PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Xanthines, Plain

    DEA CLASS

    Rx

    DESCRIPTION

    Methylxanthine with a narrow therapeutic window
    Aminophylline is converted to theophylline systemically; 1 mg aminophylline = 0.8 mg theophylline
    Used as an adjunct for maintenancetherapy for asthma and COPD and acute asthma; not recommended for COPD exacerbations

    COMMON BRAND NAMES

    Elixophyllin, Quibron T/SR, T-Phyl, Theo X, Theo-24, Theo-Dur, Theochron, Theolair SR, Uni-Dur, Uniphyl

    HOW SUPPLIED

    Aminophylline/Theophylline, Dextrose Intravenous Inj Sol: 1mL, 25mg, 200-5%, 400-5%, 80-5%, 800-5%
    Elixophyllin/Theophylline, Anhydrous Oral Sol: 15mL, 80mg
    Quibron T/SR/Theo X/Theochron/Theo-Dur/Theolair SR/Theophylline/Theophylline, Anhydrous/T-Phyl/Uni-Dur/Uniphyl Oral Tab ER: 100mg, 200mg, 300mg, 400mg, 450mg, 600mg
    Theo-24 Oral Cap ER: 100mg, 200mg, 300mg, 400mg

    DOSAGE & INDICATIONS

    For treatment of reversible airways obstruction (i.e., for bronchospasm prophylaxis) associated with asthma or chronic obstructive pulmonary disease (COPD) (e.g., emphysema or chronic bronchitis).
    For adjunct treatment of acute exacerbations of reversible airflow obstruction associated with asthma and other chronic lung diseases (e.g., COPD) along with inhaled beta-2 selective agonists and systemic corticosteroids.
    Intravenous continuous infusion maintenance dosage (dosage is expressed as theophylline)
    Adults 60 years and older

    Initially, 0.3 mg/kg/hour IV. Give 0.2 mg/kg/hour IV to patients with CHF, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, shock, or other factors for reduced theophylline clearance. Calculate initial mg/kg dose based on ideal body weight as theophylline distributes poorly into body fat. Reduced doses may be needed in patients receiving other drugs that decrease theophylline clearance; review drug interactions. Adjust dosage based on subsequent serum theophylline concentrations. Usual Max: 400 mg/day, unless serum concentration and patient condition indicate the need for a higher dosage. Methylxanthines are not recommended in the management of COPD exacerbations due to increased side effect profiles.

    Adults 18 to 59 years

    Initially, 0.4 mg/kg/hour IV (up to a maximum of 900 mg/day in otherwise healthy nonsmokers); although no specific dosing guidance is available, patients who smoke may require an increased dose as smoking increases drug clearance. Give 0.2 mg/kg/hour IV (up to 400 mg/day) to patients with CHF, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, shock, or other factors for reduced theophylline clearance. Calculate initial mg/kg dose based on ideal body weight as theophylline distributes poorly into body fat. Reduced doses may be needed in patients receiving other drugs that decrease theophylline clearance; review drug interactions. Adjust dosage based on subsequent serum theophylline concentrations. Methylxanthines are not recommended in the management of COPD exacerbations due to increased side effect profiles.

    Adolescents 16 to 17 years

    Initially, 0.4 mg/kg/hour IV (up to a maximum of 900 mg/day in otherwise healthy nonsmokers). Give 0.2 mg/kg/hour IV (up to 400 mg/day) to patients with CHF, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, shock, or other factors for reduced theophylline clearance. Calculate initial mg/kg dose based on ideal body weight as theophylline distributes poorly into body fat. Reduced doses may be needed in patients receiving other drugs that decrease theophylline clearance; review drug interactions. Adjust dosage based on subsequent serum theophylline concentrations.

    Children and Adolescents 12 to 15 years

    Initially, 0.5 mg/kg/hour IV in otherwise healthy nonsmokers (up to 900 mg/day); 0.7 mg/kg/hour IV in smokers. Dose at 0.2 mg/kg/hour IV (up to 400 mg/day) in patients with cardiac decompensation, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, shock, or other factors associated with reduced clearance. Further dose adjustments may be needed due to concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. The National Asthma Education and Prevention Program (NAEPP) and Global Initiative for Asthma (GINA) guidelines do not recommend theophylline for acute exacerbations because it appears to provide no additional benefit to optimal inhaled beta-2 agonist therapy and may increase risk of adverse effects.

    Children 9 to 11 years

    Initially, 0.7 mg/kg/hour IV. Give 0.2 mg/kg/hour IV (up to 400 mg/day) to patients with cardiac decompensation, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, shock or other factors associated with reduced clearance. Further dose adjustments may be needed due to concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. The National Asthma Education and Prevention Program (NAEPP) and Global Initiative for Asthma (GINA) guidelines do not recommend theophylline for acute exacerbations because it appears to provide no additional benefit to optimal inhaled beta-2 agonist therapy and may increase risk of adverse effects.

    Children 1 to 8 years

    Initially, 0.8 mg/kg/hour IV. Dose at 0.2 mg/kg/hour IV (up to 400 mg/day) in patients with cardiac decompensation, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, shock or other factors associated with reduced clearance. Further dose adjustments may be needed due to concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. The National Asthma Education and Prevention Program (NAEPP) and Global Initiative for Asthma (GINA) guidelines do not recommend theophylline for acute exacerbations because it appears to provide no additional benefit to optimal inhaled beta-2 agonist therapy and my increase risk of adverse effects.

    Infants 6 to 52 weeks

    Calculate initial dosage using the following equation: (0.008 x age in weeks) + 0.21 = theophylline dosage in mg/kg/hour IV; reduced doses may be needed in patients with risk factors for reduced theophylline clearance (e.g., cardiac or liver dysfunction, renal dysfunction in infants younger than 3 months). Further dose adjustments may be needed due to concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. The National Asthma Education and Prevention Program (NAEPP) and Global Initiative for Asthma (GINA) guidelines do not recommend theophylline for acute exacerbations because it appears to provide no additional benefit to optimal inhaled beta-2 agonist therapy and may increase risk of adverse effects.

    For maintenance therapy of asthma or COPD using oral dosage.
    Oral maintenance dosage (dosage is expressed as theophylline using immediate-release products)
    Adults

    Initially, 300 mg/day PO in divided doses every 6 to 8 hours. After 3 days, if tolerated, increase dose to 400 mg/day PO in divided doses every 6 to 8 hours. After 3 more days, if tolerated, increase dose to 600 mg/day PO in divided doses given every 6 to 8 hours. Adjust dose to maintain therapeutic range; doses of 400 to 1,600 mg/day PO may be needed. Do not exceed 400 mg/day in patients with risk factors for decreased theophylline clearance, such as the elderly (older than 60 years), and in those who cannot receive recommended serum concentration monitoring. Consider smaller, more frequent doses of immediate-release products or use of extended-release products in patients with rapid metabolism, identified by higher than average dose requirements. Further dose adjustments may be needed due to concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. Methylxanthines are not recommended in the management of COPD exacerbations due to increased side effect profiles.

    Children weighing more than 45 kg and Adolescents 16 years and older

    Initially, 300 mg/day PO in divided doses every 6 to 8 hours. After 3 days, if tolerated, increase dose to 400 mg/day PO in divided doses every 6 to 8 hours. After 3 more days, if tolerated, increase dose to 600 mg/day PO in divided doses given every 6 to 8 hours. Adjust dose to maintain therapeutic range; doses of 400 to 1,600 mg/day PO may be needed. Further dose adjustments may be needed due to concurrent medical conditions that reduce clearance or concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. Do not exceed 400 mg/day in patients with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider smaller, more frequent doses of immediate-release products or use of extended-release products in patients with rapid metabolism, identified by higher than average dose requirements. The National Asthma Education and Prevention (NAEPP) expert panel recommends initial dose for asthma of 10 mg/kg/day (Max: 300 mg/day) PO with titration to serum concentration of 5 to 15 mcg/mL (Usual Max: 800 mg/day in patients 12 years and older and 16 mg/kg/day in children 1 to 11 years).

    Children weighing 45 kg or less and Adolescents 15 years and younger

    Initially, 12 to 14 mg/kg/day (Max: 300 mg/day) PO in divided doses every 4 to 6 hours. After 3 days, if tolerated, may increase to 16 mg/kg/day (Max: 400 mg/day) in divided doses every 4 to 6 hours. After 3 more days, if tolerated and if needed, increase dose to 20 mg/kg/day (Max: 600 mg/day) in divided doses every 4 to 6 hours. Further dose adjustments may be needed due to concurrent medical conditions that reduce clearance or concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. Do not exceed 16 mg/kg/day (Max: 400 mg/day) in patients with risk factors for decreased theophylline clearance or who cannot receive recommended serum concentration monitoring. The National Asthma Education and Prevention (NAEPP) expert panel recommends initial dose for asthma of 10 mg/kg/day (Max: 300 mg/day) PO with titration to serum concentration of 5 to 15 mcg/mL (Usual Max: 800 mg/day in patients 12 years and older and 16 mg/kg/day in children 1 to 11).

    Infants 26 weeks and older

    Calculate initial total daily dose using the following equation: Total daily dose (mg) = [(0.2 x age in weeks) + 5] x (kg body weight). Divide dose and administer every 6 hours. Adjust dose to maintain a steady-state serum concentration of 10 to 15 mcg/mL. Reduced doses may be needed for infants with risk factors for reduced theophylline clearance (e.g., cardiac or liver dysfunction, renal dysfunction). Further dose adjustments may be needed due to concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. The National Asthma Education and Prevention (NAEPP) expert panel recommends initial dose for asthma of 10 mg/kg/day PO with titration to theophylline serum concentration of 5 to 15 mcg/mL.

    Infants younger than 26 weeks

    Calculate initial total daily dose using the following equation: Total daily dose (mg) = [(0.2 x age in weeks) + 5] x (kg body weight). Divide dose and administer every 8 hours. Adjust dose to maintain a steady-state serum concentration of 10 to 15 mcg/mL. Reduced doses may be needed for infants with risk factors for reduced theophylline clearance (e.g., cardiac or liver dysfunction, renal dysfunction). Further dose adjustments may be needed due to concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. The National Asthma Education and Prevention (NAEPP) expert panel recommends initial dose for asthma of 10 mg/kg/day PO with titration to theophylline serum concentration of 5 to 15 mcg/mL.

    Term Neonates

    Calculate initial total daily dose using the following equation: Total daily dose (mg) = [(0.2 x age in weeks) + 5] x (kg body weight). Divide dose and administer every 8 hours. Consider increased monitoring and dose reductions in neonates with renal impairment. Further dose adjustments may be needed due to concomitant drug therapy; review drug interactions. Adjust dose to maintain a steady-state serum concentration of 5 to 10 mcg/mL. The National Asthma Education and Prevention (NAEPP) expert panel recommends initial dose for asthma of 10 mg/kg/day PO with titration to theophylline serum concentration of 5 to 15 mcg/mL.

    Oral maintenance dosage (dosage is expressed as theophylline using extended-release dosage forms, e.g., Theolair-SR)
    Adults 60 years and older

    Initially, 300 mg/day PO in divided doses every 8 to 12 hours. After 3 days, if tolerated, increase dosage to 400 mg/day PO in divided doses every 8 to 12 hours. Further dose adjustments may be needed due to concurrent medical conditions that reduce clearance or concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. Max: 400 mg/day unless serum concentration and patient condition indicate need for higher dose. Consider smaller, more frequent doses in patients with rapid metabolism, identified by higher than average dose requirements. Extended-release products should NOT be used to treat acute symptoms. An NIH expert panel recommends initial dose for asthma of 10 mg/kg/day (Max: 300 mg/day) PO with titration to theophylline serum concentration of 5 to 15 mcg/mL. Methylxanthines are not recommended in the management of COPD exacerbations due to increased side effect profiles.

    Adults

    Initially, 300 mg/day PO in divided doses every 8 to 12 hours. After 3 days, if tolerated, increase to 400 mg/day PO in divided doses every 8 to 12 hours; then after 3 more days, if tolerated, increase to 600 mg/day in divided doses every 8 to 12 hours. Adjust dose to maintain therapeutic range; doses of 400 to 1,600 mg/day PO may be needed. Further dose adjustments may be needed due to concurrent medical conditions that reduce clearance or concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. Max: 400 mg/day in patients with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider smaller, more frequent doses in patients with rapid metabolism, identified by higher than average dose requirements. Extended-release products should NOT be used to treat acute symptoms. An NIH expert panel recommends initial dose for asthma of 10 mg/kg/day (Max: 300 mg/day) PO with titration to theophylline serum concentration of 5 to 15 mcg/mL. Methylxanthines are not recommended in the management of COPD exacerbations due to increased side effect profiles.

    Children and Adolescents 6 to 17 years weighing more than 45 kg

    Initially, 300 mg/day PO in divided doses every 8 to 12 hours. After 3 days, if tolerated, increase to 400 mg/day PO in divided doses every 8 to 12 hours; then after 3 more days, if tolerated, increase to 600 mg/day in divided doses every 8 to 12 hours. Adjust dose to maintain therapeutic range; doses of 400 to 1,600 mg/day PO may be needed. Further dose adjustments may be needed due to concurrent medical conditions that reduce clearance or concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. Max: 400 mg/day in patients with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider smaller, more frequent doses in patients with rapid metabolism, identified by higher than average dose requirements. Extended-release products should NOT be used to treat acute symptoms. An NIH expert panel recommends initial dose for asthma of 10 mg/kg/day (Max: 300 mg/day) PO with titration to theophylline serum concentration of 5 to 15 mcg/mL (Usual Max: 800 mg/day in patients 12 years and older and 16 mg/kg/day in children 1 to 11 years).

    Children and Adolescents 6 to 15 years weighing 45 kg or less

    Initially, 12 to 14 mg/kg/day (Max: 300 mg/day) PO given in divided doses every 8 to 12 hours. After 3 days, if tolerated, may increase dose to 16 mg/kg/day (Max: 400 mg/day) PO in divided doses every 8 to 12 hours. After 3 more days, if tolerated, increase dose to 20 mg/kg/day (Max: 600 mg/day) PO in divided doses every 8 to 12 hours. Further dose adjustments may be needed due to concurrent medical conditions that reduce clearance or concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. Adjust dose to maintain therapeutic range; doses of 10 to 36 mg/kg/day PO in children younger than 9 years and 400 to 1,600 mg/day PO in patients 16 years and older may be needed. Do not exceed 16 mg/kg/day (up to 400 mg/day) in patients with risk factors for decreased theophylline clearance or who cannot receive recommended serum concentration monitoring. Extended-release products should NOT be used to treat acute symptoms. An NIH expert panel recommends initial dose for asthma of 10 mg/kg/day (Max: 300 mg/day) PO with titration to theophylline serum concentration of 5 to 15 mcg/mL (Usual Max: 800 mg/day in patients 12 years and older and 16 mg/kg/day in children 1 to 11 years).

    Oral maintenance dosage (dosage is expressed as theophylline using controlled-release dosage, e.g., Theo-24 Capsules)
    Adults

    Initially, 300 to 400 mg/day PO every 24 hours; evening dosing is not recommended. After 3 days, if tolerated, increase dosage to 400 to 600 mg/day PO every 24 hours. Adjust dose to maintain therapeutic range; doses of 400 to 1,600 mg/day PO may be needed. Further dose adjustments may be needed due to concurrent medical conditions that reduce clearance or concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. Max: 400 mg/day in patients with risk factors for decreased theophylline clearance, such as the elderly (older than 60 years), and in those who cannot receive recommended serum concentration monitoring. Consider twice daily dosing in patients with rapid metabolism and who repeatedly have symptoms at the end of a 24-hour dosing interval. Extended-release products should NOT be used to treat acute symptoms. An NIH expert panel recommends initial dose for asthma of 10 mg/kg/day (Max: 300 mg/day) PO with titration to serum concentration of 5 to 15 mcg/mL (Usual Max: 800 mg/day). Methylxanthines are not recommended in the management of COPD exacerbations due to increased side effect profiles.

    Children and Adolescents 12 to 15 years weighing more than 45 kg and Adolescents 16 to 17 years

    Initially, 300 to 400 mg/day PO every 24 hours; evening dosing is not recommended. After 3 days, if tolerated, increase dosage to 400 to 600 mg/day PO. Adjust dose to maintain therapeutic range; doses of 400 to 1,600 mg/day PO may be needed. Further dose adjustments may be needed due to concurrent medical conditions that reduce clearance or concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. Do not exceed 400 mg/day in patients with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider twice daily dosing in patients with rapid metabolism and who repeatedly have symptoms at the end of a 24-hour dosing interval. Extended-release products should NOT be used to treat acute symptoms. An NIH expert panel recommends initial dose for asthma of 10 mg/kg/day (Max: 300 mg/day) PO with titration to serum concentration of 5 to 15 mcg/mL (Usual Max: 800 mg/day).

    Children and Adolescents 12 to 15 years weighing less than 45 kg

    Initially, 12 to 14 mg/kg/day (Max: 300 mg/day) PO every 24 hours; evening dosing is not recommended. After 3 days, if tolerated, may increase dose to 16 mg/kg/day (Max: 400 mg/day) PO. After 3 more days, if tolerated and if needed, increase to 20 mg/kg/day (Max: 600 mg/day) PO. Further dose adjustments may be needed due to concurrent medical conditions that reduce clearance or concomitant drug therapy; review drug interactions. Adjust subsequent dosage based on serum theophylline concentrations. Do not exceed 16 mg/kg/day (up to 400 mg/day) in patients with risk factors for decreased theophylline clearance or who cannot receive recommended serum concentration monitoring. Consider twice daily dosing in patients with rapid metabolism and who repeatedly have symptoms at the end of a 24-hour dosing interval. Extended-release products should NOT be used to treat acute symptoms. An NIH expert panel recommends initial dose for asthma of 10 mg/kg/day (Max: 300 mg/day) PO with titration to serum concentration of 5 to 15 mcg/mL (Usual Max: 800 mg/day).

    For the treatment of acute exacerbations† of reversible airways obstruction (including status asthmaticus) in patients who are not responding to first-line therapies.
    NOTE: Although reference texts continue to list this indication, several studies have failed to demonstrate a benefit of theophylline in the management of acute bronchospasm. The FDA no longer includes acute bronchospasm as an approved indication. Most clinicians do not feel theophylline is warranted in the treatment of acute bronchospasm unless the patient is not responding to other treatments. The National Asthma Education and Prevention Program does not recommend theophylline for acute exacerbations because it appears to provide no additional benefit to optimal inhaled beta-2-agonist therapy and may increase risk of adverse effects.
    Intravenous loading dosage (dosage is expressed as theophylline)
    Adults, Adolescents, and Children

    4.6 mg/kg IV loading dose infused over 30 minutes in a patient who has received no theophylline in the previous 24 hours will produce an average peak serum theophylline concentration of 10 mcg/mL (range 6 to 16 mcg/mL); calculate mg/kg dose based on ideal body weight. In patients who have received theophylline within the previous 24 hours, a theophylline serum concentration must be drawn and loading dose, if needed, calculated accordingly. If dosing with theophylline is continued, follow maintenance dosage below.

    Oral loading dosage (dosage is expressed as theophylline - NOTE- do not use sustained-release dosage forms)
    Adults, Adolescents, and Children

    5 mg/kg PO loading dose using an immediate-release product in a patient who has received no theophylline in the previous 24 hours will produce an average peak serum theophylline concentration of 10 mcg/mL (range 5 to 15 mcg/mL); calculate mg/kg dose based on ideal body weight. If dosing with theophylline is continued, follow maintenance dosage below.

    Continuous intravenous infusion dosage (dosage is expressed as theophylline)
    Adolescents 16 to 17 years

    Initially, 0.4 mg/kg/hour IV (Max: 900 mg/day) in otherwise healthy nonsmokers; although no specific dosing guidance is available, patients who smoke may require an increased dose. Begin with 0.2 mg/kg/hour IV (Max: 400 mg/day) to patients with CHF, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, shock, or other factors for reduced theophylline clearance. Reduced doses may be needed in patients receiving other drugs that decrease theophylline clearance. Adjust dosage based on subsequent serum concentrations and clinical response. NOTE: The National Asthma Education and Prevention Program (NAEPP) and Global Initiative for Asthma (GINA) guidelines do not recommend theophylline for acute exacerbations because it appears to provide no additional benefit to optimal inhaled beta2-agonist therapy and may increase risk of adverse effects.

    Children and Adolescents 12 to 15 years

    Initially, 0.5 mg/kg/hour IV in otherwise healthy nonsmokers (Max: 900 mg/day); 0.7 mg/kg/hour IV in smokers. Reduced doses may be needed in patients receiving other drugs that decrease theophylline clearance. Begin with 0.2 mg/kg/hour IV (Max: 400 mg/day) in patients with cardiac decompensation, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, or shock. Adjust dosage based on subsequent serum concentrations and clinical response. NOTE: The National Asthma Education and Prevention Program (NAEPP) and Global Initiative for Asthma (GINA) guidelines do not recommend theophylline for acute exacerbations because it appears to provide no additional benefit to optimal inhaled beta2-agonist therapy and may increase risk of adverse effects.

    Children 9 to 11 years

    Initially, 0.7 mg/kg/hour IV. Reduced doses may be needed in patients receiving other drugs that decrease theophylline clearance. Begin with 0.2 mg/kg/hour IV (Max: 400 mg/day) to patients with cardiac decompensation, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, or shock. Adjust dosage based on subsequent serum concentrations and clinical response. NOTE: The National Asthma Education and Prevention Program (NAEPP) and Global Initiative for Asthma (GINA) guidelines do not recommend theophylline for acute exacerbations because it appears to provide no additional benefit to optimal inhaled beta2-agonist therapy and may increase risk of adverse effects.

    Children 1 to 8 years

    Initially, 0.8 mg/kg/hour IV; reduced doses may be needed in patients receiving other drugs that decrease theophylline clearance. Begin with 0.2 mg/kg/hour IV (Max: 400 mg/day) in patients with cardiac decompensation, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, or shock. Adjust dosage based on subsequent serum concentrations. NOTE: The National Asthma Education and Prevention Program (NAEPP) and Global Initiative for Asthma (GINA) guidelines do not recommend theophylline for acute exacerbations because it appears to provide no additional benefit to optimal inhaled beta2-agonist therapy and may increase risk of adverse effects.

    Infants 6 to 52 weeks

    Calculate initial dosage using the following equation: (0.008 x age in weeks) + 0.21 = theophylline dosage in mg/kg/hour IV; reduced doses may be needed in patients with risk factors for reduced theophylline clearance (e.g. drug interactions, cardiac or hepatic impairment, renal dysfunction in infants younger than 3 months). Adjust dosage based on subsequent serum concentrations and clinical response. NOTE: The National Asthma Education and Prevention Program (NAEPP) and Global Initiative for Asthma (GINA) guidelines do not recommend theophylline for acute exacerbations because it appears to provide no additional benefit to optimal inhaled beta2-agonist therapy and may increase risk of adverse effects.

    For the treatment of neonatal apnea of prematurity when non-pharmacologic therapies are ineffective.
    Intravenous loading dosage (aminophylline or theophylline)
    Neonates

    5 to 8 mg/kg (aminophylline or theophylline) IV infused over 30 minutes. In a randomized controlled trial that included 61 premature neonates, a loading dose of 8 mg/kg of aminophylline achieved therapeutic serum concentrations more frequently than 6 mg/kg.

    Intravenous or Oral maintenance dosage (aminophylline or theophylline)
    Term Neonates and Infants

    The total daily dose should be divided and given PO every 8 hours. Calculate initial dose using the following equation: Total daily dose (mg) = [(0.2 x age in weeks) + 5] x (body weight in kg). Monitor clinical status and theophylline serum concentrations frequently.

    Premature Neonates

    0.8 to 3 mg/kg/dose (aminophylline or theophylline) IV or PO every 8 to 12 hours have been used in clinical trials. The manufacturer recommends 1 mg/kg (theophylline) IV or PO every 12 hours in premature neonates (postnatal age younger than 24 days) and 1.5 mg/kg (theophylline) IV or PO every 12 hours for premature neonates (postnatal age 24 days and older). Monitor clinical status and theophylline serum concentrations frequently. Dosage of theophylline must be individualized. When switching from IV aminophylline to PO theophylline in preterm infants, no initial dosage adjustment is necessary.

    For the treatment of sleep apnea† in patients with chronic heart failure-induced systolic dysfunction.
    Oral dosage (dosage is expressed as theophylline using extended-release dosage forms)
    Adults

    The effects of theophylline or placebo were evaluated in 15 men with stable heart failure and documented sleep apnea. Treatment with theophylline resulted in a considerable reduction in periodic breathing and episodes of sleep apnea. In this study, theophylline was administered as Theo-Dur® tablets (NOTE: no longer commercially available) 3.3 mg/kg PO twice daily for 5 days. Mean serum theophylline concentration on day 5 was 11 +/- 2 mcg/mL (range 6.9 to 14.9 mcg/mL).

    †Indicates off-label use

    MAXIMUM DOSAGE

    Theophylline has a narrow therapeutic index. The maximum dosage is individualized based on therapeutic drug concentration monitoring and assessment of efficacy and safety parameters. The following are some general guidelines in chronic use (dosage expressed as theophylline):

    Adults

    < 60 years: Individualize dosage; 400 mg/day PO if risk factors for decreased clearance are present or recommended serum concentration monitoring is not possible.
    >= 60 years: 400 mg/day PO.

    Geriatric

    400 mg/day PO.

    Adolescents

    16 years and older: Individualize dosage; 400 mg/day PO if risk factors for decreased clearance are present or recommended serum concentration monitoring is not possible.
    Younger than 16 years: Individualize dosage; 16 mg/kg/day up to 400 mg/day PO if risk factors for decreased clearance are present or recommended serum concentration monitoring is not possible.

    Children

    Individualize dosage; do not exceed 16 mg/kg/day up to 400 mg/day PO if risk factors for decreased clearance are present or recommended serum theophylline concentration monitoring is not possible.

    Infants

    Must individualize dosage; infant dosing is based on age/weight.

    Neonates

    Must individualize dosage; loading doses of 8 mg/kg IV or PO have been used.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Reduced dosage is needed in patients with liver disease, including cirrhosis and acute hepatitis. Maximum initial dose = 0.2 mg/kg/day IV (theophylline) in patients >= 1 year. Do not exceed 400 mg/day IV, 400 mg/day PO in patients >= 16 years, or 16 mg/kg/day up to 400 mg/day PO in patients < 16 years unless serum theophylline concentration and patient condition warrant higher dose; careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required.

    Renal Impairment

    Reduced dosage is needed in neonates and infants < 3 months as roughly 50% of the administered theophylline dose is excreted unchanged in the urine in this population; careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required. In adults, children, and infants > 3 months of age, no dosage adjustment is necessary.

    ADMINISTRATION

    For storage information, see the specific product information within the the How Supplied section.

    Oral Administration

    For faster absorption, administer theophylline with a full glass of water on an empty stomach 30—60 minutes before meals or 2 hours after meals. If gastrointestinal irritation occurs, administer with food or antacids.

    Oral Solid Formulations

    Enteric-coated or timed-release capsules or tablets: Do not crush or chew. For patients with difficulty swallowing, the capsule formulations may be opened and mixed with soft food; do not chew or crush medication beads.
    Theo-24 capsules: Administer on an empty stomach; administration with a high-fat-content meal may increase the peak serum theophylline concentration ('dose-dumping') which could result in toxicity. Administration is usually in the morning at approximately the same time daily; when two doses per day are prescribed, administer the second dose 10—12 hours after the morning dose and before the evening meal.
    Uni-Dur Tablets: Do not crush or chew. May be administered once daily, in the AM or in the PM and without regard to meals. When two doses per day are prescribed, administer the second dose 12 hours after the morning dose.

    Oral Liquid Formulations

    Elixir, solution, syrup: Administer theophylline using a calibrated measuring device to ensure accurate dosing.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Discard solution if it is not clear.
    Do not use if crystals are present.

    Intravenous Administration

    Intravenous loading dose bolus:
    If the patient has received any theophylline within 24 hours, obtain serum theophylline concentration prior to administration of a theophylline loading dose.
    Manufacturers recommend administering the bolus dose over 30 minutes.
    Monitor patient clinically as appropriate during infusion.
    Obtain theophylline serum concentration 30 minutes after administration of intravenous loading dose to assess the need for and size of subsequent loading doses, if clinically indicated, and for guidance of continuing therapy.
     
    Intravenous continuous infusion:
    Infusion rate should be individualized and is dependent on interpatient variability of theophylline clearance (see Dosage).
    Monitor patient clinically as appropriate during infusion.
    Obtain theophylline serum concentration at one expected half-life after starting the constant infusion and again 12 to 24 hours later, then monitor every 24 hours during infusion.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use
    Elixophyllin:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Quibron T:
    - Store between 59 to 77 degrees F
    Quibron T/SR:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Theo X:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Theo-24:
    - Store below 77 degrees F
    Theochron:
    - Storage information not available
    Theo-Dur:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Theolair SR:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    T-Phyl:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Uni-Dur:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Uniphyl:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Theophylline can alter the results of some common laboratory tests. Serum concentrations levels of glucose, uric acid, free fatty acids (cholesterol, HDL), and urinary free cortisol excretion may all be reportedly increased. Also, transient decreases in triiodothyronine levels have been reported. The clinician should be aware of these alterations and should weigh the clinical importance of these changes to the benefits of theophylline therapy.

    Cardiac arrhythmias, cardiac disease, cor pulmonale, coronary artery disease, heart failure, myocardial infarction

    Patients with cardiac disease should be monitored more closely for adverse reactions to theophylline. Lower doses may be necessary for patients with congestive heart failure, including cor pulmonale, due to decreased theophylline clearance (>= 50% decrease). Also, theophylline can exacerbate existing cardiac arrhythmias and should be used with caution in patients at risk. Similarly, because theophylline can increase oxygen demand, it should be prescribed carefully in patients with coronary artery disease, especially those with a history of myocardial infarction.

    Hypothyroidism, pulmonary edema, sepsis, shock

    Patients with hypothyroidism, acute pulmonary edema, sepsis with multiple organ failure, or shock may have decreased theophylline clearance. Any patients with any of the above conditions should be monitored carefully while receiving theophylline.

    Cystic fibrosis, hyperthyroidism

    Increased theophylline clearance may occur in patients with hyperthyroidism or cystic fibrosis. Hypercalcemia has been reported in a patient with hyperthyroid disease at therapeutic theophylline concentrations. Any patients with cystic fibrosis or conditions affecting the thyroid should be monitored carefully while receiving theophylline.

    Acidemia

    Patients with uncorrected acidemia can have an increase in the volume of distribution of theophylline due to a decrease in plasma protein binding. Unbound serum theophylline concentrations should be monitored in these patients to avoid toxicity.

    Cholestasis, hepatic disease, hepatitis, infants, neonates, renal impairment

    Since theophylline is metabolized hepatically, doses may need to be lower in patients with moderate to severe hepatic disease such as cirrhosis, acute hepatitis, cholestasis, or alcoholic liver disease. Patients who regularly consume ethanol but do not exhibit overt hepatic dysfunction may actually require larger doses than normal. The elderly may also have reduced hepatic metabolism, and their doses should generally be lower with cautious titration. Doses should be decreased in in infants under 1 year of age, especially premature neonates due to a less developed hepatic metabolism. Also, since neonates and young infants have a higher percentage of unchanged theophylline excreted via the kidneys (approximately 50% in newborns as compared to 10% in those older than 3 months), neonates and infants less than 3 months with renal impairment require lower doses.

    Tobacco smoking

    Tobacco smoking has been shown to increase the clearance of theophylline by about 50% in young adult tobacco smokers and about 80% in elderly tobacco smokers. Also, passive smoke exposure may cause a an increase in theophylline clearance by up to 50%. Because the effect of tobacco on hepatic microsomal enzymes is not related to the nicotine component, sudden smoking cessation may result in a reduced clearance of theophylline, despite the initiation of nicotine replacement products. Following 1 week of abstinence from chronic tobacco smoking, theophylline clearance may decrease by roughly 40%, leading to an increase in serum theophylline concentrations. Theophylline serum concentrations should be monitored carefully when changes in smoking status occur.

    Fever, hypoxemia

    Prolonged fever has been reported to reduce theophylline clearance. Lower doses should be considered in these conditions. Theophylline also should be used cautiously in patients with respiratory infection or severe hypoxemia.

    Gastritis, gastroesophageal reflux disease (GERD), hiatal hernia, peptic ulcer disease

    Since theophylline can stimulate gastric secretions, it should be used with caution in patients with gastritis or active peptic ulcer disease. Theophylline may aggravate symptoms related to hiatal hernia or gastroesophageal reflux disease (GERD).

    Prostatic hypertrophy

    Theophylline relaxes smooth muscle and can increase urinary retention, so it should be used with caution in patients with prostatic hypertrophy. Use of theophylline initially can cause a diuretic effect.

    Pregnancy

    Theophylline is classified as a FDA pregnancy risk category C drug. Theophylline has not been proven to be teratogenic in humans, but use during pregnancy may lead to potentially dangerous serum theophylline and caffeine concentrations in neonates, as well as tachycardia, irritability, and other symptoms of theophylline toxicity. Decreased theophylline clearance has been reported during the third trimester of pregnancy. Despite these precautions, theophylline is considered an alternative therapy to inhaled corticosteroids for mild persistent asthma during pregnancy according to the 2004 guidelines of the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group. If used, it is recommended that serum theophylline concentrations be regularly monitored and maintained between 5—12 mcg/mL. It should be noted that inhaled corticosteroids are the preferred treatment due to the potential toxicities of theophylline, including side effects and drug interactions. However, maintaining a previously established treatment regimen may be more beneficial to the patient. Therefore, selection of any pharmacologic treatment for asthma control during pregnancy should include the specific needs of the patient, based on an individual evaluation, and consideration of the potential benefits or risks to the fetus.

    Breast-feeding

    Theophylline is excreted in breast milk in concentrations similar to the serum concentration of the mother. Neonates whose mothers have been taking theophylline during pregnancy or while breast-feeding should be monitored carefully. Breast fed infants whose mothers are taking theophylline may experience irritability or other mild signs of toxicity; however, serious adverse events are unlikely unless the mother has toxic serum concentrations. Theophylline is considered an alternative therapy to inhaled corticosteroids for mild persistent asthma during pregnancy and lactation according to the 2004 guidelines of the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group. If used, it is recommended that serum theophylline concentrations be regularly monitored and maintained between 5—12 mcg/mL. The American Academy of Pediatrics considers theophylline to be usually compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Corn hypersensitivity

    Theophylline is contraindicated in patients who have demonstrated a hypersensitivity reaction to theophylline or any component in the commercial product. Some pre-mixed theophylline in dextrose intravenous infusions may be manufactured using corn or corn products and may be contraindicated in patients with corn hypersensitivity.

    Seizure disorder

    Theophylline should be used cautiously in patients with a history of seizure disorder due to the risk of exacerbating their condition.

    Geriatric

    Careful consideration must be given to the benefits and risks of theophylline or aminophylline use and the need for more intensive monitoring of serum theophylline concentrations in older adult and geriatric patients more than 60 years of age. The clearance of theophylline is decreased by an average of 30% in healthy geriatric adults vs younger adults; clearance may be further significantly decreased if concomitant disease states or other factors for reduced clearance are present. If the total daily dose is not appropriately reduced, severe and potentially fatal theophylline toxicity can occur. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, periodic monitoring of serum theophylline concentrations helps identify or verify toxicity, as well as monitoring the clinical status of the patient for signs and symptoms of toxicity, such as arrhythmias, seizures, GI upset, diarrhea, nausea/vomiting, abdominal pain, nervousness, headache, insomnia, distress, dizziness, muscle cramps, and tremor. There are potentially significant interactions with many other medications, particularly antibiotics, anticonvulsants, and cardiac medications.

    ADVERSE REACTIONS

    Severe

    exfoliative dermatitis / Delayed / 0-1.0
    hematemesis / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    atrial flutter / Early / Incidence not known
    atrial fibrillation / Early / Incidence not known
    atrial tachycardia / Early / Incidence not known

    Moderate

    hypercalcemia / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    palpitations / Early / Incidence not known
    premature ventricular contractions (PVCs) / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    metabolic acidosis / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known

    Mild

    nausea / Early / 10.0
    vomiting / Early / 10.0
    insomnia / Early / 10.0
    headache / Early / 10.0
    anorexia / Delayed / Incidence not known
    gastroesophageal reflux / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    diarrhea / Early / Incidence not known
    agitation / Early / Incidence not known
    dizziness / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    restlessness / Early / Incidence not known
    irritability / Delayed / Incidence not known
    hyperactivity / Early / Incidence not known
    diuresis / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    vitamin B6 deficiency / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. In neonates, theophylline is metabolized to caffeine; initiating caffeine after theophylline therapy is halted may result in caffeine toxicity in neonates if serum caffeine levels are not monitored prior to the initiation of caffeine therapy. Concurrent use of theophylline with caffeine in neonates is not recommended due to the potential for additive toxicity.
    Acetaminophen; Butalbital: (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Acetaminophen; Butalbital; Caffeine: (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. In neonates, theophylline is metabolized to caffeine; initiating caffeine after theophylline therapy is halted may result in caffeine toxicity in neonates if serum caffeine levels are not monitored prior to the initiation of caffeine therapy. Concurrent use of theophylline with caffeine in neonates is not recommended due to the potential for additive toxicity. (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. In neonates, theophylline is metabolized to caffeine; initiating caffeine after theophylline therapy is halted may result in caffeine toxicity in neonates if serum caffeine levels are not monitored prior to the initiation of caffeine therapy. Concurrent use of theophylline with caffeine in neonates is not recommended due to the potential for additive toxicity. (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Acetaminophen; Caffeine: (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. In neonates, theophylline is metabolized to caffeine; initiating caffeine after theophylline therapy is halted may result in caffeine toxicity in neonates if serum caffeine levels are not monitored prior to the initiation of caffeine therapy. Concurrent use of theophylline with caffeine in neonates is not recommended due to the potential for additive toxicity.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. In neonates, theophylline is metabolized to caffeine; initiating caffeine after theophylline therapy is halted may result in caffeine toxicity in neonates if serum caffeine levels are not monitored prior to the initiation of caffeine therapy. Concurrent use of theophylline with caffeine in neonates is not recommended due to the potential for additive toxicity.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. In neonates, theophylline is metabolized to caffeine; initiating caffeine after theophylline therapy is halted may result in caffeine toxicity in neonates if serum caffeine levels are not monitored prior to the initiation of caffeine therapy. Concurrent use of theophylline with caffeine in neonates is not recommended due to the potential for additive toxicity.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. In neonates, theophylline is metabolized to caffeine; initiating caffeine after theophylline therapy is halted may result in caffeine toxicity in neonates if serum caffeine levels are not monitored prior to the initiation of caffeine therapy. Concurrent use of theophylline with caffeine in neonates is not recommended due to the potential for additive toxicity.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Acetaminophen; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Acrivastine; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Acyclovir: (Minor) Caution is advised when administering theophylline, aminophylline with acyclovir. Theophylline is primarily metabolized by CYP1A2; acyclovir is a weak inhibitor of CYP1A2. Taking these drugs together may increase the serum concentration of theophylline. Since the therapeutic range of theophylline is narrow, it is prudent to monitor theophylline serum concentrations upon initiation, dosage adjustment, or discontinuation of medications that may alter the function of CYP1A2.
    Adenosine: (Major) Methylxanthines, such as theophylline, aminophylline, or caffeine, competitively block the effects of adenosine. If possible, stop use of methylxanthines at least 5 half-lives prior to administering adenosine. Patients receiving theophylline, aminophylline and adenosine should be monitored for adenosine efficacy; larger doses of adenosine may be required to achieve antiarrhythmic goals in some patients. In addition, larger doses of adenosine may be required for therapeutic effect if administered to patients with high daily caffeine intake (including caffeine from foods and beverages such as coffee, green tea, other teas, colas, and chocolate). Theophylline, aminophylline may increase the risk of seizures associated with adenosine; avoid methylxanthine use in patients who have experienced an adenosine-associated seizure. Methylxanthines, such as caffeine, theophylline, and theobromine, are also found in guarana.
    Albendazole: (Moderate) Albendazole has been shown to induce the hepatic CYP1A microsomal enzymes. It is possible that the prescription of albendazole may result in an increased clearance of theophylline via induction of CYP1A enzymes. Conversely, the discontinuation of albendazole therapy may result in a reduced clearance of theophylline, leading to an increase in serum theophylline concentrations. Theophylline serum concentrations and the patient's clinical status should be monitored carefully when albendazole is prescribed and on discontinuation of albendazole therapy. (Moderate) Albendazole has been shown to induce the hepatic CYP1A microsomal enzymes. It is possible that the prescription of albendazole may result in an increased clearance of aminophylline via induction of CYP1A enzymes. Conversely, the discontinuation of albendazole therapy may result in a reduced clearance of aminophylline, leading to an increase in serum aminophylline concentrations. Aminophylline serum concentrations and the patient's clinical status should be monitored carefully when albendazole is prescribed and on discontinuation of albendazole therapy.
    Albuterol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Albuterol; Ipratropium: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Allopurinol: (Minor) Allopurinol in large doses can decrease aminophylline clearance. It appears that the significance of this drug interaction depends on the dose of allopurinol. (Minor) Allopurinol in large doses can decrease theophylline clearance. It appears that the significance of this drug interaction depends on the dose of allopurinol.
    Alpha interferons: (Major) Alpha interferons, when administered systemically, may decrease the clearance of aminophylline resulting in increased plasma concentrations. Concomitant use may result in a significant increase in theophylline concentrations due to reduced aminophylline clearance. In studies, increases in theophylline levels of 25% up to 100% have occurred. Reductions in CYP1A2 activity have been noted with various alpha interferons, and likely provide a mechanism for the interaction. Monitor theophylline concentrations and for signs and symptoms of toxicity when interferons are used concomitantly; consider appropriate dose adjustments as clinically indicated. (Major) Alpha interferons, when administered systemically, may decrease the clearance of theophylline resulting in increased plasma concentrations. Concomitant use may result in a significant increase in theophylline concentrations due to reduced theophylline clearance. In studies, increases in theophylline levels of 25% up to 100% have occurred. Reductions in CYP1A2 activity have been noted with various alpha interferons, and likely provide a mechanism for the interaction. Monitor theophylline concentrations and for signs and symptoms of theophylline toxicity when interferons are used concomitantly; consider appropriate dose adjustments as clinically indicated.
    Alprazolam: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Amifampridine: (Major) Carefully consider the need for aminophylline, as use with amifampridine may increase the risk of seizures. Consider alternatives to aminophylline. If use together is medically necessary, closely monitor patients for seizure activity and closely monitor theophylline concentrations. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Aminophylline is converted to theophylline and is known to have a dose-dependent risk for seizures. (Major) Carefully consider the need for theophylline, as use with amifampridine may increase the risk of seizures. Consider alternatives to theophylline. If use together is medically necessary, closely monitor patients for seizure activity and closely monitor theophylline concentrations. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Theophylline is known to have a dose-dependent risk for seizures.
    Amiodarone: (Moderate) Amiodarone inhibits cytochrome P450 CYP1A2 isoenzymes, which can potentially lead to increased plasma concentrations of CYP1A2 substrates like aminophylline. (Moderate) Amiodarone inhibits cytochrome P450 CYP1A2 isoenzymes, which can potentially lead to increased plasma concentrations of CYP1A2 substrates like theophylline.
    Amitriptyline; Chlordiazepoxide: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Amobarbital: (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Clarithromycin can inhibit aminophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. The labeling for aminophylline products states that aminophylline clearance may be decreased by up to 35% when clarithromycin is prescribed concurrently; these interactions can be clinically important. These interactions are particularly significant when aminophylline serum concentrations are already in the high therapeutic range (i.e., > 15 mcg/ml). If clarithromycin is used with aminophylline therapy, patients should be monitored for elevated theophylline levels and/or theophylline toxicity. Of the macrolides, azithromycin may be an alternative since it does not inhibit cytochrome P450 enzymes; no dosage adjustment of theophylline (or aminophylline) is required when azithromycin is coadministered. (Major) Clarithromycin can inhibit theophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. The labeling for theophylline products states that theophylline clearance may be decreased by up to 35% when clarithromycin is prescribed concurrently; these interactions can be clinically important. These interactions are particularly significant when theophylline serum concentrations are already in the high therapeutic range (i.e., > 15 mcg/ml). If clarithromycin is used with aminophylline or theophylline therapy, patients should be monitored for elevated theophylline levels and/or theophylline toxicity. Of the macrolides, azithromycin may be an alternative since it does not inhibit cytochrome P450 enzymes; no dosage adjustment of theophylline (or aminophylline) is required when azithromycin is coadministered. (Minor) Concomitant use of theophylline, a CYP1A2 and CYP3A substrate, and lansoprazole has led to a small increase in theophylline clearance. Aminophylline may require dosage adjustment when therapy with lansoprazole is initiated or discontinued. (Minor) Concomitant use of theophylline, a CYP1A2 and CYP3A substrate, and lansoprazole has led to a small increase in theophylline clearance. Theophylline may require dosage adjustment when therapy with lansoprazole is initiated or discontinued.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Clarithromycin can inhibit aminophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. The labeling for aminophylline products states that aminophylline clearance may be decreased by up to 35% when clarithromycin is prescribed concurrently; these interactions can be clinically important. These interactions are particularly significant when aminophylline serum concentrations are already in the high therapeutic range (i.e., > 15 mcg/ml). If clarithromycin is used with aminophylline therapy, patients should be monitored for elevated theophylline levels and/or theophylline toxicity. Of the macrolides, azithromycin may be an alternative since it does not inhibit cytochrome P450 enzymes; no dosage adjustment of theophylline (or aminophylline) is required when azithromycin is coadministered. (Major) Clarithromycin can inhibit theophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. The labeling for theophylline products states that theophylline clearance may be decreased by up to 35% when clarithromycin is prescribed concurrently; these interactions can be clinically important. These interactions are particularly significant when theophylline serum concentrations are already in the high therapeutic range (i.e., > 15 mcg/ml). If clarithromycin is used with aminophylline or theophylline therapy, patients should be monitored for elevated theophylline levels and/or theophylline toxicity. Of the macrolides, azithromycin may be an alternative since it does not inhibit cytochrome P450 enzymes; no dosage adjustment of theophylline (or aminophylline) is required when azithromycin is coadministered.
    Amphetamine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Amphetamine; Dextroamphetamine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Anagrelide: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including aminophylline, could lead to increases in the serum concentrations of aminophylline and thus, adverse effects. Patients receiving anagrelide and aminophylline concomitantly should be monitored for increased toxicity of aminophylline. (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including theophylline, could lead to increases in the serum concentrations of theophylline and thus, adverse effects. Patients receiving anagrelide and theophylline concomitantly should be monitored for increased toxicity of theophylline.
    Antithyroid agents: (Minor) Patients with hyperthyroidism may exhibit accelerated clearance of theophylline. Correction of hyperthyroidism can lead to a decrease in theophylline clearance. Theophylline serum concentrations should be monitored closely during the initial stages of treatment for hyperthyroidism.
    Aprepitant, Fosaprepitant: (Major) Use caution if theophylline, aminophylline and aprepitant, fosaprepitant are used concurrently and monitor for an increase in theophylline- or aminophylline-related adverse effects and altered serum levels for several days after administration of a multi-day aprepitant regimen. Theophylline and aminophylline are CYP3A4 substrates. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of theophylline or aminophylline. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. (Moderate) Aminophylline is a substrate for CYP3A4 and, theoretically, plasma concentrations could be increased via CYP3A4 inhibition by aprepitant/fosaprepitant, although this interaction has not been studied.
    Arformoterol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Armodafinil: (Minor) In vitro data indicate that armodafinil is an inducer of CYP3A4/5 isoenzymes. Although theophylline is only metabolized by CYP3A4 to a minor degree, caution is warranted due to the narrow therapeutic index of the drug. Theophylline concentrations should be monitored closely after the addition or discontinuation of armodafinil until a new steady-state level is achieved. (Minor) In vitro data indicate that armodafinil is an inducer of CYP3A4/5 isoenzymes. Although theophylline/aminophylline is only metabolized by CYP3A4 to a minor degree, caution is warranted due to the narrow therapeutic index of the drug. Theophylline/aminophylline concentrations should be monitored closely after the addition or discontinuation of armodafinil until a new steady-state level is achieved.
    Articaine; Epinephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. In neonates, theophylline is metabolized to caffeine; initiating caffeine after theophylline therapy is halted may result in caffeine toxicity in neonates if serum caffeine levels are not monitored prior to the initiation of caffeine therapy. Concurrent use of theophylline with caffeine in neonates is not recommended due to the potential for additive toxicity. (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. In neonates, theophylline is metabolized to caffeine; initiating caffeine after theophylline therapy is halted may result in caffeine toxicity in neonates if serum caffeine levels are not monitored prior to the initiation of caffeine therapy. Concurrent use of theophylline with caffeine in neonates is not recommended due to the potential for additive toxicity. (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. In neonates, theophylline is metabolized to caffeine; initiating caffeine after theophylline therapy is halted may result in caffeine toxicity in neonates if serum caffeine levels are not monitored prior to the initiation of caffeine therapy. Concurrent use of theophylline with caffeine in neonates is not recommended due to the potential for additive toxicity.
    Aspirin, ASA; Caffeine; Orphenadrine: (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. In neonates, theophylline is metabolized to caffeine; initiating caffeine after theophylline therapy is halted may result in caffeine toxicity in neonates if serum caffeine levels are not monitored prior to the initiation of caffeine therapy. Concurrent use of theophylline with caffeine in neonates is not recommended due to the potential for additive toxicity.
    Aspirin, ASA; Dipyridamole: (Major) Aminophylline may cause false-negative results during dipyridamole-thallium 201 stress testing. Discontinue aminophylline for at least 24 hours prior to this type of stress testing. Maintenance aminophylline therapy and other xanthine derivatives may abolish the coronary vasodilatation induced by dipyridamole administration via antagonism of adenosine. No interaction of concern is expected when aminophylline is used concomitantly with the chronic dipyridamole therapy. (Major) Theophylline may cause false-negative results during dipyridamole-thallium 201 stress testing. Discontinue theophylline for at least 24 hours prior to this type of stress testing. Maintenance theophylline therapy and other xanthine derivatives may abolish the coronary vasodilatation induced by dipyridamole administration via antagonism of adenosine. No interaction of concern is expected when theophylline is used concomitantly with the chronic dipyridamole therapy.
    Atazanavir: (Moderate) Caution is warranted when atazanavir is administered with theophylline; aminophylline as there is a potential for elevated theophylline concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Theophylline is a substrate of CYP3A4; atazanavir is a CYP3A4 inhibitor.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when atazanavir is administered with theophylline; aminophylline as there is a potential for elevated theophylline concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Theophylline is a substrate of CYP3A4; atazanavir is a CYP3A4 inhibitor. (Moderate) Caution is warranted when cobicistat is administered with theophylline; aminophylline as there is a potential for elevated theophylline concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Theophylline is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Azelastine: (Minor) Coadministration of oral azelastine 4 mg twice daily and theophylline 300 mg or 400 mg twice daily did not result in a significant pharmacokinetic interaction.
    Azelastine; Fluticasone: (Minor) Coadministration of oral azelastine 4 mg twice daily and theophylline 300 mg or 400 mg twice daily did not result in a significant pharmacokinetic interaction.
    Barbiturates: (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline. (Moderate) The metabolism of theophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to theophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by theophylline.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Benzodiazepines: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines. (Moderate) Theophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of theophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If theophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Benzphetamine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Beta-agonists: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated. (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, (e.g., theophylline, aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Blinatumomab: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as aminophylline. The dose of the concomitant drug may need to be adjusted. (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as theophylline. The dose of the concomitant drug may need to be adjusted.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering theophylline, aminophylline with boceprevir due to an increased potential for theophylline-related adverse events. If theophylline dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of theophylline. Theophylline is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated theophylline plasma concentrations.
    Brodalumab: (Moderate) If brodalumab is initiated or discontinued in a patient taking aminophylline, monitor theophylline concentrations; aminophylline dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during brodalumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as aminophylline. (Moderate) If brodalumab is initiated or discontinued in a patient taking theophylline, monitor theophylline concentrations; theophylline dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during brodalumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as theophylline.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Brompheniramine; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Budesonide; Formoterol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as aminophylline. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, when bupropion is used for smoking cessation, it should be noted that cessation of smoking may result in elevated serum concentrations of some drugs that are hepatically metabolized, such as theophylline or aminophylline, due to lowered induction of hepatic oxidative microsomal enzymes (tobacco smoke induces hepatic enzymes). Downward dosage adjustments of such drugs and more frequent monitoring may be required during smoking cessation. (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as theophylline. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, when bupropion is used for smoking cessation, it should be noted that cessation of smoking may result in elevated serum concentrations of some drugs that are hepatically metabolized, such as theophylline or aminophylline, due to lowered induction of hepatic oxidative microsomal enzymes (tobacco smoke induces hepatic enzymes). Downward dosage adjustments of such drugs and more frequent monitoring may be required during smoking cessation.
    Bupropion; Naltrexone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as aminophylline. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, when bupropion is used for smoking cessation, it should be noted that cessation of smoking may result in elevated serum concentrations of some drugs that are hepatically metabolized, such as theophylline or aminophylline, due to lowered induction of hepatic oxidative microsomal enzymes (tobacco smoke induces hepatic enzymes). Downward dosage adjustments of such drugs and more frequent monitoring may be required during smoking cessation. (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as theophylline. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, when bupropion is used for smoking cessation, it should be noted that cessation of smoking may result in elevated serum concentrations of some drugs that are hepatically metabolized, such as theophylline or aminophylline, due to lowered induction of hepatic oxidative microsomal enzymes (tobacco smoke induces hepatic enzymes). Downward dosage adjustments of such drugs and more frequent monitoring may be required during smoking cessation.
    Butabarbital: (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Caffeine: (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophyllinemay produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. In neonates, theophylline is metabolized to caffeine; initiating caffeine after theophylline therapy is halted may result in caffeine toxicity in neonates if serum caffeine levels are not monitored prior to the initiation of caffeine therapy. Concurrent use of theophylline with caffeine in neonates is not recommended due to the potential for additive toxicity. (Moderate) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects.
    Caffeine; Ergotamine: (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. In neonates, theophylline is metabolized to caffeine; initiating caffeine after theophylline therapy is halted may result in caffeine toxicity in neonates if serum caffeine levels are not monitored prior to the initiation of caffeine therapy. Concurrent use of theophylline with caffeine in neonates is not recommended due to the potential for additive toxicity.
    Canakinumab: (Moderate) If canakinumab is initiated or discontinued in a patient taking aminophylline, monitor theophylline concentrations; aminophylline dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during canakinumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as aminophylline. (Moderate) If canakinumab is initiated or discontinued in a patient taking theophylline, monitor theophylline concentrations; theophylline dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during canakinumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as theophylline.
    Cannabidiol: (Moderate) Consider a dose adjustment of theophylline when coadministered with cannabidiol. Coadministration may alter plasma concentrations of theophylline resulting in an increased risk of adverse reactions and/or decreased efficacy. Theophylline is a substrate of CYP1A2; cannabidiol may inhibit and/or induce CYP1A2 at clinically relevant concentrations.
    Carbamazepine: (Major) Aminophylline is expected to decrease plasma concentrations of carbamazepine via 3A4 induction. Also, aminophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme. Carbamazepine can stimulate the hepatic metabolism of aminophylline if used concurrently. Aminophylline doses may need to be increased if carbamazepine is added. More importantly, serious aminophylline toxicity can result if carbamazepine is discontinued and the dose of aminophylline is not correspondingly decreased. (Major) Theophylline is expected to decrease plasma concentrations of carbamazepine via 3A4 induction. Theophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme. Carbamazepine can stimulate the hepatic metabolism of theophylline if used concurrently. Theophylline doses may need to be increased if carbamazepine is added. More importantly, serious theophylline toxicity can result if carbamazepine is discontinued and the dose of theophylline is not correspondingly decreased.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Carbetapentane; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Carbetapentane; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Carbinoxamine; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Carbinoxamine; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Ceritinib: (Major) Avoid the use of ceritinib, a time-dependent inhibitor of CYP3A4, with CYP3A4 substrates that have a narrow therapeutic index, such as theophylline, aminophylline as theophylline exposure may be increased. If co-administration is unavoidable, consider a theophylline dose reduction and monitor for theophylline toxicity.
    Cetirizine: (Minor) Large doses of aminophylline may reduce the clearance of cetirizine/levocetirizine. Monitor the patient clinically for an altered response to cetirizine/levocetirizine if coadministered with aminophylline. (Minor) Large doses of theophylline may reduce the clearance of cetirizine/levocetirizine. Monitor the patient clinically for increased cetirizine/levocetirizine-related adverse effects if coadministered with theophylline.
    Cetirizine; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible. (Minor) Large doses of aminophylline may reduce the clearance of cetirizine/levocetirizine. Monitor the patient clinically for an altered response to cetirizine/levocetirizine if coadministered with aminophylline. (Minor) Large doses of theophylline may reduce the clearance of cetirizine/levocetirizine. Monitor the patient clinically for increased cetirizine/levocetirizine-related adverse effects if coadministered with theophylline.
    Charcoal: (Major) Charcoal exerts a nonspecific effect, and many medications can be adsorbed by activated charcoal. When taken as a dietary supplement for flatulence or other purposes, activated charcoal will decrease the effectiveness of other regularly taken medications (e.g., theophylline, aminophylline) by reducing oral drug absorption. Activated charcoal (repeat dosing) is an important therapeutic adjunct in severe theophylline drug overdoses; repeat doses also increase the elimination of the drug. (Major) Note that charcoal exerts a nonspecific effect, and many medications can be adsorbed by activated charcoal. When taken as a dietary supplement for flatulence or other purposes, activated charcoal will decrease the effectiveness of other regularly taken medications (e.g., theophylline or aminophylline) by increasing drug clearance. Activated charcoal is an important therapeutic adjunct in theophylline drug overdoses, but otherwise should be avoided in non-emergent use.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Chlordiazepoxide: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Chlordiazepoxide; Clidinium: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Chlorpheniramine; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Cimetidine: (Major) Aminophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme. Cimetidine inhibits the CYP1A2 isoenzyme and not only reduces the hepatic metabolism of aminophylline, but a reduction in the renal clearance of theophylline may occur via competition for renal tubular secretion. However, the hepatic-based interaction is more significant. In patients receiving aminophylline, an alternative to cimetidine should be considered when possible. Alternatively, if concomitant therapy is necessary, patients should be monitored closely for increased effects of theophylline and the need for aminophylline dosage adjustments. The Beers criteria recommends that this drug combination be avoided in older adults. (Major) Theophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme. Cimetidine inhibits the CYP1A2 isoenzyme and not only reduces the hepatic metabolism of theophylline, but a reduction in the renal clearance of theophylline may occur via competition for renal tubular secretion. However, the hepatic-based interaction is more significant. In patients receiving theophylline, an alternative to cimetidine should be considered when possible. Alternatively, if concomitant therapy is necessary, patients should be monitored closely for increased effects of theophylline and the need for theophylline dosage adjustments.
    Ciprofloxacin: (Major) Avoid coadministration of ciprofloxacin and aminophylline due to the potential for increased and prolonged plasma exposure of theophylline. Monitor theophylline concentrations and adjust dosage as appropriate if concurrent administration cannot be avoided. Ciprofloxacin reduces the clearance of theophylline by 31%. Serious and fatal reactions have occurred in patients receiving concurrent ciprofloxacin and theophylline. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar serious adverse reactions have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be eliminated. Ciprofloxacin is CYP1A2 inhibitor, and theophylline is a substrate of CYP1A2. (Major) Avoid coadministration of ciprofloxacin and theophylline due to the potential for increased and prolonged plasma exposure of theophylline. Monitor theophylline concentrations and adjust dosage as appropriate if concurrent administration cannot be avoided. Ciprofloxacin reduces the clearance of theophylline by 31%. Serious and fatal reactions have occurred in patients receiving concurrent ciprofloxacin and theophylline. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar serious adverse reactions have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be eliminated. Ciprofloxacin is CYP1A2 inhibitor, and theophylline is a substrate of CYP1A2.
    Clarithromycin: (Major) Clarithromycin can inhibit aminophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. The labeling for aminophylline products states that aminophylline clearance may be decreased by up to 35% when clarithromycin is prescribed concurrently; these interactions can be clinically important. These interactions are particularly significant when aminophylline serum concentrations are already in the high therapeutic range (i.e., > 15 mcg/ml). If clarithromycin is used with aminophylline therapy, patients should be monitored for elevated theophylline levels and/or theophylline toxicity. Of the macrolides, azithromycin may be an alternative since it does not inhibit cytochrome P450 enzymes; no dosage adjustment of theophylline (or aminophylline) is required when azithromycin is coadministered. (Major) Clarithromycin can inhibit theophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. The labeling for theophylline products states that theophylline clearance may be decreased by up to 35% when clarithromycin is prescribed concurrently; these interactions can be clinically important. These interactions are particularly significant when theophylline serum concentrations are already in the high therapeutic range (i.e., > 15 mcg/ml). If clarithromycin is used with aminophylline or theophylline therapy, patients should be monitored for elevated theophylline levels and/or theophylline toxicity. Of the macrolides, azithromycin may be an alternative since it does not inhibit cytochrome P450 enzymes; no dosage adjustment of theophylline (or aminophylline) is required when azithromycin is coadministered.
    Clonazepam: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Clorazepate: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with theophylline; aminophylline as there is a potential for elevated theophylline concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Theophylline is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Colesevelam: (Moderate) Colesevelam may decrease the absorption of oral aminophylline. To minimize potential for interactions, consider administering oral aminophylline at least 1 hour before or at least 4 hours after colesevelam. (Moderate) Colesevelam may decrease the absorption of oral theophylline. To minimize potential for interactions, consider administering oral theophylline at least 1 hour before or at least 4 hours after colesevelam.
    Darunavir: (Moderate) Caution is warranted when darunavir is administered with theophylline; aminophylline as there is a potential for elevated theophylline concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Theophylline is a substrate of CYP3A4; darunavir is a CYP3A4 inhibitor.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with theophylline; aminophylline as there is a potential for elevated theophylline concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Theophylline is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor. (Moderate) Caution is warranted when darunavir is administered with theophylline; aminophylline as there is a potential for elevated theophylline concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Theophylline is a substrate of CYP3A4; darunavir is a CYP3A4 inhibitor.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with theophylline; aminophylline as there is a potential for elevated theophylline concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Theophylline is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor. (Moderate) Caution is warranted when darunavir is administered with theophylline; aminophylline as there is a potential for elevated theophylline concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Theophylline is a substrate of CYP3A4; darunavir is a CYP3A4 inhibitor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Ritonavir decreased theophylline AUC and Cmax by 43% and 52%, respectively, when the two drugs were coadministered. Higher dosages of aminophylline might be required. (Moderate) Ritonavir decreased theophylline AUC and Cmax by 43% and 52%, respectively, when the two drugs were coadministered. If these drugs are used together, therapeutic drug monitoring should be considered. Higher dosages of theophylline might be required.
    Desloratadine; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Dexmethylphenidate: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia.
    Dextroamphetamine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Diazepam: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and theophylline, aminophylline together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including theophylline, aminophylline. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Diethylpropion: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Diltiazem: (Moderate) Diltiazem may inhibit the cytochrome P-450 metabolism of aminophylline. Since the therapeutic range is narrow for aminophylline, it is prudent to monitor aminophylline serum concentrations during diltiazem therapy. (Moderate) Diltiazem may inhibit the cytochrome P-450 metabolism of theophylline. Since the therapeutic range is narrow for theophylline, it is prudent to monitor theophylline serum concentrations during diltiazem therapy.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Diphenhydramine; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Dipyridamole: (Major) Aminophylline may cause false-negative results during dipyridamole-thallium 201 stress testing. Discontinue aminophylline for at least 24 hours prior to this type of stress testing. Maintenance aminophylline therapy and other xanthine derivatives may abolish the coronary vasodilatation induced by dipyridamole administration via antagonism of adenosine. No interaction of concern is expected when aminophylline is used concomitantly with the chronic dipyridamole therapy. (Major) Theophylline may cause false-negative results during dipyridamole-thallium 201 stress testing. Discontinue theophylline for at least 24 hours prior to this type of stress testing. Maintenance theophylline therapy and other xanthine derivatives may abolish the coronary vasodilatation induced by dipyridamole administration via antagonism of adenosine. No interaction of concern is expected when theophylline is used concomitantly with the chronic dipyridamole therapy.
    Disulfiram: (Major) Aminophylline is a prodrug of theophylline. Disulfiram inhibits the hepatic hydroxylation and demethylation of theophylline, thereby increasing the serum levels of theophylline and increasing the risk for theophylline toxicity. Patients should be monitored for theophylline toxicity if disulfiram is added to aminophylline therapy. If aminophylline is added after disulfiram is begun and disulfiram is later discontinued, subtherapeutic theophylline serum concentrations can result. In addition, some preparations of aminophylline elixir may contain significant amounts of ethanol, which can cause reactions with disulfiram; read labels carefully. (Major) Disulfiram inhibits the hepatic hydroxylation and demethylation of theophylline, thereby increasing the serum levels of theophylline and increasing the risk for theophylline toxicity. Patients should be monitored for theophylline toxicity if disulfiram is added to theophylline therapy. If theophylline is added after disulfiram is begun and disulfiram is later discontinued, subtherapeutic theophylline serum concentrations can result. In addition, some preparations of theophylline elixir contain significant amounts of ethanol, which can cause reactions with disulfiram; read labels carefully.
    Dobutamine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Dopamine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Dronabinol: (Major) Use caution if coadministration of dronabinol with theophylline, aminophylline is necessary, and monitor for increased theophylline levels and theophylline-related adverse effects. Dronabinol is highly bound to plasma proteins, and may displace and increase the free fraction of other concomitantly administered protein-bound drugs; caution is recommended with other drugs with a narrow therapeutic index. Additionally, however, increased theophylline metabolism has been reported with smoking of marijuana; the interaction is similar in effect to that of smoking tobacco, which may substantially decrease theophylline serum concentrations. Because dronabinol, THC is a synthetic analog of a naturally occurring substance found in marijuana, this interaction may also theoretically occur with dronabinol. However, it is also probable that compounds produced via the smoking process (i.e., hydrocarbons) may be responsible for the reduced theophylline levels seen with marijuana smoking, as occurs with tobacco smoking; the smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Aminophylline is a substrate for CYP3A4, CYP1A2, and CYP2E1. Although the concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate, data from clinical studies indicate dronedarone does not increase the steady state aminophylline exposure. (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Theophylline is a substrate for CYP3A4, CYP1A2, and CYP2E1. Although the concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate, data from clinical studies indicate dronedarone does not increase the steady state theophylline exposure.
    Drospirenone; Ethinyl Estradiol: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Duloxetine: (Moderate) Close monitoring of theophylline levels is advisable during concurrent use of duloxetine and theophylline. Theophylline is a substrate for CYP1A2 and duloxetine is a CYP1A2 inhibitor. In two clinical studies, the average increase in the theophylline AUC was 7% (range: 1%-15%) and 20% (range: 13%-27%) when co-administered with duloxetine.
    Dupilumab: (Moderate) Coadministration of dupilumab may result in altered exposure to theophylline. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as theophylline. Monitor theophylline concentrations if dupilumab is initiated or discontinued in a patient taking theophylline; theophylline dose adjustments may be needed.
    Dyphylline: (Major) Dyphylline is a xanthine derivative and should not be administered with other methylxanthines (e.g., theophylline, aminophylline, and others) due to the duplicative nature of therapy and the potential increased risk for methylxanthine-related side effects such as nausea, irritability, or nervousness. Adverse effects such as diarrhea, tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of methylxanthine drugs are taken.
    Dyphylline; Guaifenesin: (Major) Dyphylline is a xanthine derivative and should not be administered with other methylxanthines (e.g., theophylline, aminophylline, and others) due to the duplicative nature of therapy and the potential increased risk for methylxanthine-related side effects such as nausea, irritability, or nervousness. Adverse effects such as diarrhea, tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of methylxanthine drugs are taken.
    Echinacea: (Moderate) Aminophylline is metabolized by both CYP1A2 and CYP3A4. Echinacea may inhibit CYP1A2, induce hepatic CYP3A4, and inhibit intestinal CYP3A4. The efficacy and safety of aminophylline if used in combination with echinacea are unknown. Monitor for changes in efficacy or toxicity if aminophylline is used in combination with echinacea, until more data are available. (Moderate) Theophylline is metabolized by both CYP1A2 and CYP3A4. Echinacea may inhibit CYP1A2, induce hepatic CYP3A4, and inhibit intestinal CYP3A4. The efficacy and safety of theophylline if used in combination with echinacea are unknown. Monitor for changes in efficacy or toxicity if theophylline is used in combination with echinacea, until more data are available.
    Elbasvir; Grazoprevir: (Moderate) Administering theophylline, aminophylline with elbasvir; grazoprevir may result in elevated theophylline plasma concentrations. Theophylline is a minor substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with theophylline; aminophylline as there is a potential for elevated theophylline concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Theophylline is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with theophylline; aminophylline as there is a potential for elevated theophylline concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Theophylline is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor.
    Emapalumab: (Moderate) Monitor for decreased efficacy of theophylline and adjust the dose as needed during coadministration with emapalumab. Theophylline is a CYP1A2 substrate with a narrow therapeutic index. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
    Enflurane: (Moderate) Aminophylline used concurrently with inhaled general anesthetics may increase the risk of cardiac arrhythmias. (Moderate) Theophylline used concurrently with inhaled general anesthetics may increase the risk of cardiac arrhythmias. When ketamine and theophylline are given concurrently a clinically significant reduction in the seizure threshold is observed.
    Ephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Epinephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Erythromycin: (Major) Erythromycin can inhibit aminophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. If erythromycin is used with aminophylline therapy, patients should be monitored for elevated theophylline levels and/or toxicity. (Major) Erythromycin can inhibit theophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. If erythromycin is used with theophylline therapy, patients should be monitored for elevated theophylline levels and/or theophylline toxicity.
    Erythromycin; Sulfisoxazole: (Major) Erythromycin can inhibit aminophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. If erythromycin is used with aminophylline therapy, patients should be monitored for elevated theophylline levels and/or toxicity. (Major) Erythromycin can inhibit theophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. If erythromycin is used with theophylline therapy, patients should be monitored for elevated theophylline levels and/or theophylline toxicity.
    Estazolam: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Ethinyl Estradiol: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Ethinyl Estradiol; Desogestrel: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Ethinyl Estradiol; Norethindrone: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Ethinyl Estradiol; Norgestimate: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Ethinyl Estradiol; Norgestrel: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations.
    Ethotoin: (Moderate) Theophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme, and also by the CYP3A4 isoenzyme. Medications that cause induction of hepatic CYP450 enzymes, such as phenytoin, ethotoin, or fosphenytoin, may increase the hepatic oxidative metabolism of theophylline or aminophylline. Theophylline doses may need to be increased if hydantoin anticonvulsants are added. More importantly, serious theophylline toxicity can result if any of these drugs are discontinued and the dose of theophylline is not correspondingly decreased. Also, theophylline may inhibit the oral absorption of phenytoin.
    Etomidate: (Moderate) Aminophylline used concurrently with inhaled general anesthetics may increase the risk of cardiac arrhythmias. (Moderate) Theophylline used concurrently with inhaled general anesthetics may increase the risk of cardiac arrhythmias. When ketamine and theophylline are given concurrently a clinically significant reduction in the seizure threshold is observed.
    Famotidine: (Minor) Aminophylline is a prodrug of theophylline, and is primarily metabolized in the liver by the CYP1A2 isoenzyme. In general, famotidine does not interact with aminophylline and does not affect theophylline levels in most patients. One small study documented a significant decrease in theophylline clearance after therapy with famotidine. Be alert for any evidence of interaction, and monitor the patients aminophylline therapy as per standard of care or if side effects are reported. (Minor) Theophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme. In general, famotidine does not interact with theophylline and does not affect theophylline levels in most patients. One small study documented a significant decrease in theophylline clearance after therapy with famotidine. Be alert for any evidence of interaction, and monitor the patients theophylline therapy as per standard of care or if side effects are reported.
    Famotidine; Ibuprofen: (Minor) Aminophylline is a prodrug of theophylline, and is primarily metabolized in the liver by the CYP1A2 isoenzyme. In general, famotidine does not interact with aminophylline and does not affect theophylline levels in most patients. One small study documented a significant decrease in theophylline clearance after therapy with famotidine. Be alert for any evidence of interaction, and monitor the patients aminophylline therapy as per standard of care or if side effects are reported. (Minor) Theophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme. In general, famotidine does not interact with theophylline and does not affect theophylline levels in most patients. One small study documented a significant decrease in theophylline clearance after therapy with famotidine. Be alert for any evidence of interaction, and monitor the patients theophylline therapy as per standard of care or if side effects are reported.
    Febuxostat: (Moderate) Use caution if febuxostat and aminophylline are used concurrently. Aminophylline is converted to the active form, theophylline, in the body. By inhibiting xanthine oxidase, febuxostat alters theophylline metabolism. Monitor theophylline concentrations. In a study conducted in healthy adults, coadministration of febuxostat (80 mg PO daily) resulted in increased theophylline Cmax (6%) and AUC (6.5%). These changes were not considered statistically significant. An approximately 400-fold increase in the amount of 1-methylxanthine (a major metabolite of theophylline) excreted in the urine was also noted. Since the long-term safety of exposure to 1-methylxanthine in humans is unknown, use with caution when coadministering febuxostat with aminophylline. (Moderate) Use caution if febuxostat and theophylline are used concurrently. By inhibiting xanthine oxidase, febuxostat alters theophylline metabolism. Monitor theophylline concentrations. In a study conducted in healthy adults, coadministration of febuxostat (80 mg PO daily) resulted in increased theophylline Cmax (6%) and AUC (6.5%). These changes were not considered statistically significant. An approximately 400-fold increase in the amount of 1-methylxanthine (a major metabolite of theophylline) excreted in the urine was also noted. Since the long-term safety of exposure to 1-methylxanthine in humans is unknown, use with caution when coadministering febuxostat with theophylline.
    Fexofenadine; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Fluconazole: (Moderate) Fluconazole may increase the serum concentrations of aminophylline. Serum aminophylline concentrations should be monitored closely if fluconazole is added. (Moderate) Fluconazole may increase the serum concentrations of theophylline. Serum theophylline concentrations should be monitored closely if fluconazole is added.
    Flurazepam: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Fluticasone; Salmeterol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Fluticasone; Vilanterol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Fluvoxamine: (Major) Fluvoxamine inhibits the activity of the hepatic isozyme CYP1A2. Aminophylline is metabolized by this enzyme. If aminophylline is co-administered with fluvoxamine, the aminophylline daily dosage should be reduced and plasma aminophylline concentrations should be monitored. Patients should report any increase in methylxanthine-induced side effects, like tremor, nausea, or vomiting promptly. (Major) Fluvoxamine inhibits the activity of the hepatic isozyme CYP1A2. Theophylline is metabolized by this enzyme. If theophylline is co-administered with fluvoxamine, the theophylline daily dosage should be reduced and plasma theophylline concentrations should be monitored. Patients should report any increase in methylxanthine-induced side effects, like tremor, nausea, or vomiting promptly.
    Formoterol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Formoterol; Mometasone: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Fosphenytoin: (Moderate) Theophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme, and also by the CYP3A4 isoenzyme. Medications that cause induction of hepatic CYP450 enzymes, such as phenytoin, ethotoin, or fosphenytoin, may increase the hepatic oxidative metabolism of theophylline or aminophylline. Theophylline doses may need to be increased if hydantoin anticonvulsants are added. More importantly, serious theophylline toxicity can result if any of these drugs are discontinued and the dose of theophylline is not correspondingly decreased. Also, theophylline may inhibit the oral absorption of phenytoin.
    Glycerol Phenylbutyrate: (Moderate) Concomitant use of glycerol phenylbutyrate and theophylline may result in decreased exposure of theophylline. Theophylline is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of theophylline during coadministration.
    Glycopyrrolate; Formoterol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Golimumab: (Moderate) If golimumab is initiated or discontinued in a patient taking aminophylline, monitor the theophylline concentration; aminophylline dose adjustment may be needed. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF-alpha) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during golimumab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as aminophylline. (Moderate) If golimumab is initiated or discontinued in a patient taking theophylline, monitor the theophylline concentration; theophylline dose adjustment may be needed. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF-alpha) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during golimumab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as theophylline.
    Green Tea: (Major) Some green tea products contain caffeine. Concurrent administration of aminophylline with caffeine can produce excessive CNS stimulation such as nervousness, irritability, tremors, or insomnia. Caffeine-like side effects, such as headache and nausea, may also increase. Seizures or cardiac arrhythmias are also possible. It is recommended that dietary caffeine consumption be controlled during aminophylline administration and minimized if possible. Decreased elimination of both caffeine and theophylline may explain some of these reactions; decreased elimination has been demonstrated in healthy men on theophylline consuming dietary caffeine. Caffeine concentrations increased by 158% and the clearance of theophylline decreased by 23%. (Major) Some green tea products contain caffeine. Concurrent administration of theophylline with caffeine can produce excessive CNS stimulation such as nervousness, irritability, tremors, or insomnia. Caffeine-like side effects, such as headache and nausea, may also increase. Seizures or cardiac arrhythmias are also possible. Decreased elimination of both caffeine and theophylline may explain some of these reactions; decreased elimination has been demonstrated in healthy men on theophylline consuming dietary caffeine. Caffeine concentrations increased by 158% and the clearance of theophylline decreased by 23%. It is recommended that dietary caffeine consumption be controlled during aminophylline administration and minimized if possible.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Guaifenesin; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Guaifenesin; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Guarana: (Major) Caffeine and, to a small extent, theophylline are active constituents of guarana. The concurrent administration of guarana to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of guarana are taken concurrently with theophylline. Patients taking theophylline should avoid medications or dietary supplements containing guarana. Patients may also need to limit their intake of guarana-containing beverages to avoid caffeine-like side effects.
    Halothane: (Severe) Use of halothane in a patient taking aminophylline is not recommended due to an increased risk of ventricular arrhythmias. Halothane sensitizes the myocardial conduction system to catecholamines, and aminophylline increases the release of endogenous catecholamines. (Severe) Use of halothane in a patient taking theophylline is not recommended due to an increased risk of ventricular arrhythmias. Halothane sensitizes the myocardial conduction system to catecholamines, and theophylline increases the release of endogenous catecholamines.
    Hydantoins: (Moderate) Theophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme, and also by the CYP3A4 isoenzyme. Medications that cause induction of hepatic CYP450 enzymes, such as phenytoin, ethotoin, or fosphenytoin, may increase the hepatic oxidative metabolism of theophylline or aminophylline. Theophylline doses may need to be increased if hydantoin anticonvulsants are added. More importantly, serious theophylline toxicity can result if any of these drugs are discontinued and the dose of theophylline is not correspondingly decreased. Also, theophylline may inhibit the oral absorption of phenytoin.
    Hydrochlorothiazide, HCTZ; Propranolol: (Major) Propranolol may significantly decrease aminophylline clearance by inhibiting CYP1A2. In some patients, theophylline levels can increase up to 100%. On average, co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%. If aminophylline is being initiated in a patient who is already taking a drug that inhibits its clearance, the dose required to achieve a therapeutic serum theophylline concentration will be smaller. Patients should be closely monitored for toxicity. Serum theophylline concentrations should be monitored. Because propranolol is non-selective, the beta-2 blocking activity may reduce the effectiveness of aminophylline and other treatments for asthma or COPD. Discontinuation of a concomitant drug that inhibits aminophylline clearance will result in decreased serum theophylline concentrations, unless the aminophylline dose is appropriately increased. (Major) Propranolol may significantly decrease theophylline clearance by inhibiting CYP1A2. In some patients, theophylline levels can increase up to 100%. On average, co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%. If theophylline is being initiated in a patient who is already taking a drug that inhibits its clearance, the dose of theophylline required to achieve a therapeutic theophylline concentration will be smaller. Patients should be closely monitored for toxicity. Serum theophylline concentrations should be monitored. Because propranolol is non-selective, the beta-2 blocking activity may reduce the effectiveness of theophylline and other treatments for asthma or COPD. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased theophylline concentrations, unless the theophylline dose is appropriately increased.
    Hydrocodone; Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Hydrocodone; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Hydroxyprogesterone: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP1A2 isoenzymes. The metabolism of drugs metabolized by CYP1A2, such as theophylline, aminophylline may be increased during treatment with hydroxyprogesterone.
    Ibuprofen; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with theophylline, aminophylline, a CYP3A substrate, as theophylline, aminophylline toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Imipenem; Cilastatin: (Moderate) Generalized seizures have occurred in patients who were receiving imipenem-cilastatin concomitantly with aminophylline. The mechanism of this interaction is not known. Patients should be monitored for signs of CNS toxicity during coadministration. (Moderate) Generalized seizures have occurred in patients who were receiving imipenem-cilastatin concomitantly with theophylline. The mechanism of this interaction is not known. Patients should be monitored for signs of CNS toxicity during coadministration.
    Indacaterol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Indacaterol; Glycopyrrolate: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Infliximab: (Moderate) The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF-alpha) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during infliximab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as theophylline. If infliximab is initiated or discontinued in a patient taking theophylline, monitor the theophylline concentration; theophylline dose adjustment may be needed.
    Interferon Alfa-2a: (Major) Alpha interferons, when administered systemically, may decrease the clearance of aminophylline resulting in increased plasma concentrations. Concomitant use may result in a significant increase in theophylline concentrations due to reduced aminophylline clearance. In studies, increases in theophylline levels of 25% up to 100% have occurred. Reductions in CYP1A2 activity have been noted with various alpha interferons, and likely provide a mechanism for the interaction. Monitor theophylline concentrations and for signs and symptoms of toxicity when interferons are used concomitantly; consider appropriate dose adjustments as clinically indicated.
    Interferon Alfa-2b: (Major) Alpha interferons, when administered systemically, may decrease the clearance of aminophylline resulting in increased plasma concentrations. Concomitant use may result in a significant increase in theophylline concentrations due to reduced aminophylline clearance. In studies, increases in theophylline levels of 25% up to 100% have occurred. Reductions in CYP1A2 activity have been noted with various alpha interferons, and likely provide a mechanism for the interaction. Monitor theophylline concentrations and for signs and symptoms of toxicity when interferons are used concomitantly; consider appropriate dose adjustments as clinically indicated.
    Interferon Alfa-2b; Ribavirin: (Major) Alpha interferons, when administered systemically, may decrease the clearance of aminophylline resulting in increased plasma concentrations. Concomitant use may result in a significant increase in theophylline concentrations due to reduced aminophylline clearance. In studies, increases in theophylline levels of 25% up to 100% have occurred. Reductions in CYP1A2 activity have been noted with various alpha interferons, and likely provide a mechanism for the interaction. Monitor theophylline concentrations and for signs and symptoms of toxicity when interferons are used concomitantly; consider appropriate dose adjustments as clinically indicated.
    Interferon Alfacon-1: (Major) Alpha interferons, when administered systemically, may decrease the clearance of aminophylline resulting in increased plasma concentrations. Concomitant use may result in a significant increase in theophylline concentrations due to reduced aminophylline clearance. In studies, increases in theophylline levels of 25% up to 100% have occurred. Reductions in CYP1A2 activity have been noted with various alpha interferons, and likely provide a mechanism for the interaction. Monitor theophylline concentrations and for signs and symptoms of toxicity when interferons are used concomitantly; consider appropriate dose adjustments as clinically indicated.
    Interferon Alfa-n3: (Major) Alpha interferons, when administered systemically, may decrease the clearance of aminophylline resulting in increased plasma concentrations. Concomitant use may result in a significant increase in theophylline concentrations due to reduced aminophylline clearance. In studies, increases in theophylline levels of 25% up to 100% have occurred. Reductions in CYP1A2 activity have been noted with various alpha interferons, and likely provide a mechanism for the interaction. Monitor theophylline concentrations and for signs and symptoms of toxicity when interferons are used concomitantly; consider appropriate dose adjustments as clinically indicated.
    Interferon Gamma-1b: (Major) Interferons, when administered systemically, may decrease the clearance of aminophylline resulting in increased plasma levels. Until additional information is available,interferons should be used cautiously in patients receiving aminophylline. Monitor theophylline concentrations and for signs and symptoms of toxicity. (Major) Interferons, when administered systemically, may decrease the clearance of theophylline resulting in increased plasma levels. Until additional information is available,interferons should be used cautiously in patients receiving theophylline. Monitor theophylline concentrations and for signs and symptoms of toxicity.
    Iopamidol: (Major) Use of medications that lower the seizure threshold, such as aminophylline, should be carefully evaluated when considering intrathecal iopamidol. Some physicians discontinue these drugs at least 48 hours before and for at least 24 hours after intrathecal use. (Major) Use of medications that lower the seizure threshold, such as theophylline, should be carefully evaluated when considering intrathecal iopamidol. Some physicians discontinue these drugs at least 48 hours before and for at least 24 hours after intrathecal use.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with theophylline, aminophylline may result in increased serum concentrations of theophylline. Theophylline and aminophylline are substrates of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoflurane: (Moderate) Aminophylline used concurrently with inhaled general anesthetics may increase the risk of cardiac arrhythmias. (Moderate) Theophylline used concurrently with inhaled general anesthetics may increase the risk of cardiac arrhythmias. When ketamine and theophylline are given concurrently a clinically significant reduction in the seizure threshold is observed.
    Isoniazid, INH: (Minor) Isoniazid, INH may reduce aminophylline clearance. Although data regarding this drug interaction are conflicting, it appears that this can be explained by the duration of isoniazid administration. Larger doses of isoniazid and longer duration of isoniazid administration are more likely to affect aminophylline pharmacokinetics. At least one patient developed aminophylline toxicity as a result of this interaction with isoniazid. (Minor) Isoniazid, INH may reduce theophylline clearance. Although data regarding this drug interaction are conflicting, it appears that this can be explained by the duration of isoniazid administration. Larger doses of isoniazid and longer duration of isoniazid administration are more likely to affect theophylline pharmacokinetics. At least one patient developed theophylline toxicity as a result of this interaction with isoniazid.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of aminophylline. Dosages of aminophylline may need to be adjusted while the patient is receiving rifampin. (Major) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of theophylline. Dosages of theophylline may need to be adjusted while the patient is receiving rifampin. (Minor) Isoniazid, INH may reduce aminophylline clearance. Although data regarding this drug interaction are conflicting, it appears that this can be explained by the duration of isoniazid administration. Larger doses of isoniazid and longer duration of isoniazid administration are more likely to affect aminophylline pharmacokinetics. At least one patient developed aminophylline toxicity as a result of this interaction with isoniazid. (Minor) Isoniazid, INH may reduce theophylline clearance. Although data regarding this drug interaction are conflicting, it appears that this can be explained by the duration of isoniazid administration. Larger doses of isoniazid and longer duration of isoniazid administration are more likely to affect theophylline pharmacokinetics. At least one patient developed theophylline toxicity as a result of this interaction with isoniazid.
    Isoniazid, INH; Rifampin: (Major) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of aminophylline. Dosages of aminophylline may need to be adjusted while the patient is receiving rifampin. (Major) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of theophylline. Dosages of theophylline may need to be adjusted while the patient is receiving rifampin. (Minor) Isoniazid, INH may reduce aminophylline clearance. Although data regarding this drug interaction are conflicting, it appears that this can be explained by the duration of isoniazid administration. Larger doses of isoniazid and longer duration of isoniazid administration are more likely to affect aminophylline pharmacokinetics. At least one patient developed aminophylline toxicity as a result of this interaction with isoniazid. (Minor) Isoniazid, INH may reduce theophylline clearance. Although data regarding this drug interaction are conflicting, it appears that this can be explained by the duration of isoniazid administration. Larger doses of isoniazid and longer duration of isoniazid administration are more likely to affect theophylline pharmacokinetics. At least one patient developed theophylline toxicity as a result of this interaction with isoniazid.
    Isoproterenol: (Major) Although beta2-agonists are commonly used with theophylline, the combination of isoproterenol and theophylline could potentially increase cardiac adverse reactions such as cardiac arrhythmias. In addition, isoproterenol infusions have been shown to increase the clearance of theophylline by 20 to 40%. If isoproterenol and theophylline are used together, theophylline serum concentrations should be closely monitored. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia.
    Ixekizumab: (Moderate) If ixekizumab is initiated or discontinued in a patient taking aminophylline, monitor theophylline concentrations; aminophylline dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during ixekizumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as aminophylline. (Moderate) If ixekizumab is initiated or discontinued in a patient taking theophylline, monitor theophylline concentrations; theophylline dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during ixekizumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as theophylline.
    Ketamine: (Moderate) Theophylline used concurrently with inhaled general anesthetics may increase the risk of cardiac arrhythmias. When ketamine and theophylline are given concurrently a clinically significant reduction in the seizure threshold is observed. (Moderate) When ketamine and theophylline are given concurrently a clinically significant reduction in the seizure threshold is observed. This combination may also increase the risk of cardiac arrhythmias.
    Ketoconazole: (Minor) Ketoconazole has been reported to decrease theophylline serum concentrations when theophylline was administered orally as sustained-release tablets, however, no interaction was noted when theophylline was administered IV. Since ketoconazole is well-known to inhibit the hepatic metabolism of many drugs and theophylline concentrations would be expected to increase, it is suspected that ketoconazole may have interfered with oral bioavailability of theophylline. As these results are based on a single case report, additional clinical data are necessary.
    Lansoprazole: (Minor) Concomitant use of theophylline, a CYP1A2 and CYP3A substrate, and lansoprazole has led to a small increase in theophylline clearance. Aminophylline may require dosage adjustment when therapy with lansoprazole is initiated or discontinued. (Minor) Concomitant use of theophylline, a CYP1A2 and CYP3A substrate, and lansoprazole has led to a small increase in theophylline clearance. Theophylline may require dosage adjustment when therapy with lansoprazole is initiated or discontinued.
    Lansoprazole; Naproxen: (Minor) Concomitant use of theophylline, a CYP1A2 and CYP3A substrate, and lansoprazole has led to a small increase in theophylline clearance. Aminophylline may require dosage adjustment when therapy with lansoprazole is initiated or discontinued. (Minor) Concomitant use of theophylline, a CYP1A2 and CYP3A substrate, and lansoprazole has led to a small increase in theophylline clearance. Theophylline may require dosage adjustment when therapy with lansoprazole is initiated or discontinued.
    Leflunomide: (Moderate) Closely monitor for reduced efficacy of theophylline if coadministered with leflunomide. An adjustment of the theophylline dose may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as theophylline, may decrease theophylline exposure and lead to a reduction in efficacy.
    Lesinurad; Allopurinol: (Minor) Allopurinol in large doses can decrease aminophylline clearance. It appears that the significance of this drug interaction depends on the dose of allopurinol. (Minor) Allopurinol in large doses can decrease theophylline clearance. It appears that the significance of this drug interaction depends on the dose of allopurinol.
    Letermovir: (Moderate) An increase in the plasma concentration of theophylline may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Theophylline is partially metabolized by CYP3A3. Letermovir is a moderate CYP3A inhibitor; however, when given with cyclosporine, the combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor. In drug interaction studies, concurrent administration with other moderate CYP3A inhibitors resulted in increased theophylline effect ranging from 25% to 35%.
    Levalbuterol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Levocetirizine: (Minor) Large doses of aminophylline may reduce the clearance of cetirizine/levocetirizine. Monitor the patient clinically for an altered response to cetirizine/levocetirizine if coadministered with aminophylline. (Minor) Large doses of theophylline may reduce the clearance of cetirizine/levocetirizine. Monitor the patient clinically for increased cetirizine/levocetirizine-related adverse effects if coadministered with theophylline.
    Levothyroxine: (Minor) Correction of hypothyroidism to the euthyroid state may precipitate certain drug interactions. For example, hypothyroidism causes decreased clearance of theophylline, which returns to normal in the euthyroid state. Aminophylline is converted to theophylline in the body. Aminophylline dosage adjustments may be needed with thyroid hormone replacement.
    Levothyroxine; Liothyronine (Porcine): (Minor) Correction of hypothyroidism to the euthyroid state may precipitate certain drug interactions. For example, hypothyroidism causes decreased clearance of theophylline, which returns to normal in the euthyroid state. Aminophylline is converted to theophylline in the body. Aminophylline dosage adjustments may be needed with thyroid hormone replacement.
    Levothyroxine; Liothyronine (Synthetic): (Minor) Correction of hypothyroidism to the euthyroid state may precipitate certain drug interactions. For example, hypothyroidism causes decreased clearance of theophylline, which returns to normal in the euthyroid state. Aminophylline is converted to theophylline in the body. Aminophylline dosage adjustments may be needed with thyroid hormone replacement.
    Liothyronine: (Minor) Correction of hypothyroidism to the euthyroid state may precipitate certain drug interactions. For example, hypothyroidism causes decreased clearance of theophylline, which returns to normal in the euthyroid state. Aminophylline is converted to theophylline in the body. Aminophylline dosage adjustments may be needed with thyroid hormone replacement.
    Lisdexamfetamine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Lithium: (Major) Theophylline; aminophylline can significantly increase the urinary excretion of lithium; therefore, close monitoring is recommended during concurrent use. Dosage adjustments may be necessary, particularly during initiation of theophylline therapy or following changes in theophylline dosage. It should be noted that theophylline and aminophylline have been used to treat lithium toxicity. (Moderate) Aminophylline can increase renal clearance of lithium, reducing its therapeutic effectiveness. Clinicians should be alert to loss of lithium therapeutic effectiveness if aminophylline is added.
    Lopinavir; Ritonavir: (Moderate) Ritonavir decreased theophylline AUC and Cmax by 43% and 52%, respectively, when the two drugs were coadministered. Higher dosages of aminophylline might be required. (Moderate) Ritonavir decreased theophylline AUC and Cmax by 43% and 52%, respectively, when the two drugs were coadministered. If these drugs are used together, therapeutic drug monitoring should be considered. Higher dosages of theophylline might be required.
    Loratadine; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Lorazepam: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Lumacaftor; Ivacaftor: (Major) Concomitant use of theophylline and lumacaftor; ivacaftor is not recommended. Lumacaftor; ivacaftor may decrease the systemic exposure of theophylline, a narrow therapeutic index drug. The clinical significance of this interaction is unclear. Lumacaftor; ivacaftor is a potent CYP3A inducer. Theophylline is primarily metabolized by CYP1A2, with secondary pathways by CYP3A and CYP2E1. In vitro data suggests metabolism by CYP3A is minor. However, since the therapeutic range of theophylline is narrow, if concurrent use cannot be avoided, monitor theophylline serum concentrations closely and adjust the dose accordingly.
    Mephobarbital: (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Mepivacaine; Levonordefrin: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia.
    Mestranol; Norethindrone: (Moderate) Serum concentrations of aminophylline may be increased during concurrent administration with mestranol. The resulting increased half-life and decreased clearance may necessitate a decrease in aminophylline dosage. (Moderate) Serum concentrations of theophylline or caffeine may be increased during concurrent administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. The resulting increased half-life and decreased clearance may necessitate a decrease in theophylline dosage. This may occur with mestranol.
    Metaproterenol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Methamphetamine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Methohexital: (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Methotrexate: (Moderate) Methotrexate may decrease the clearance of aminophylline. Aminophylline levels should be closely monitored when used concurrently with methotrexate. In a small number of patients with either leukemia or lymphoma and acute methotrexate neurotoxicity, theophylline attenuated methotrexate-induced neurotoxicity, a syndrome believed due to elevated adenosine CNS concentrations. (Moderate) Methotrexate may decrease the clearance of theophylline. Theophylline levels should be closely monitored when used concurrently with methotrexate. In a small number of patients with either leukemia or lymphoma and acute methotrexate neurotoxicity, theophylline attenuated methotrexate-induced neurotoxicity, a syndrome believed due to elevated adenosine CNS concentrations.
    Methylphenidate: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia.
    Metreleptin: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving theophylline, drug concentration monitoring should be performed and the theophylline dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as theophylline.
    Mexiletine: (Moderate) Mexiletine has been shown to decrease theophylline clearance, increase theophylline concentrations, and produce theophylline toxicity. Lower doses of theophylline should be used in patients receiving mexiletine or when mexiletine is added.
    Midazolam: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Midodrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Mitotane: (Major) Use caution if mitotane and theophylline, aminophylline are used concomitantly, and monitor for decreased efficacy of theophylline and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and theophylline is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of theophylline. When administered with other moderate to strong CYP3A inducers, average steady-state theophylline concentrations decreased by 25 to 40%.
    Modafinil: (Moderate) Modafinil induces induces CYP3A4 and has the potential to induce other hepatic microsomal enzymes such as CYP1A2. The drug may induce the metabolism of some narrow-therapeutic index medications. Theophylline is primarily metabolized by CYP1A2 isoenzymes, with secondary pathways by CYP2E1 and CYP3A4 (minor). Patients on theophylline or aminophylline may need to be monitored for reduced methylxanthine efficacy when modafinil is added to therapy. In some cases, monitoring of theophylline concentrations may be helpful. When modafinil is discontinued, monitor the patient for potential increases in theophylline concentrations. (Moderate) Modafinil induces induces CYP3A4 and has the potential to induce other hepatic microsomal enzymes such as CYP1A2. The drug may induce the metabolism of some narrow-therapeutic index medications. Theophylline is primarily metabolized by CYP1A2 isoenzymes, with secondary pathways by CYP2E1 and CYP3A4 (minor). Patients on theophylline or aminophylline may need to be monitored for reduced methylxanthine efficacy when modafinil is added to therapy. In some cases, monitoring of theophylline concentrations may be helpful.. When modafinil is discontinued, monitor the patient for potential increases in theophylline concentrations.
    Moricizine: (Moderate) Moricizine can enhance the hepatic metabolism of aminophylline. Moricizine has been shown to reduce theophylline AUC and half-life. Moricizine may decrease the effectiveness of aminophylline. (Moderate) Moricizine can enhance the hepatic metabolism of theophylline. Moricizine has been shown to reduce theophylline AUC and half-life. Moricizine may decrease the effectiveness of theophylline.
    Mycophenolate: (Minor) Mycophenolic acid is highly protein bound. Administration of mycophenolate mofetil decreases the protein binding of aminophylline. Monitor patients receiving mycophenolate with highly protein bound drugs, such as aminophylline for changes in clinical status. (Minor) Mycophenolic acid is highly protein bound. Administration of mycophenolate mofetil decreases the protein binding of theophylline. Monitor patients receiving mycophenolate with highly protein bound drugs, such as theophylline for changes in clinical status.
    Nabilone: (Minor) Increased theophylline metabolism has been reported with smoking of marijuana. This interaction may also occur with nabilone which is a synthetic analog of a naturally occurring substance found in marijuana. (Minor) Increased theophylline metabolism has been reported with smoking of marijuana. This interaction may also occur with nabilone which is a synthetic analog of a naturally occurring substance found in marijuana.
    Naproxen; Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Nilutamide: (Moderate) Nilutamide inhibits the activity of hepatic cytochrome P450 isoenzymes and may reduce the metabolism of drugs metabolized by these enzymes including aminophylline. (Moderate) Nilutamide inhibits the activity of hepatic cytochrome P450 isoenzymes and may reduce the metabolism of drugs metabolized by these enzymes including theophylline.
    Norepinephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as theophylline, aminophylline. Since the therapeutic range is narrow, it is prudent to monitor theophylline serum concentrations upon initiation, dosage adjustment, or discontinuation of medications that may alter the function of CYP1A2.
    Olodaterol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Ritonavir decreased theophylline AUC and Cmax by 43% and 52%, respectively, when the two drugs were coadministered. Higher dosages of aminophylline might be required. (Moderate) Ritonavir decreased theophylline AUC and Cmax by 43% and 52%, respectively, when the two drugs were coadministered. If these drugs are used together, therapeutic drug monitoring should be considered. Higher dosages of theophylline might be required.
    Oritavancin: (Moderate) Avoid oritavancin with drugs that have a narrow therapeutic window, such as aminophylline. Aminophylline is a derivative of theophylline. Theophylline metabolism by CYP3A4 is minor and independent of theophylline plasma concentration; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of aminophylline may be reduced if these drugs are administered concurrently. Monitor for lack of aminophylline efficacy. (Moderate) Avoid oritavancin with drugs that have a narrow therapeutic window, such as theophylline. Theophylline metabolism by CYP3A4 is minor and independent of theophylline plasma concentration; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of theophylline may be reduced if these drugs are administered concurrently. Monitor for lack of theophylline efficacy.
    Oxazepam: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Paroxetine: (Major) Paroxetine has been reported to cause elevations of theophylline serum concentrations. Monitor aminophylline serum concentrations when paroxetine is given concurrently with aminophylline. Observe patients for signs or symptoms of aminophylline toxicity. (Major) Paroxetine has been reported to cause elevations of theophylline serum concentrations. The interaction has not been formally studied. It is recommended that theophylline serum concentrations be monitored when paroxetine is given concurrently with theophylline or aminophylline. Observe patients for signs or symptoms of theophylline toxicity.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and theophylline, aminophylline, a CYP3A4 substrate, may cause an increase in systemic concentrations of theophylline, aminophylline. Use caution when administering these drugs concomitantly.
    Peginterferon Alfa-2a: (Major) Alpha interferons, when administered systemically, may decrease the clearance of aminophylline resulting in increased plasma concentrations. Concomitant use may result in a significant increase in theophylline concentrations due to reduced aminophylline clearance. In studies, increases in theophylline levels of 25% up to 100% have occurred. Reductions in CYP1A2 activity have been noted with various alpha interferons, and likely provide a mechanism for the interaction. Monitor theophylline concentrations and for signs and symptoms of toxicity when interferons are used concomitantly; consider appropriate dose adjustments as clinically indicated.
    Peginterferon Alfa-2b: (Major) Alpha interferons, when administered systemically, may decrease the clearance of aminophylline resulting in increased plasma concentrations. Concomitant use may result in a significant increase in theophylline concentrations due to reduced aminophylline clearance. In studies, increases in theophylline levels of 25% up to 100% have occurred. Reductions in CYP1A2 activity have been noted with various alpha interferons, and likely provide a mechanism for the interaction. Monitor theophylline concentrations and for signs and symptoms of toxicity when interferons are used concomitantly; consider appropriate dose adjustments as clinically indicated.
    Pemoline: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia.
    Pentobarbital: (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Pentoxifylline: (Moderate) Aminophylline serum concentrations may be increased when pentoxifylline is coadministered. Patients should be monitored for aminophylline toxicity if pentoxifylline is added. (Moderate) Theophylline serum concentrations may be increased when pentoxifylline is coadministered. Patients should be monitored for theophylline toxicity if pentoxifylline is added.
    Phendimetrazine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Phenobarbital: (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Phentermine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Phentermine; Topiramate: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Phenylephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Phenylephrine; Promethazine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Phenytoin: (Moderate) Theophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme, and also by the CYP3A4 isoenzyme. Medications that cause induction of hepatic CYP450 enzymes, such as phenytoin, ethotoin, or fosphenytoin, may increase the hepatic oxidative metabolism of theophylline or aminophylline. Theophylline doses may need to be increased if hydantoin anticonvulsants are added. More importantly, serious theophylline toxicity can result if any of these drugs are discontinued and the dose of theophylline is not correspondingly decreased. Also, theophylline may inhibit the oral absorption of phenytoin.
    Pirbuterol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Posaconazole: (Major) Posaconazole and theophylline, aminophylline should be coadministered with caution due to an increased potential for theophylline-, aminophylline-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of theophylline, aminophylline. These drugs used in combination may result in elevated theophylline, aminophylline plasma concentrations, causing an increased risk for theophylline-, aminophylline-related adverse events.
    Prednisone: (Minor) Serum theophylline concentrations have been reported to be lower during concomitant administration of prednisone, but the actual magnitude of the interaction was slight.
    Prilocaine; Epinephrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Primidone: (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Propafenone: (Moderate) Although limited data are available, it appears that propafenone may affect theophylline clearance. In several patients, theophylline concentrations increased after the addition of propafenone and in at least one patient, symptoms of theophylline toxicity were suspected. Until more data are available, lower doses of theophylline should be considered in patients receiving propafenone.
    Propofol: (Moderate) Aminophylline used concurrently with inhaled general anesthetics may increase the risk of cardiac arrhythmias. (Moderate) Theophylline used concurrently with inhaled general anesthetics may increase the risk of cardiac arrhythmias. When ketamine and theophylline are given concurrently a clinically significant reduction in the seizure threshold is observed.
    Propranolol: (Major) Propranolol may significantly decrease aminophylline clearance by inhibiting CYP1A2. In some patients, theophylline levels can increase up to 100%. On average, co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%. If aminophylline is being initiated in a patient who is already taking a drug that inhibits its clearance, the dose required to achieve a therapeutic serum theophylline concentration will be smaller. Patients should be closely monitored for toxicity. Serum theophylline concentrations should be monitored. Because propranolol is non-selective, the beta-2 blocking activity may reduce the effectiveness of aminophylline and other treatments for asthma or COPD. Discontinuation of a concomitant drug that inhibits aminophylline clearance will result in decreased serum theophylline concentrations, unless the aminophylline dose is appropriately increased. (Major) Propranolol may significantly decrease theophylline clearance by inhibiting CYP1A2. In some patients, theophylline levels can increase up to 100%. On average, co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%. If theophylline is being initiated in a patient who is already taking a drug that inhibits its clearance, the dose of theophylline required to achieve a therapeutic theophylline concentration will be smaller. Patients should be closely monitored for toxicity. Serum theophylline concentrations should be monitored. Because propranolol is non-selective, the beta-2 blocking activity may reduce the effectiveness of theophylline and other treatments for asthma or COPD. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased theophylline concentrations, unless the theophylline dose is appropriately increased.
    Pseudoephedrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Quazepam: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Quinine: (Major) The coadministration of theophylline, aminophylline with quinine may increase the Cmax and AUC of quinine and decrease the AUC of theophylline, aminophylline. This interaction may be due to the potential induction of the CYP1A2 isoenzyme by quinine as the CYP1A2 isoenzyme is the primary route of metabolism for theophylline, aminophylline. Coadministration does not require any dosage changes; however, side effects of quinine should be monitored and plasma concentrations of theophylline should be frequently monitored to ensure therapeutic concentrations.
    Rabeprazole: (Minor) Rabeprazole is metabolized by cytochrome P450 enzymes in the liver. Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with some drugs metabolized by the CYP450 system, such as theophylline (CYP1A2 substrate) given as a single oral dose. However, it may be prudent to monitor patients taking aminophylline or theophylline products and rabeprazole concurrently, since theophylline has a narrow therapeutic window.
    Racepinephrine: (Major) Concurrent administration of theophylline or aminophylline with racepinephrine inhalations is not advised. If a patient is taking prescribed medications containing theophylline, aminophylline, then they should seek health care professional advice prior to the use of racepinephrine. Additive adverse effects on the cardiovascular and nervous system are possible, some which may be undesirable. Side effects such as nausea, tremor, nervousness, difficulty with sleep, and increased heart rate may be additive. Consider alternatives to racepinephrine for the treatment of asthma. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia.
    Regadenoson: (Major) Methylxanthines, such as theophylline or aminophylline, are non-specific adenosine receptor antagonists and may interfere with the vasodilation activity of adenosine receptor agonists, such as regadenoson. Patients should avoid any drugs containing theophylline, aminophylline for at least 12 hours before regadenoson administration. Methylxanthines attenuate the duration, but not the peak increase of coronary blood flow produced by regadenoson; aminophylline may be used to attenuate severe or persistent adverse reactions of regadenoson. Aminophylline injected 1 minute after regadenoson in subjects undergoing cardiac catheterization was shown to shorten the duration of the coronary blood flow response as measured by pulsed-wave Doppler ultrasonography. In addition, theophylline, aminophylline may increase the risk of seizures associated with regadenoson; avoid methylxanthine use in patients who have experienced a regadenoson-associated seizure.
    Rifampin: (Major) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of aminophylline. Dosages of aminophylline may need to be adjusted while the patient is receiving rifampin. (Major) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of theophylline. Dosages of theophylline may need to be adjusted while the patient is receiving rifampin.
    Rifapentine: (Major) Rifapentine induces hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, such as aminophylline, may require dosage adjustments when administered concurrently with rifapentine. (Major) Rifapentine induces hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, such as theophylline, may require dosage adjustments when administered concurrently with rifapentine.
    Riociguat: (Severe) Coadministration of riociguat and phosphodiesterase inhibitors, including nonspecific phosphodiesterase inhibitors (e.g., theophylline, aminophylline) is contraindicated due to the risk of hypotension.
    Ritodrine: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Ritonavir: (Moderate) Ritonavir decreased theophylline AUC and Cmax by 43% and 52%, respectively, when the two drugs were coadministered. Higher dosages of aminophylline might be required. (Moderate) Ritonavir decreased theophylline AUC and Cmax by 43% and 52%, respectively, when the two drugs were coadministered. If these drugs are used together, therapeutic drug monitoring should be considered. Higher dosages of theophylline might be required.
    Rofecoxib: (Major) Rofecoxib may increase the AUC and half-life of theophylline, while decreasing the oral clearance of theophyline. Adequate monitoring of theophylline levels should be considered when therapy with rofecoxib is initiated or changed in patients receiving theophylline.
    Roflumilast: (Major) Drug interaction studies were performed with roflumilast and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. No significant drug interactions were observed when 500 mcg oral roflumilast was administered with theophylline, aminophylline. While a pharmacokinetic interaction did not occur, patients were prohibited from taking theophylline in roflumilast clinical trials. Current guidelines in the management of patients with COPD do not recommend co-use of theophylline or aminophylline with roflumilast, presumably due to a pharmacodynamic effect (additive actions on cyclic AMP) and the potential for similar side effect profiles (e.g., diarrhea, weight loss, appetite changes, nausea, headache). (Major) Drug interaction studies were performed with roflumilast and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. No significant drug interactions were observed when 500 mcg oral roflumilast was administered with theophylline, aminophylline. While a pharmacokinetic interaction did not occur, patients were prohibited from taking theophylline in roflumilast clinical trials. Current guidelines in the management of patients with COPD do not recommend the routine co-use of theophylline or aminophylline with roflumilast, presumably due to a pharmacodynamic effect (additive actions on cyclic AMP) and the potential for similar side effect profiles (e.g., diarrhea, weight loss, appetite changes, nausea, headache).
    Ropivacaine: (Minor) Agents that are also metabolized by cytochrome P450 1A2, such as aminophylline, may decrease the metabolism of ropivacaine through competitive inhibition. (Minor) Agents that are also metabolized by cytochrome P450 1A2, such as theophylline, may decrease the metabolism of ropivacaine through competitive inhibition.
    Rucaparib: (Moderate) Monitor theophylline levels and watch for an increase in theophylline-related adverse reactions if coadministration with rucaparib is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and rucaparib is a moderate CYP1A2 inhibitor. (Minor) Monitor theophylline levels and watch for an increase in theophylline-related adverse reactions if coadministration with rucaparib is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and rucaparib is a moderate CYP1A2 inhibitor.
    Salmeterol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Sarilumab: (Moderate) In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP3A4. A 45% decrease in simvastatin exposure was noted 1 week after a single sarilumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using sarilumab with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable such as theophylline.
    Secobarbital: (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Secukinumab: (Moderate) If secukinumab is initiated or discontinued in a patient taking aminophylline, monitor theophylline concentrations; aminophylline dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during secukinumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as aminophylline. (Moderate) If secukinumab is initiated or discontinued in a patient taking theophylline, monitor theophylline concentrations; theophylline dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during secukinumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as theophylline.
    Sevelamer: (Moderate) Although drug interaction studies have not been conducted, it may be prudent to separate the timing of administration of oral theophylline from sevelamer. According to the manufacturer of sevelamer, clinicians should consider separating the timing of administration of sevelamer and drugs where a reduction in the bioavailability of would have a clinically significant effect on its safety or efficacy. The duration of separation should be based on the absorption characteristics of the coadministered drug. Because theophylline; aminophylline has a narrow therapeutic index, consider monitoring clinical response and serum concentrations during concurrent use of sevelamer.
    Sevoflurane: (Moderate) Aminophylline used concurrently with inhaled general anesthetics may increase the risk of cardiac arrhythmias. (Moderate) Theophylline used concurrently with inhaled general anesthetics may increase the risk of cardiac arrhythmias. When ketamine and theophylline are given concurrently a clinically significant reduction in the seizure threshold is observed. A similar interaction may occur with other general anesthetics.
    Siltuximab: (Moderate) Use siltuximab and theophylline together with caution; monitor theophylline levels and adjust the dose of theophylline as necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as theophylline, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. (Moderate) When siltuximab is initiated or discontinued in patients being treated with CYP450 substrates with a narrow therapeutic index, such as theophylline, aminophylline, monitor appropriately for effect and drug concentrations as necessary. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Simeprevir: (Moderate) Theophylline, aminophylline is primarily metabolized by CYP1A2 isoenzymes. Since the therapeutic range is narrow for theophylline, it is prudent to monitor theophylline serum concentrations upon initiation, dosage adjustment, or discontinuation of medications that may alter the function of CYP1A2, such as simeprevir, which is a mild CYP1A2 inhibitor.
    Sincalide: (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by concurrent aminophylline. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of procedure results. (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by concurrent theophylline. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of procedure results.
    St. John's Wort, Hypericum perforatum: (Major) St. John's wort induces the metabolism o aminophylline and a decrease in theophylline plasma concentrations may occur. Higher doses of aminophylline may be required to achieve the desired effect. Discontinuation of St. John's Wort in a patient on aminophylline may result in theophylline toxicity. Close monitoring of drug concentrations and clinical status of the patient is recommended. Iinteractions with St. John's wort have been reported. St. John's wort appears to increase the metabolism of aminophylline through induction of the hepatic CYP1A2 isoenzyme. (Moderate) Higher doses of theophylline may be required to achieve the desired effect during coadministration of St. John's Wort. Monitor theophylline concentrations and clinical status of patient closely. St. John's Wort induces the metabolism of theophylline through induction of the hepatic CYP1A2 isoenzyme and a decrease in theophylline plasma concentrations may occur. Discontinuation of St. John's Wort in a patient on theophylline may result in theophylline toxicity.
    Sucralfate: (Major) Sucralfate, because it contains aluminum in its structure and due to its mechanism of action, can bind with certain drugs in the GI tract, including aminophylline, reducing its bioavailability. Sucralfate should be given 2 hours before or after the oral administration of aminophylline. (Major) Sucralfate, because it contains aluminum in its structure and due to its mechanism of action, can bind with certain drugs in the GI tract, including theophylline, reducing its bioavailability. Sucralfate should be given 2 hours before or after the oral administration of theophylline.
    Sulfinpyrazone: (Moderate) The results of one small study indicate that the plasma clearance of theophylline is increased by 22% when administered with sulfinpyrazone. This exact mechanism for this interaction has not been determined.
    Sympathomimetics: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia.
    Tacrine: (Major) Aminophylline, like theophylline, is primarily metabolized in the liver by the CYP1A2 isoenzyme. Tacrine significantly decreases theophylline clearance, apparently by inhibiting CYP1A2. Coadministration of tacrine increased theophylline elimination half-life and average plasma theophylline concentrations by approximately 2-fold. Anticipating the interaction and reducing the aminophylline dose before tacrine initiation can help limit the risk of toxicity. If both medications are initiated concurrently or if theophylline is being initiated in a patient receiving tacrine, the initial dosage of aminophylline may need to be reduced by 25% to 50% to avoid toxicity. Close monitoring of theophylline levels is required during concomitant therapy with tacrine. Aminophylline dose reduction may be necessary. (Major) Theophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme. Tacrine significantly decreases theophylline clearance, apparently by inhibiting CYP1A2. Coadministration of tacrine with theophylline increased theophylline elimination half-life and average plasma theophylline concentrations by approximately 2-fold. Anticipating the interaction and reducing the theophylline dose before tacrine initiation can help limit the risk of toxicity. If both medications are initiated concurrently or if theophylline is being initiated in a patient receiving tacrine, the initial dosage of theophylline may need to be reduced by 25% to 50% to avoid toxicity. Close monitoring of theophylline levels is required during concomitant therapy with tacrine. Theophylline dose may be necessary.
    Tacrolimus: (Moderate) Addition of aminophylline to tacrolimus therapy may result in increased concentrations of tacrolimus. Monitor serum tacrolimus and creatinine concentrations and renal function in patents who are stabilized on tacrolimus if aminophylline is added. (Moderate) Addition of theophylline to tacrolimus therapy may result in increased concentrations of tacrolimus. Closely monitor serum tacrolimus concentrations, serum creatinine concentrations, and renal function in patents who are stabilized on tacrolimus if theophylline is added, changed or discontinued.
    Teduglutide: (Moderate) Teduglutide may increase the oral absorption of theophylline because of teduglutide's effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of theophylline or aminophylline is recommended.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering theophylline, aminophylline with telaprevir due to an increased potential for theophylline-related adverse events. If theophylline dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of theophylline. Theophylline is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated theophylline plasma concentrations.
    Telithromycin: (Moderate) Telithromycin can increase the AUC and Cmax of aminophylline, which is converted to theophylline. When theophylline was given with repeated doses of telithromycin, there was an increase of approximately 16% and 17% in the steady-state Cmax and AUC of theophylline. Additionally, coadministration may worsen gastrointestinal (GI) adverse effects such as nausea and vomiting, especially in female patients. It is recommended that telithromycin and oral aminophylline be taken 1 hour apart to decrease the likelihood of GI adverse effects. (Moderate) Telithromycin can increase the AUC and Cmax of theophylline. When theophylline was given with repeated doses of telithromycin, there was an increase of approximately 16% and 17% in the steady-state Cmax and AUC of theophylline. Additionally, coadministration may worsen gastrointestinal (GI) adverse effects such as nausea and vomiting, especially in female patients. It is recommended that telithromycin and oral theophylline be taken 1 hour apart to decrease the likelihood of GI adverse effects.
    Telotristat Ethyl: (Major) Use caution if coadministration of telotristat ethyl and theophylline is necessary, as the systemic exposure of theophylline may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of theophylline; consider increasing the dose of theophylline if necessary. Theophylline is primarily metabolized by CYP1A2, and is a minor CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temazepam: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Terbinafine: (Minor) Oral terbinafine is reported to decrease theophylline clearance by 14%. It is unknown if this interaction would be clinically significant. Patients who receive aminophylline concurrently with terbinafine should be monitored for increased or decreased effects of these narrow therapeutic window drugs. (Minor) Oral terbinafine is reported to decrease theophylline clearance by 14%. It is unknown if this interaction would be clinically significant. Patients who receive theophylline or aminophylline concurrently with terbinafine should be monitored for increased or decreased effects of these narrow therapeutic window drugs.
    Terbutaline: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Teriflunomide: (Moderate) Use caution when administering teriflunomide and theophylline; aminophylline concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as theophylline; aminophylline, may decrease theophylline exposure and lead to a reduction in efficacy.
    Thiabendazole: (Major) Thiabendazole is a potent inhibitor of CYP1A2 hepatic enzymes. Thiabendazole can interfere with the CYP1A2 metabolism of xanthine derivatives, such as theophylline, aminophylline, reducing clearance by up to 50%. Toxic serum concentrations of theophylline can result; use together with close medical supervision of the patient. Monitoring of theophylline concentrations and reduction of the theophylline or aminophylline dosage may be necessary during concomitant treatment.
    Thiopental: (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline.
    Thyroid hormones: (Minor) Correction of hypothyroidism to the euthyroid state may precipitate certain drug interactions. For example, hypothyroidism causes decreased clearance of theophylline, which returns to normal in the euthyroid state. Aminophylline is converted to theophylline in the body. Aminophylline dosage adjustments may be needed with thyroid hormone replacement. (Minor) Correction of hypothyroidism to the euthyroid state may precipitate certain drug interactions. For example, hypothyroidism causes decreased clearance of theophylline, which returns to normal in the euthyroid state. Theophylline dosage adjustments may be needed with thyroid hormone replacement.
    Ticlopidine: (Major) Aminophylline clearance may be significantly reduced when ticlopidine is administered concomitantly. Aminophylline serum concentrations should be monitored when ticlopidine is added or withdrawn. (Major) Coadministration of theophylline and ticlopidine can result in increased theophylline exposure and risk for toxicity. Theophylline half-life increased from 8.6 hours to 12.2 hours in healthy volunteers when ticlopidine was added. Monitor serum theophylline concentrations and signs of theophylline toxicity and efficiacy when ticlopidine is added to or withdrawn from a medication regimen containing theophylline.
    Tiotropium; Olodaterol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Tobacco: (Major) Tobacco smoking results in an increased clearance of theophylline that is clinically significant. The sudden cessation of tobacco smoking may result in a reduced clearance of theophylline, despite the initiation of a nicotine replacement product. Theophylline serum concentrations should be monitored carefully when changes in smoking status occur. No interaction is expected to directly occur from the use of nicotine replacement products with theophylline or aminophylline.
    Tocilizumab: (Moderate) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP3A4. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable such as theophylline.
    Trandolapril; Verapamil: (Moderate) Verapamil has been reported to decrease theophylline clearance. The mechanism is most likely reduced cytochrome P-450 metabolism of theophylline. Since the therapeutic range is narrow for theophylline, monitor theophylline serum concentrations during verapamil therapy. (Moderate) Verapamil may decrease aminophylline clearance due to reduced cytochrome P-450 metabolism of aminophylline. Since the therapeutic range is narrow for aminophylline, monitor serum concentrations during verapamil therapy.
    Triazolam: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
    Umeclidinium; Vilanterol: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Vemurafenib: (Major) Coadministration of vemurafenib and caffeine increased the caffeine AUC by 2.6-fold. Vemurafenib is a CYP1A2 inhibitor and caffeine is a CYP1A2 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP1A2 is not recommended. Theophylline (or aminophylline), another methylxanthine, is also primarily a CYP1A2 substrate with a narrow therapeutic index. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug; it may also be prudent to monitor for signs and symptoms of theophylline toxicity during coadministration. Some patients may need to reduce intake of caffeine from non-drug sources (e.g., beverages) during treatment to avoid caffeine-related side effects.
    Verapamil: (Moderate) Verapamil has been reported to decrease theophylline clearance. The mechanism is most likely reduced cytochrome P-450 metabolism of theophylline. Since the therapeutic range is narrow for theophylline, monitor theophylline serum concentrations during verapamil therapy. (Moderate) Verapamil may decrease aminophylline clearance due to reduced cytochrome P-450 metabolism of aminophylline. Since the therapeutic range is narrow for aminophylline, monitor serum concentrations during verapamil therapy.
    Zafirlukast: (Moderate) Increased theophylline levels with clinical signs and symptoms of toxicity after the addition of zafirlukast to an existing theophylline regimen have been reported. Monitor for signs and symptoms of toxicity, as well as serum aminophylline levels, when zafirlukast is used in combination with aminophylline. (Moderate) Increased theophylline levels with clinical signs and symptoms of toxicity after the addition of zafirlukast to an existing theophylline regimen have been reported. Monitor for signs and symptoms of toxicity, as well as serum theophylline levels, when zafirlukast is used in combination with theophylline.
    Zileuton: (Major) Concurrent use of zileuton and theophylline results in an approximate doubling of theophylline serum concentrations and increased frequency of theophylline-related adverse effects. Aminophylline is a salt form of theophylline. It has been recommended to reduce the theophylline dose by approximately 50% and monitor theophylline plasma concentrations when zileuton is prescribed to an existing regimen; a similar strategy may be employed with aminophylline. When initiating therapy with aminophylline in a patient receiving zileuton, adjust the maintenance dose and/or dosing interval of aminophylline based on serum theophylline concentrations. Theophylline is primarily metabolized by CYP1A2, with secondary pathways by CYP2E1 and CYP3A4; zileuton is a CYP1A2 inhibitor. (Major) Concurrent use of zileuton and theophylline results in an approximate doubling of theophylline serum concentrations and increased frequency of theophylline-related adverse effects. Reduce the theophylline dose by approximately 50% and monitor theophylline plasma concentrations when zileuton is prescribed to an existing regimen. When initiating therapy with theophylline in a patient receiving zileuton, adjust the maintenance dose and/or dosing interval of theophylline based on serum theophylline concentrations. Theophylline is primarily metabolized by CYP1A2, with secondary pathways by CYP2E1 and CYP3A4; zileuton is a CYP1A2 inhibitor.

    PREGNANCY AND LACTATION

    Pregnancy

    Theophylline is classified as a FDA pregnancy risk category C drug. Theophylline has not been proven to be teratogenic in humans, but use during pregnancy may lead to potentially dangerous serum theophylline and caffeine concentrations in neonates, as well as tachycardia, irritability, and other symptoms of theophylline toxicity. Decreased theophylline clearance has been reported during the third trimester of pregnancy. Despite these precautions, theophylline is considered an alternative therapy to inhaled corticosteroids for mild persistent asthma during pregnancy according to the 2004 guidelines of the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group. If used, it is recommended that serum theophylline concentrations be regularly monitored and maintained between 5—12 mcg/mL. It should be noted that inhaled corticosteroids are the preferred treatment due to the potential toxicities of theophylline, including side effects and drug interactions. However, maintaining a previously established treatment regimen may be more beneficial to the patient. Therefore, selection of any pharmacologic treatment for asthma control during pregnancy should include the specific needs of the patient, based on an individual evaluation, and consideration of the potential benefits or risks to the fetus.

    Theophylline is excreted in breast milk in concentrations similar to the serum concentration of the mother. Neonates whose mothers have been taking theophylline during pregnancy or while breast-feeding should be monitored carefully. Breast fed infants whose mothers are taking theophylline may experience irritability or other mild signs of toxicity; however, serious adverse events are unlikely unless the mother has toxic serum concentrations. Theophylline is considered an alternative therapy to inhaled corticosteroids for mild persistent asthma during pregnancy and lactation according to the 2004 guidelines of the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group. If used, it is recommended that serum theophylline concentrations be regularly monitored and maintained between 5—12 mcg/mL. The American Academy of Pediatrics considers theophylline to be usually compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Despite decades of research, the mechanism of action for theophylline is still being debated. While its bronchoprotective effects are most well-known, theophylline appears to also possess antiinflammatory and immunomodulatory actions. Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels. In patients with asthma, theophylline reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. The ability of theophylline to control chronic asthma, however, is disproportionately greater than is explainable by its relatively weak bronchodilatory action. Theophylline may even possess antiinflammatory actions as evidenced by its ability to attenuate late-phase reactions in asthma.Regarding its biochemical action, originally, it was believed that theophylline exerted its effects via the inhibition of type III or type IV phosphodiesterase (PDE) which is responsible for breaking down cyclic AMP in smooth muscle cells. While theophylline does possess this property, it is negligible at therapeutic serum concentrations and there is no evidence that intracellular concentrations of theophylline in airway smooth muscle cells are higher than serum concentrations. Drugs that exert greater inhibition of PDE than theophylline (e.g., dipyridamole, papaverine) have no bronchodilator effect.Other explanations theophylline's action have been proposed including changes in smooth muscle calcium ion concentration, inhibition of histamine release and adenosine antagonism. Adenosine antagonism has been considered as an explanation for theophylline's bronchodilating effects. Supporting this theory are the facts that adenosine and theophylline are structurally similar, adenosine can provoke bronchoconstriction in asthmatic patients, and adenosine can antagonize theophylline-induced bronchodilation. In addition, theophylline can antagonize adenosine's actions in other tissues. However, controversy surrounds this explanation also. Contradicting the theory that theophylline bronchodilation is mediated by adenosine antagonism is the fact that enprofylline, another xanthine that is five times as potent a bronchodilator as theophylline, does not antagonize adenosine. Thus, clinicians do not believe adenosine antagonism explains the bronchoprotective actions of theophylline.Actions of theophylline other than bronchodilation, particularly those that are excitatory, may indeed be a function of adenosine antagonism, however. Since adenosine is a CNS depressant, antagonism of adenosine may explain theophylline's stimulant action on the medullary respiratory center, increasing the sensitivity to carbon dioxide. Further support of adenosine antagonism as an explanation for the extrapulmonary actions of theophylline was demonstrated by theophylline's ability to attenuate methotrexate-induced neurotoxicity, a syndrome believed due to elevated adenosine CNS concentrations. As a bronchodilator, theophylline's cellular mechanism of action is still uncertain.Theophylline relaxes other types of smooth muscle but can stimulate cardiac and skeletal muscle contraction. Increased cardiac output can lead to diuresis, but tolerance may develop to this effect. Other extrapulmonary effects attributed to theophylline include CNS stimulation, improved diaphragmatic contractility, and prostaglandin inhibition. A central mechanism appears to be responsible for theophylline's ability to reduce central sleep apnea in patients with heart failure.

    PHARMACOKINETICS

    Theophylline can be administered orally or intravenously. When rapid attainment of therapeutic serum concentrations is desired, IV "loading" doses can be given, although oral administration with regular-release tablets is equally effective. Unbound theophylline serum concentrations are usually in the range of 6—12 mcg/ml and concentrations should be obtained in patients with low protein binding (i.e., neonates, hepatic cirrhosis). Steady state serum concentrations are reached in 30—65 hours in adults. Aminophylline, a salt of theophylline, is the form frequently used for IV therapy. Since 100 mg of aminophylline is equivalent to 80 mg of theophylline, errors in dosing are possible, and clinicians should carefully assess dose adjustments and calculations when switching between aminophylline dose forms and theophylline dose forms.
     
    Protein binding is approximately 40% for healthy adults and is lower in neonates and patients with hepatic impairment. Target peak serum concentration ranges for neonates for the treatment of apnea are therefore lower than those of adults, due to a greater proportion of free "active" theophylline. Unbound theophylline is distributed throughout extracellular body fluids and tissues, however, distribution into body fat is poor. Theophylline readily crosses the placenta and the blood-brain barrier and is excreted into breast milk.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  CYP1A2, CYP2E1, CYP3A4
    Theophylline is primarily metabolized by CYP1A2 isoenzymes, with secondary pathways by CYP2E1 and CYP3A4. In vitro data suggest that while metabolism is mediated by CYP1A2 at low plasma concentrations, metabolism shifts to CYP2E1 at higher concentrations, and metabolism by CYP3A4 is minor, independent of theophylline plasma concentration. The manufacturer states that theophylline is a substrate of hepatic enzymes CYP1A2, 2E1, and 3A3 without mention of 3A4 ; however, cytochrome P450 genome experts no longer support the existence of CYP3A3 and instead attribute this isoform to a coding error of or a variant of CYP3A4. Since the therapeutic range is narrow, it is prudent to monitor theophylline serum concentrations upon initiation, dosage adjustment, or discontinuation of medications that may alter the function of CYP1A2, CYP2E1, and/or CYP3A4 isoforms.
     
    In the premature neonate, theophylline is metabolized to caffeine in significant amounts, and this compound can accumulate due to its long half-life. Elimination is usually a first-order process, but zero-order elimination has been reported in some cases. Theophyllines' half-life varies with patient age, hepatic function, smoking status, and drug interactions. Nonsmoking adults usually have a half-life of 6.5—10.5 hours. Metabolites are eliminated renally, with only about 10% excreted as unchanged theophylline.

    Oral Route

    Theophylline is generally well absorbed after oral administration. Regular (i.e., nonsustained-release) tablets produce peak serum concentrations within 60 minutes after administration. Liquids and suspensions are absorbed more rapidly. Sustained-release preparations vary in the rate of absorption. Food can delay the rate, but not the extent, of absorption of some sustained-release products. Large volumes of fluid can increase absorption.
     
    Peak concentrations should usually occur 1—2 hours after oral dosing. Serum concentrations of 10—20 mcg/ml (55—110 micromoles/L) generally are regarded as therapeutic, however, the FDA has now lowered the target peak concentration range to 10—15 mcg/ml to minimize the risk of adverse reactions. Most clinicians use 8—15 mcg/ml as the target range.