Theophyllines

Drug class: Antineoplastic Agents

Usage of 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. (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.

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.

Relate drugs

How to use Theophyllines

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. (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.

    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

    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.

    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.

    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.

    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.

    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.

    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. 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. (See Warnings/Precautions under Cautions and also see Interactions.)

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

    Unless serum concentration indicates need for larger dosage.

    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. 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. (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.

    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.

    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:

    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 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.

    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.

    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. 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; 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. (See Warning/Precautions under Cautions and also see Interactions.)

    Unless serum concentration indicates need for larger dosage.

    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. 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. (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.

    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.

    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:

    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.

    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. (See Elimination: Special Populations under Pharmacokinetics.) 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. (See Elimination: Special Populations under Pharmacokinetics.)

    Warnings

    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. (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. (See Interactions.)

    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; (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.

    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. (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).

    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. (See Elimination: Special Populations under Pharmacokinetics.)

    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). (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.

    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.

    What other drugs will affect Theophyllines

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

    Specific Drugs and Tests

    Drugs and Tests

    Interaction

    Comments

    Adenosine

    Theophylline blocks adenosine receptor

    Higher adenosine doses may be required to achieve desired effect

    Alcohol

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

    Warn patients of concomitant interaction

    Allopurinol

    Decreased theophylline clearance at allopurinol dosages ≥600 mg daily

    Monitor theophylline concentrations and adjust dosage accordingly

    Aminoglutethimide

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

    Monitor theophylline concentrations and adjust dosage accordingly

    Anticoagulants, oral

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

    Probably little or no effect on anticoagulant response

    Benzodiazepines (Diazepam, flurazepam, lorazepam, midazolam)

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

    May require larger diazepam dosages

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

    Carbamazepine

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

    Monitor theophylline concentrations and adjust dosage accordingly

    Cardiac glycosides

    May enhance sensitivity and toxic potential of cardiac glycosides

    Cimetidine

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

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

    Disulfiram

    Decreased theophylline clearance by inhibiting hydroxylation and demethylation

    Monitor theophylline concentrations and adjust dosage accordingly

    Estrogen (oral contraceptives)

    Possible decrease in theophylline clearance in dose-dependent fashion

    Adjust theophylline dosage accordingly

    Fluoroquinolones (ciprofloxacin, enoxacin)

    May decrease hepatic clearance and increase theophylline concentrations (e.g., by 40% with ciprofloxacin or 300% with enoxacin)

    Use alternative antibiotic or adjust theophylline dose

    Fluvoxamine

    May decrease hepatic clearance and increase serum theophylline concentrations

    Monitor theophylline concentrations and adjust dosage accordingly

    Halothane

    Myocardial sensitization, possible increased risk of ventricular arrhythmias

    Consider risk if used concomitantly

    Interferon, human recombinant α-A

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

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

    Isoproterenol

    Increases theophylline clearance; possible 20% decrease in serum theophylline concentrations

    Monitor theophylline concentrations and adjust dosage accordingly

    Ketamine

    May lower theophylline seizure threshold

    Lithium

    Possible increase in renal lithium clearance

    If used concomitantly, monitor lithium levels and adjust dosages accordingly

    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)

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

    Methotrexate (MTX)

    Possible decrease in theophylline clearance. Possible 20% increase in serum theophylline concentration with low-dose MTX

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

    Methylxanthines (e.g., theophylline, dyphylline)

    Possible synergistic effects

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

    Do not administer concomitantly

    Mexiletine

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

    Monitor theophylline concentrations and adjust dosage accordingly

    Moricizine

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

    Monitor theophylline concentrations and adjust dosage accordingly

    Nicotine

    Tobacco and marijuana smoking increases theophylline clearance

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

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

    Nicotine gum does not appear to affect theophylline clearance

    Pancuronium

    Possible pharmacokinetic interaction

    May require larger dose of pancuronium to achieve neuromuscular blockade

    Pentoxifylline

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

    Monitor theophylline concentrations and adjust dosage accordingly

    Phenobarbital

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

    Monitor theophylline concentrations and adjust dosage accordingly

    Phenytoin

    Possible increase in theophylline clearance

    Theophylline decreases phenytoin absorption

    Monitor serum theophylline and phenytoin concentrations and adjust dosages accordingly

    Probenecid

    May increase half-life of dyphylline

    Propafenone

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

    β-blocking effect may reduce theophylline efficacy

    Monitor theophylline concentrations and adjust dosages accordingly

    Propranolol

    May decrease hepatic clearance and increase serum theophylline concentrations

    β2-blocking effect may reduce theophylline efficacy

    Rifampin

    May increase theophylline clearance; possible 20–40% decrease in serum theophylline concentrations

    Monitor theophylline concentrations and adjust dosage accordingly

    St. John's wort (hypericum perforatum)

    Possible decrease in theophylline plasma concentrations

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

    Sympathomimetics (e.g., ephedrine)

    Synergistic CNS effects (e.g., increased nausea, nervousness, insomnia)

    May increase risk of cardiac arrhythmias

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

    If used concomitantly, monitor closely for theophylline toxicity

    Sulfinpyrazone

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

    Monitor theophylline concentrations and adjust dosage accordingly

    Tests, cholesterol

    Pharmacologic effects may increase total cholesterol, HDL, and HDL/LDL ratio

    Test, glucose

    Pharmacologic effects may modestly increase plasma glucose

    Tests for serum uric acid (Bittner or colorimetric method)

    Pharmacologic effects may slightly increase serum uric acid

    Possible false-positive elevation of serum uric acid

    Use uricase method

    Thiabendazole

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

    Monitor theophylline concentrations and adjust dosage accordingly

    Ticlopidine

    Decrease in theophylline clearance; possible 60% increase in serum theophylline concentrations

    Monitor theophylline concentrations and adjust dosage accordingly

    Verapamil

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

    Monitor theophylline concentrations and adjust dosage accordingly

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