil HCl

Incompatible

Ascorbic acid injection

Ceftriaxone sodium

Y-Site Compatibility (for Theophylline)HID

Compatible

Acyclovir sodium

Ampicillin sodium

Ampicillin sodium-sulbactam-sodium

Aztreonam

Bivalirudin

Cefazolin sodium

Cefotetan disodium

Ceftriaxone sodium

Cisatracurium besylate

Clindamycin phosphate

Clonidine HCl

Dexamethasone sodium phosphate

Dexmedetomidine HCl

Diltiazem HCl

Dobutamine HCl

Dopamine HCl

Doxycycline hyclate

Erythromycin lactobionate

Famotidine

Fenoldopam mesylate

Fluconazole

Gentamicin sulfate

Haloperidol lactate

Heparin sodium

Hetastarch in lactated electrolyte injection (Hextend)

Hydrocortisone sodium succinate

Lidocaine HCl

Linezolid

Methyldopate HCl

Methylprednisolone sodium succinate

Metronidazole

Micafungin sodium

Midazolam HCl

Milrinone lactate

Nafcillin sodium

Nitroglycerin

Oxaliplatin

Penicillin G potassium

Potassium chloride

Ranitidine HCl

Remifentanil HCl

Sodium nitroprusside

Ticarcillin disodium–clavulanate potassium

Tigecycline

Tobramycin sulfate

Vancomycin HCl

Incompatible

Cefepime HCl

Hetastarch in sodium chloride 0.9%

Phenytoin sodium

Variable

Ceftazidime

Actions

Advice to Patients

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Aminophylline (Hydrous)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

100 mg (79 mg of anhydrous theophylline)*

Aminophylline Tablets

200 mg (158 mg of anhydrous theophylline)*

Aminophylline Tablets

Parenteral

Injection

25 mg (19.7 mg of anhydrous theophylline) per mL*

Aminophylline Injection

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Aminophylline (Anhydrous)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

105 mg (90 mg of anhydrous theophylline) per 5 mL*

Aminophylline Oral Solution

Dyphylline

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

33 mg/5 mL

Dylix Elixir

Lunsco

Tablets

200 mg

Lufyllin (scored)

Meda

400 mg

Lufyllin (scored)

Meda

Dyphylline and Guaifenesin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

33.3 mg/5 mL Dyphylline and Guaifenesin 33.3 mg/5 mL

Dyphylline GG

Silarx

Lufyllin-GG Elixir

Meda

100 mg/5 mL Dyphylline and Guaifenesin 100 mg/5 mL

Dy-G

Cypress

Lufyllin-GG Elixir

Meda

Tablets

200 mg Dyphylline and Guaifenesin 200 mg

Lufyllin-GG (scored)

Meda

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Theophylline (Anhydrous)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Bulk

Powder*

Oral

Capsules, extended-release

100 mg

Theo-24 (24 hours)

UCB

125 mg

Theophylline Extended-Release Capsules (12 hours)

200 mg

Theo-24 (24 hours)

UCB

Theophylline Extended-Release Capsules (12 hours)

300 mg

Theo-24 (24 hours)

UCB

Theophylline Extended-Release Capsules (12 hours)

400 mg

Theo-24 (24 hours)

UCB

Solution

27 mg/5 mL*

Elixophyllin Elixir

Forest

Tablets, extended-release

100 mg*

Theochron (12 hours; scored)

Forest

Theophylline Extended-Release Tablets (12 hours)

200 mg*

Theochron

Forest

Theophylline Extended-Release Tablets (12 hours)

Inwood

300 mg

Theochron (12 hours; scored)

Forest

Theophylline Extended-Release Tablets (12 hours)

Inwood

400 mg

Uniphyl Unicontin (24 hours, scored)

Purdue Frederick

450 mg

Theochron (12 hours, scored)

Forest

600 mg

Uniphyl Unicontin (24 hours, scored)

Purdue Frederick

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Theophylline (Anhydrous) in Dextrose

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV infusion

0.8 mg/mL (400 and 800 mg) Theophylline (anhydrous) in 5% Dextrose*

Theophylline and 5% Dextrose Injection (LifeCare [Hospira], Excel [Braun], Viaflex [Baxter])

1.6 mg/mL (400 and 800 mg) Theophylline (anhydrous) in 5% Dextrose*

Theophylline and 5% Dextrose Injection (LifeCare [Hospira], Excel [Braun], Viaflex [Baxter])

2 mg/mL (200 mg) Theophylline (anhydrous) in 5% Dextrose*

Theophylline and 5% Dextrose Injection (LifeCare [Hospira], Viaflex [Baxter])

3.2 mg/mL (800 mg) Theophylline (anhydrous) in 5% Dextrose*

Theophylline and 5% Dextrose Injection (LifeCare [Hospira], Viaflex [Baxter])

4 mg/mL (200 and 400 mg) Theophylline (anhydrous) in 5% Dextrose*

Theophylline and 5% Dextrose Injection (LifeCare [Hospira], Viaflex [Baxter])

AHFS DI Essentials™. © Copyright 2024, Selected Revisions September 4, 2013. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Off-label: 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. From NIH website. Accessed 2004 Sep. 15. http://www.nhlbi.nih.gov/guidelines/archives/epr-2_upd/asthmafullrpt_archive.pdf

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. 02-3659. From GINA website. Accessed Mar. 09, 2006. http://www.ginasthma.com

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.

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. http://www.ncbi.nlm.nih.gov/pubmed/11281744?dopt=AbstractPlus

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.

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.

a. AHFS drug information 2008. McEvoy GK, ed. Theophyllines. Bethesda, MD: American Society of Health-System Pharmacists; 2008:3650–7.

b. Beckwith MC, Barton RG, Graves, C. A guide to drug therapy in patients with enteral feeding tubes: dosage form selection and administration methods. Hosp Pharm. 1997; 32:57-64.

c. Holtz L, Milton J, Sturek JK. Compatibility of medications with enteral feedings. J Parenter Enteral Nutr. 1987; 11:183-186.

d. Silarx Pharmaceuticals, Inc. Dyphylline-GG elixir prescribing information. Spring Valley, NY; 1998 Sept.

e. Cypress Pharmaceutical, Inc. Dy-G (dyphylline and guaifenesin) liquid prescribing information. Madison, MS; 2007 Feb.

f. Forest Pharmaceuticals, Inc. Elixophyllin elixir (theophylline anhydrous) prescribing information. St. Louis, MO; 2004 Sept.

g. Forest Pharmaceuticals, Inc. Theochron (theophylline anhydrous) extended-release tablets prescribing information. St. Louis, MO; 2002 Feb.

h. Meda Pharmaceuticals. Lufyllin GG (dyphylline and guaifenesin) tablets and elixir prescribing information. Somerset, NJ; 2006 May.

i. West-ward Pharmaceuticals. Aminophylline tablets prescribing information. Eatontown, NJ; 2002 Dec.

j. Rabe KF, Hurd S, Anzueto A et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. GOLD Executive Summary. Am J Respir Crit Care Med. 2007; 176:532–55. http://www.ncbi.nlm.nih.gov/pubmed/17507545?dopt=AbstractPlus

k. Hospira. Theophylline 200, 400 and 800 mg in 5% dextrose injection prescribing information. Lake Forest, IL; 2004 Mar.

l. Hospira. Aminophylline injection prescribing information. Lake Forest, IL; 2004 Jun.

m. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR–3) Full Report 2007: Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program Coordinating Committee; 2007. Available from National Heart, Lung, and Blood Institute Information Center. From NIH website. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf

n. Global strategy for asthma management and prevention (updated 2007): Global Initiative for Asthma (GINA). From GINA website. Accessed 2007 May 2. http://www.ginasthma.org

o. Javaheri S, Parker TJ, Wexler L et al. Effect of theophylline on sleep-disordered breathing in heart failure. N Engl J Med. 1996; 335:562-7. http://www.ncbi.nlm.nih.gov/pubmed/8678934?dopt=AbstractPlus

p. Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnea in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 3. Art. No.: CD000140. DOI: 10.1002/14651858.CD000140.

q. O'Donnell DE, Aaron S, Bourbeau J et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease—2007 update. Can Respir J. 2007; 14(Suppl B):5B-32B. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2806792&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/17885691?dopt=AbstractPlus

r. Pesek CA, Cooley R, Narkiewicz K et al. Theophylline therapy for near-fatal Cheyne–Stokes respiration. Ann Intern Med. 1999; 130:427-30. http://www.ncbi.nlm.nih.gov/pubmed/10068417?dopt=AbstractPlus

HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013: 71-80, 1077-80.