Theophyllines (Monograph)

Brand names: Dy-G, Dylix, Dyphylline-GG, Elixophyllin, Lufyllin, ... show all 9 brands Lufyllin GG, Theo-24, Theochron, Uniphyl
Drug class: Respiratory Smooth Muscle Relaxants

Introduction

Xanthine derivative; respiratory smooth muscle relaxant, bronchodilator.

Uses for Theophyllines

Symptomatic management or prevention of asthma and reversible bronchospasm associated with COPD, including chronic bronchitis and emphysema.

Aminophylline and dyphylline generally share the same indications as theophylline.

Bronchospasm in Asthma

Symptomatic management or prevention of bronchospasm in patients with reversible, obstructive airway disease (e.g., asthma).

In the stepped-care approach recommended in current asthma management guidelines, 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.

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.

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. 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. 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.

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.

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. 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. 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.

Dyphylline not indicated for the management of status asthmaticus.

Bronchospasm in COPD

Management of symptoms and reversible airflow obstruction in patients with COPD.

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.

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).

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. However, such use considered controversial by some experts because of modest/inconsistent response and frequent adverse effects; use suggested in patients with severe exacerbations who have inadequate response to short-acting bronchodilators (e.g., inhaled β₂-adrenergic agonist).

Other Uses

Has been used to relieve periodic apnea and increase arterial blood pH in patients with Cheyne-Stokes respiration^{† [off-label]}.

Has been used to stimulate respiration and myocardial contractility associated with apnea in infants^{† [off-label]}.

Not for treatment of coronary thrombosis.

Theophyllines Dosage and Administration

General

• Extended-release preparations indicated in patients with relatively continuous or frequently recurring asthma symptoms; may be particularly useful in patients in whom theophylline elimination is rapid (e.g., children, adult smokers).

• Do not use extended-release dosage forms for treatment of acute bronchospasm.

Monitoring Serum Theophylline Concentrations

• Base dosage adjustments on peak serum theophylline concentrations along with patient response and tolerance to drug.

• Therapeutic serum concentrations of 10–15 mcg/mL generally produce bronchodilation without serious risk of toxicity, although lower concentrations may provide beneficial effects in some patients with mild asthma and may be effective for neonatal apnea. Some experts recommend maintaining serum theophylline concentrations in the range of 5–15 mcg/mL during long-term therapy. Toxicity may occur with serum concentrations >20 mcg/mL.

• Measure serum concentrations (1) when initiating therapy to guide final dosage adjustments after titration; (2) before increasing dosage in patients with persistent symptoms; (3) if manifestations of toxicity are present; and (4) in case of new or worsening illness or a change in treatment regimen that alters theophylline clearance (e.g., fever >39°C for ≥24 hours, hepatitis, addition or discontinuance of interacting drugs). Prior to increasing dosage based on low serum concentration, consider whether blood sample was obtained at an appropriate time and whether patient adhered to dosing regimen.

• To guide dosing after oral administration, obtain a blood sample at the time of the expected steady-state peak serum concentration, generally achieved 3 days after initiating therapy or a change in dosage provided no doses have been missed or added and none have been taken at unequal intervals.

• After steady state achieved, measure serum theophylline concentration 1–2 hours after administration of an oral solution or uncoated immediate-release tablet or 4–12 hours (depending on the particular preparation; consult manufacturer's labeling) after administration of an extended-release preparation to obtain estimate of peak serum concentration.

• To guide dosing decisions after IV administration, measure serum concentration 30 minutes after completion of IV loading dose to determine whether concentration is <10 mcg/mL (indicating need for additional loading dose) or >20 mcg/mL (indicating need for delay in initiating maintenance IV infusion).

• Do not increase IV dosage for acute exacerbation of symptoms unless serum theophylline concentrations are <10 mcg/mL.

Administration

Usually, administer theophyllines (e.g., theophylline, aminophylline) and dyphylline orally as a tablet, capsule, or solution; may also administer theophylline or aminophylline by slow IV injection or slow IV infusion.

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

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.

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

Extended-Release Preparations

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

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.

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. May split scored, extended-release tablets of Uniphyl for once-daily dosing. May also split scored, extended-release Theochron tablets for twice-daily dosing but not for once-daily dosing.

Administer extended-release (Theo-24) capsules at same time in the morning when given once daily; evening administration not recommended. In patients who require twice-daily dosing, administer second dose 10–12 hours after morning dose and before evening meal. 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.

Administer extended-release (Uniphyl) tablets at same time each day, either morning or evening. 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.

NG Tubing Administration

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

IV Administration

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

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

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.

Rate of Administration

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

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).

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.

Dosage

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

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

Low therapeutic index; cautious dosage determination essential. Do not exceed recommended dosage adjustments; risk of potentially serious adverse effects associated with large increases in serum theophylline concentration.

Dosage required to achieve therapeutic serum concentration varies fourfold among otherwise similar patients in absence of factors known to affect theophylline clearance. Adjust dosage carefully according to individual requirements and response, pulmonary function, and serum theophylline concentrations.

Calculate dosage based on ideal body weight.

Adjust dosage based on peak serum theophylline concentration.

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). Do not exceed recommended maintenance dosage and do not continue use of the drug unless well tolerated and clinically beneficial.

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), 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).

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.

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.

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

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.

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

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.

IV

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

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.

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.

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. Do not administer loading dose before obtaining serum theophylline concentration if patient has received any theophylline in past 24 hours.

Determine loading dose in patients currently receiving theophylline preparations using following formula:

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

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

Measure serum theophylline concentration 30 minutes after administration of loading dose to determine need for and size of subsequent loading doses. 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).

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

To achieve a target theophylline concentration of 10 mcg/mL.

Approximate aminophylline dosage = theophylline dosage/0.8.

Use ideal body weight for obese patients. Lower initial dosage may be required for patients with conditions or receiving drugs that decrease theophylline clearance.

To achieve a target theophylline concentration of 7.5 mcg/mL.

Unless serum concentration indicates need for larger dosage.

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) to determine if theophylline concentrations are decreasing or increasing from post-loading dose drug concentration. If theophylline concentrations decreasing, administer additional loading dose and/or increase infusion rate. 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. 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.

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.

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.

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.

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.

Administer in divided doses every 8 or 12 hours; consult manufacturer's labeling for specific recommended dosing intervals for individual preparations. 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.

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

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.

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.

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), 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).

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.

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.

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

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

IV

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

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.

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.

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. Do not administer loading dose before obtaining serum theophylline concentration if patient has received any theophylline in past 24 hours.

Determine loading dose in patients who are currently receiving theophylline preparations using following formula:

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. Ensure that desired drug concentration is conservative (e.g., 10 mcg/mL) to allow for variability in volume of distribution.

Measure serum theophylline concentration 30 minutes after administration of a loading dose to determine the need for and size of subsequent loading doses. 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).

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

To achieve target theophylline concentration of 10 mcg/mL.

Approximate aminophylline dosage = theophylline dosage/0.8.

Use ideal body weight for obese patients. Lower initial dosage may be required for patients with conditions or receiving drugs that decrease theophylline clearance.

Unless serum concentration indicates need for larger dosage.

Measure serum theophylline concentration at 1 expected half-life after starting continuous IV infusion (i.e., after 8 hours for nonsmoking adults) to determine if theophylline concentrations are decreasing or increasing from post-loading dose drug concentration. If theophylline concentrations are decreasing, administer additional loading dose and/or increase infusion rate. 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. 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.

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.

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.

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.

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.

Administer in divided doses every 8 or 12 hours; consult manufacturer's labeling for specific recommended dosing intervals for individual preparations. 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.

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

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.

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.

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. (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. (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.

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.

Adults

Asthma and COPD

Oral

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

Regardless of oral preparation, do not exceed 600 mg daily without measurement of serum theophylline concentration.

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

Geriatric patients: Maximum 400 mg daily.

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.

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).

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.

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.

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

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

Renal Impairment

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

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

Dyphylline: Consider dosage reduction in patients with renal impairment.

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. Theophylline clearance decreased in healthy adults >60 years of age. Reduced dosage and frequent monitoring of serum theophylline concentrations required in geriatric patients.

Administer oral dosages >400 mg daily with caution.

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

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. Maximum initial infusion rate: 17 mg/hour unless serum theophylline concentrations monitored at 24-hour intervals.

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

Smokers

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

Careful attention to dose and frequent monitoring of serum theophylline concentrations required in patients who stop smoking.

Cautions for Theophyllines

Contraindications

• Known allergy or hypersensitivity to any of the theophyllines, dyphylline, caffeine, aminophylline, or theobromine.

• Hypersensitivity to ethylenediamine found in aminophylline.

• Known allergy to corn or corn products, which may be included in dextrose-containing theophylline injections.

• Dyphylline: Concomitant use with other sympathomimetic agents (e.g., ephedrine) in pediatric patients.

Warnings/Precautions

Warnings

Concurrent Diseases or Conditions

Risk of exacerbation of active peptic ulcer disease, seizures, and cardiac arrhythmias (excluding bradyarrhythmias). Use extreme caution in patients with such concurrent conditions.

Dyphylline: Do not use for status asthmaticus.

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

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.

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.

Drug Interactions

When adding drug that inhibits theophylline metabolism or discontinuing drug that enhances metabolism, select dosages carefully and closely monitor serum theophylline concentrations.

Sensitivity Reactions

Hypersensitivity Effects

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

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

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.

General Precautions

Use with caution in patients with hyperthyroidism or cystic fibrosis; 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.

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

Clinical Monitoring

Wide interpatient variability in theophylline metabolic clearance; therefore, routine serum theophylline level monitoring is essential. 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). More frequent measurements recommended in the presence of any condition that may substantially alter theophylline clearance.

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).

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).

Specific Populations

Pregnancy

Theophylline: Category C.

Dyphylline: Category C.

Careful dosage selection and frequent serum theophylline concentration monitoring required in patients in third trimester of pregnancy.

Lactation

Distributed into milk; may cause irritability or mild toxicity in nursing infants. Use caution in nursing women.

Pediatric Use

Safety and efficacy established in pediatric patients; however, administer with caution.

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

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

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

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. 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.

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

Geriatric Use

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

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. Elderly patients also appear to be more sensitive to the toxic effects of theophylline after chronic overdosage than younger patients.

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).

Renal Impairment

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

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

Common Adverse Effects

Nausea, vomiting, headache, insomnia, epigastric pain, abdominal cramps, anorexia, palpitations, sinus tachycardia, extrasystoles, diarrhea, irritability, restlessness, fine skeletal muscle tremors, transient diuresis.

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

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

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

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

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

Drug Interactions

Metabolized by CYP isoenzymes; theophylline clearance decreases when used concomitantly with medications that inhibit CYP1A2 and CYP3A3.

Specific Drugs and Tests

Theophyllines Pharmacokinetics

Pharmacokinetics vary widely among similar patients and cannot be predicted by age, sex, body weight, or other demographic characteristics.

Absorption

Bioavailability

Theophylline and dyphylline rapidly and completely absorbed after oral administration.

Following oral administration of immediate-release theophylline preparations in adults, mean peak serum concentration occurs after 1–2 hours.

Following oral administration of dyphylline tablets and solution, mean peak serum concentration occurs after 45 minutes.

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

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.

Food

Food may delay but generally does not reduce theophylline absorption; however, administration of extended-release preparations with food (especially with high fat content) may increase peak serum theophylline concentrations and, with some preparations, extent of absorption.

Plasma Concentrations

Theophylline: Bronchodilation generally occurs with total (i.e., protein bound and free) serum concentrations in range of 5–20 mcg/mL.

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

Theophylline: Toxicity often associated with total serum concentrations >20 mcg/mL.

Dyphylline: Plasma concentrations dose-related and generally predictable. Range at which effective bronchodilation occurs not established.

Distribution

Extent

Theophylline: Rapidly throughout extracellular fluids and body tissue.

Theophylline: Partially penetrates erythrocytes and readily crosses placenta.

Theophylline: Distributed into milk (about 70% of serum concentration) and CSF.

Plasma Protein Binding

Theophylline: 40%, principally to albumin.

Special Populations

Theophylline: Measure unbound serum concentration in patients with reduced protein binding to provide more reliable means of dosage adjustment. Non-protein bound (free) concentrations generally considered to be therapeutic in range of 6–12 mcg/mL.

Elimination

Metabolism

Theophylline: Extensively in liver to 1-methylxanthine, 3-methylxanthine, and 1,3-dimethyluric acid.

Elimination Route

Theophylline: Mainly in urine and small amounts in feces.

Dyphylline: Not metabolized to theophylline. Excreted largely unchanged (88% of single oral dose) by kidneys.

Theophylline: In neonates, 50% of dose excreted unchanged in urine.

Theophylline: In adults and children >3 months of age, 10% of dose excreted unchanged in urine.

Half-life

Theophylline: Highly variable. 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).

Dyphylline: 1.8–2.1 hours.

Special Populations

Theophylline clearance very low in neonates. 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.

Clearance decreased by average of 30% in patients >60 years of age compared with younger healthy adults.

Clearance decreased by ≥50% in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis).

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

Clearance decreased by ≥50% in patients with CHF.

Clearance also decreased in patients in third trimester of pregnancy, those undergoing influenza immunization or who have active influenza infection, those with sustained high fever (>39°C for ≥24 hours) or lesser temperature elevations for longer periods, sepsis with multiple organ failure, or hypothyroidism.

Clearance increased in patients with hyperthyroidism or cystic fibrosis.

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.

Clearance increased in tobacco and marijuana smokers. Clearance increased by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared with non-smoking subjects. Clearance also increased by up to 50% by passive exposure to smoke. Abstinence from tobacco smoking for one week may cause reduction of approximately 40% in theophylline clearance. Use of nicotine gum does not affect theophylline clearance.

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

Stability

Storage

Oral

Capsules and Tablets

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

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

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

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

Solution

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

Theophylline: Tight containers at 15–30°C.

Parenteral

Solution

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

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

Actions

• Mechanism(s) of action not known with certainty; appears that bronchodilation is mediated by competitive inhibition of 2 isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV), while non-bronchodilator prophylactic actions are probably mediated through molecular mechanisms that do not involve inhibition of PDE III or antagonism of adenosine receptors.

• Relaxes smooth muscles (i.e., bronchodilation) and suppresses the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects).

• Relieves shortness of breath, wheezing and dyspnea, and improves pulmonary function as measured by increased flow rates and vital capacity.

• Increases the force of contraction of diaphragmatic muscles.

• Theophylline and dyphylline exert identical pharmacologic actions.

• Positive inotropic effect on the myocardium and a positive chronotropic effect at the sinoatrial (SA) node.

• Directly dilates coronary, pulmonary, renal, and general systemic arterioles and veins, decreasing peripheral vascular resistance and venous pressure. Generally only a slight increase in BP following administration of moderate doses of theophylline.

• Stimulates all levels of CNS but to a lesser degree than caffeine. Constricts cerebral vasculature; resultant decrease in cerebral blood flow and increase in carbon dioxide tension may result in respiratory center stimulation in some patients.

• Has a mild diuretic effect.

• May increase basal metabolic rate.

• Stimulates gastric secretion, relaxes smooth muscle of biliary and GI tract.

• Tolerance of low magnitude may develop to diuretic and sleep-disturbing effects of xanthine derivatives; tolerance to bronchodilator effects rarely occurs.

Advice to Patients

• Inform patients that alcohol may interact with theophylline.

• Importance of contacting their clinician if they develop a new illness or worsening of a chronic illness, especially if accompanied by a persistent fever.

• Instruct patients that if a dose is missed to take the next dose at the usually scheduled time and not to attempt to make up for the missed dose.

• Importance of informing their clinician of smoking history, and to inform their clinicians if they start or stop smoking (e.g., cigarettes, marijuana).

• Inform patients that major changes in diet are not recommended while taking theophylline.

• Advise patients to inform all clinicians involved in their care that they are taking theophylline, especially when a medication is being added or deleted from their treatment.

• Importance of informing patients that theophylline preparations should be administered in a consistent manner, either always with or always without food. Importance of not altering administration schedule of theophylline preparations without consulting clinician.

• Importance of informing patients to seek medical advice whenever nausea, vomiting, persistent headache, fever, insomnia, or rapid heartbeat occurs during treatment with theophylline, even if another cause is suspected. Inform patients to discontinue the drug if they experience toxicity.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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

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

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