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theophylline, anhydrous
Classes
Respiratory Stimulants
Xanthines, Plain
Administration
For storage information, see the specific product information within the the How Supplied section.
Oral AdministrationFor 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.
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.
Elixir, solution, syrup: Administer theophylline using a calibrated measuring device to ensure accurate dosing.
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 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.
Adverse Reactions
exfoliative dermatitis / Delayed / 0-1.0
anaphylactoid reactions / Rapid / 0-1.0
hematemesis / Delayed / Incidence not known
seizures / Delayed / Incidence not known
ventricular tachycardia / Early / Incidence not known
cardiac arrest / Early / Incidence not known
atrial tachycardia / Early / Incidence not known
atrial fibrillation / Early / Incidence not known
atrial flutter / Early / Incidence not known
rhabdomyolysis / Delayed / Incidence not known
contact dermatitis / Delayed / 0-1.0
hypercalcemia / Delayed / Incidence not known
premature ventricular contractions (PVCs) / Early / Incidence not known
hypotension / Rapid / Incidence not known
palpitations / Early / Incidence not known
metabolic acidosis / Delayed / Incidence not known
supraventricular tachycardia (SVT) / Early / Incidence not known
sinus tachycardia / Rapid / Incidence not known
hypokalemia / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known
rash / Early / 0-1.0
urticaria / Rapid / 0-1.0
pruritus / Rapid / 0-1.0
nausea / Early / 10.0
vomiting / Early / 10.0
headache / Early / 10.0
insomnia / Early / 10.0
gastroesophageal reflux / Delayed / Incidence not known
anorexia / 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
hyperactivity / Early / Incidence not known
irritability / Delayed / Incidence not known
tremor / Early / Incidence not known
restlessness / Early / Incidence not known
diuresis / Early / Incidence not known
vitamin B6 deficiency / Delayed / Incidence not known
Common Brand Names
Elixophyllin, Quibron T/SR, Theo X, Theo-24, Theo-Dur, Theochron, Theolair SR, Uni-Dur, Uniphyl
Dea Class
Rx
Description
Oral and intravenous methylxanthine
Used primarily for maintenance treatment of COPD or asthma but is not a preferred agent in either disease; also used in apnea of prematurity not responding to other therapies
Aminophylline is converted to theophylline systemically; 1 mg aminophylline = 0.8 mg theophylline
Dosage And Indications
Guidelines generally recommend against the routine use of aminophylline or theophylline in the treatment of asthma exacerbations or COPD exacerbations for most patients.
Continuous Intravenous Infusion 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.
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.
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.
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. Asthma 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.
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. Asthma 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.
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. Asthma 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.
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. Asthma 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.
Guidelines generally recommend against the routine use of aminophylline or theophylline in the treatment of asthma for most patients. Not a preferred treatment, but may be used adjunctively in selected patients. Generally not recommended in the management of COPD due to increased side effect profiles.
Oral dosage (immediate-release; dosage is expressed as theophylline) Adults 60 years and older
300 mg/day PO divided every 6 to 8 hours, initially. After 3 days, increase the dose to 400 mg/day. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations. Max: 400 mg/day unless serum concentration and condition indicate need for higher dose. Consider smaller, more frequent doses of immediate-release products or use of extended-release products in persons with rapid metabolism, identified by higher than average dose requirements. Asthma guidelines recommend 10 mg/kg/day (Max: 300 mg/day) PO initially, with titration to theophylline serum concentration of 5 to 15 mcg/mL. Methylxanthines are not recommended in the management of COPD due to increased side effect profiles.
300 mg/day PO divided every 6 to 8 hours, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 800 mg/day. Do not exceed 400 mg/day in persons 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 persons with rapid metabolism, identified by higher than average dose requirements. Theophylline is not a preferred treatment per asthma guidelines. Methylxanthines are not recommended in the management of COPD due to increased side effect profiles.
300 mg/day PO divided every 6 to 8 hours, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 800 mg/day. Do not exceed 400 mg/day in persons 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 persons with rapid metabolism, identified by higher than average dose requirements. Theophylline is not a preferred treatment per asthma guidelines.
300 mg/day PO divided every 6 to 8 hours, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 800 mg/day. Do not exceed 400 mg/day in persons 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 persons with rapid metabolism, identified by higher than average dose requirements. Theophylline is not a preferred treatment per asthma guidelines.
12 to 14 mg/kg/day (Max: 300 mg/day) PO divided every 4 to 6 hours, initially. After 3 days, increase the dose to 16 mg/kg/day (Max: 400 mg/day) and then 20 mg/kg/day (Max: 600 mg/day) if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations. Usual Max: 800 mg/day. Do not exceed 16 mg/kg/day (Max: 400 mg/day) in persons with risk factors for decreased theophylline clearance or who cannot receive recommended serum concentration monitoring. Theophylline is not a preferred treatment per asthma guidelines.
300 mg/day PO divided every 6 to 8 hours, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 16 mg/kg/day. Do not exceed 400 mg/day in persons 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 persons with rapid metabolism, identified by higher than average dose requirements. Theophylline is not a preferred treatment per asthma guidelines.
12 to 14 mg/kg/day (Max: 300 mg/day) PO divided every 4 to 6 hours, initially. After 3 days, increase the dose to 16 mg/kg/day (Max: 400 mg/day) and then 20 mg/kg/day (Max: 600 mg/day) if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations. Usual Max: 16 mg/kg/day. Do not exceed 16 mg/kg/day (Max: 400 mg/day) in persons with risk factors for decreased theophylline clearance or who cannot receive recommended serum concentration monitoring. Theophylline is not a preferred treatment per asthma guidelines.
10 mg/kg/day PO divided every 6 hours, initially. Alternately, 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 based on serum theophylline concentrations. Reduced doses may be needed for infants with risk factors for reduced theophylline clearance (e.g., cardiac or liver dysfunction, renal dysfunction). Theophylline is not a preferred treatment per asthma guidelines.
10 mg/kg/day PO divided every 8 hours, initially. Alternately, 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 based on serum theophylline concentrations. Reduced doses may be needed for infants with risk factors for reduced theophylline clearance (e.g., cardiac or liver dysfunction, renal dysfunction). Theophylline is not a preferred treatment per asthma guidelines.
10 mg/kg/day PO divided every 8 hours, initially. Alternately, 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 based on serum theophylline concentrations. Consider increased monitoring and dose reductions in neonates with renal impairment. Theophylline is not a preferred treatment per asthma guidelines.
300 mg/day PO divided every 8 to 12 hours, initially. After 3 days, increase the dose to 400 mg/day. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations. Max: 400 mg/day unless serum concentration and condition indicate need for higher dose. Consider smaller, more frequent doses in persons with rapid metabolism, identified by higher than average dose requirements. Extended-release products are not to be used to treat acute symptoms. Asthma guidelines recommend 10 mg/kg/day (Max: 300 mg/day) PO initially, with titration to theophylline serum concentration of 5 to 15 mcg/mL. Methylxanthines are not recommended in the management of COPD due to increased side effect profiles.
300 mg/day PO divided every 8 to 12 hours, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 800 mg/day. Do not exceed 400 mg/day in persons with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider smaller, more frequent doses in persons with rapid metabolism, identified by higher than average dose requirements. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines. Methylxanthines are not recommended in the management of COPD due to increased side effect profiles.
300 mg/day PO divided every 8 to 12 hours, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 800 mg/day. Do not exceed 400 mg/day in persons with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider smaller, more frequent doses in persons with rapid metabolism, identified by higher than average dose requirements. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.
300 mg/day PO divided every 8 to 12 hours, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 800 mg/day. Do not exceed 400 mg/day in persons with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider smaller, more frequent doses in persons with rapid metabolism, identified by higher than average dose requirements. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.
12 to 14 mg/kg/day (Max: 300 mg/day) PO divided every 8 to 12 hours, initially. After 3 days, increase the dose to 16 mg/kg/day (Max: 400 mg/day) and then 20 mg/kg/day (Max: 600 mg/day) if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations. Usual Max: 800 mg/day. Do not exceed 16 mg/kg/day (Max: 400 mg/day) in persons with risk factors for decreased theophylline clearance or who cannot receive recommended serum concentration monitoring. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.
300 mg/day PO divided every 8 to 12 hours, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 16 mg/kg/day. Do not exceed 400 mg/day in persons with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider smaller, more frequent doses in persons with rapid metabolism, identified by higher than average dose requirements. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.
12 to 14 mg/kg/day (Max: 300 mg/day) PO divided every 8 to 12 hours, initially. After 3 days, increase the dose to 16 mg/kg/day (Max: 400 mg/day) and then 20 mg/kg/day (Max: 600 mg/day) if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations. Usual Max: 16 mg/kg/day. Do not exceed 16 mg/kg/day (Max: 400 mg/day) in persons with risk factors for decreased theophylline clearance or who cannot receive recommended serum concentration monitoring. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.
300 to 400 mg PO once daily, initially. After 3 days, increase the dose to 400 mg/day. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations. Max: 400 mg/day unless serum concentration and condition indicate need for higher dose. Consider twice daily dosing in persons with rapid metabolism and who repeatedly have symptoms at the end of a 24-hour dosing interval. Extended-release products are not to be used to treat acute symptoms. Asthma guidelines recommend 10 mg/kg/day (Max: 300 mg/day) PO initially, with titration to theophylline serum concentration of 5 to 15 mcg/mL. Methylxanthines are not recommended in the management of COPD due to increased side effect profiles.
300 to 400 mg PO once daily, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 800 mg/day. Do not exceed 400 mg/day in persons with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider twice daily dosing in persons with rapid metabolism and who repeatedly have symptoms at the end of a 24-hour dosing interval. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines. Methylxanthines are not recommended in the management of COPD due to increased side effect profiles.
300 to 400 mg PO once daily, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 800 mg/day. Do not exceed 400 mg/day in persons with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider twice daily dosing in persons with rapid metabolism and who repeatedly have symptoms at the end of a 24-hour dosing interval. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.
300 to 400 mg PO once daily, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 800 mg/day. Do not exceed 400 mg/day in persons with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider twice daily dosing in persons with rapid metabolism and who repeatedly have symptoms at the end of a 24-hour dosing interval. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.
12 to 14 mg/kg/day (Max: 300 mg/day) PO once daily, initially. After 3 days, increase the dose to 16 mg/kg/day (Max: 400 mg/day) and then 20 mg/kg/day (Max: 600 mg/day) if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations. Usual Max: 800 mg/day. Do not exceed 16 mg/kg/day (Max: 400 mg/day) in persons with risk factors for decreased theophylline clearance or who cannot receive recommended serum concentration monitoring. Consider twice daily dosing in persons with rapid metabolism and who repeatedly have symptoms at the end of a 24-hour dosing interval. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.
NOTE: 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. NAEPP and GINA 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.
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.
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.
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. 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.
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. 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.
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. 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.
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. 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.
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. 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.
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.
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.
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.
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).
6 mg/kg IV once.
300 mg IV once followed by oral dosing.
5 to 10 mg/kg/day PO after initial IV dose; titrate dose to effect. Usual dose: 450 +/- 100 mg/day.[63867]
6 mg/kg IV once.
5 to 10 mg/kg/day PO; titrate dose to effect.
†Indicates off-label use
Dosing Considerations
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 ImpairmentReduced 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.
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; 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; Pyrilamine: (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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Acetaminophen; Chlorpheniramine; Phenylephrine : (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Acetaminophen; 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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Acetaminophen; Phenylephrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Acetaminophen; Pseudoephedrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Aclidinium; 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.
Acrivastine; Pseudoephedrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Acyclovir: (Moderate) Monitor theophylline concentrations and watch for an increase in theophylline-related adverse reactions if coadministration with acyclovir is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and acyclovir is a CYP1A2 inhibitor. Coadministration of 320 mg of theophylline with acyclovir 800 mg five times daily increased theophylline AUC 1.4x fold. (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) Larger doses of adenosine may be required or adenosine may not be effective in the presence of methylxanthines. The effects of adenosine are antagonized by methylxanthines. When used for diagnostic purposes, instruct patients to avoid consumption of methylxanthine-containing products, including caffeinated beverages, for at least 5 half-lives prior to the imaging study.
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; Budesonide: (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: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
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.
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; 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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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 sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity. (Moderate) Theophylline may potentiate the hypokalemic effects of epinephrine.
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; 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.
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.
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.
Benzodiazepines: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
Benzphetamine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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.
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; Dextromethorphan; Phenylephrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Brompheniramine; Phenylephrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Brompheniramine; Pseudoephedrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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.
Budesonide; 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.
Bupivacaine; Epinephrine: (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity. (Moderate) Theophylline may potentiate the hypokalemic effects of epinephrine.
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.
Butalbital; Acetaminophen: (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.
Butalbital; 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. (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.
Butalbital; Acetaminophen; 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.
Butalbital; Aspirin; 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.
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; Sodium Benzoate: (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.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (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.
Cannabidiol: (Moderate) Monitor theophylline concentrations during coadministration with cannabidiol. Consider a dose reduction of theophylline as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Increased theophylline exposure is possible. Theophylline is a CYP1A2 substrate and cannabidiol is a weak CYP1A2 inhibitor.
Capmatinib: (Moderate) Monitor theophylline concentrations and watch for an increase in aminophylline-related adverse reactions if coadministration with capmatinib is necessary; an aminophylline dose reduction may be necessary. Aminophylline is a CYP1A2 substrate with a narrow therapeutic index and capmatinib is a weak CYP1A2 inhibitor. (Moderate) Monitor theophylline concentrations and watch for an increase in theophylline-related adverse reactions if coadministration with capmatinib is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and capmatinib is a CYP1A2 inhibitor.
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.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity. (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 decrea
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Chlordiazepoxide: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
Chlordiazepoxide; Amitriptyline: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
Chlordiazepoxide; Clidinium: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Chlorpheniramine; Phenylephrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Chlorpheniramine; Pseudoephedrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
Clorazepate: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
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; Guaifenesin; Pseudoephedrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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.
Desloratadine; Pseudoephedrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Desogestrel; 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.
Dexbrompheniramine; Pseudoephedrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Dexmethylphenidate: (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Dextroamphetamine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Dextromethorphan; 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.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Diazepam: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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; Phenylephrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Dopamine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Doxapram: (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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.
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.
Ephedrine: (Moderate) Concomitant use of theophylline and ephedrine may produce synergistic CNS effects, resulting in nausea, nervousness, and insomnia. Monitor the patient for worsening symptoms and manage according to clinical practice. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Ephedrine; Guaifenesin: (Moderate) Concomitant use of theophylline and ephedrine may produce synergistic CNS effects, resulting in nausea, nervousness, and insomnia. Monitor the patient for worsening symptoms and manage according to clinical practice. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Epinephrine: (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity. (Moderate) Theophylline may potentiate the hypokalemic effects of epinephrine.
Ergotamine; 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.
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.
Estazolam: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
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; 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.
Ethynodiol Diacetate; 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.
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.
Etonogestrel; 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.
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.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
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.
Food: (Major) Advise patients to avoid cannabis use during theophylline treatment due to decreased exposure of theophylline which may alter its efficacy. Cannabis use induces CYP1A2 and theophylline is a CYP1A2 substrate. The induction potential of cannabis is greatest with chronic inhalation. Other routes of administration or sporadic use may have less of an effect. Chronic, inhaled cannabis use has been observed to increase theophylline clearance 1.4-fold.
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.
Givosiran: (Major) Avoid concomitant use of givosiran and aminophylline due to the risk of increased aminophylline-related adverse reactions. If use is necessary, consider decreasing the aminophylline dose. Aminophylline is a sensitive CYP1A2 substrate. Givosiran may moderately reduce hepatic CYP1A2 enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway. (Major) Avoid concomitant use of givosiran and theophylline due to the risk of increased theophylline-related adverse reactions. If use is necessary, consider decreasing the theophylline dose. Theophylline is a sensitive CYP1A2 substrate. Givosiran may moderately reduce hepatic CYP1A2 enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway.
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; Phenylephrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Guaifenesin; Pseudoephedrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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.
Hydrocodone; Pseudoephedrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Ibuprofen; 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.
Ibuprofen; Pseudoephedrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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.
Imipenem; Cilastatin; Relebactam: (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-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-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.
Ipratropium; 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.
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 p ossibly 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 sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Ketamine: (Major) Consider using an alternative to ketamine in patients receiving aminophylline; concomitant use may lower the seizure threshold. (Major) Consider using an alternative to ketamine in patients receiving theophylline; concomitant use may lower the seizure threshold.
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; Amoxicillin; 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. (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.
Leniolisib: (Moderate) Monitor theophylline concentrations and watch for an increase in theophylline-related adverse reactions if coadministration with leniolisib is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and leniolisib is a CYP1A2 inhibitor.
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.
Levoketoconazole: (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.
Levonorgestrel; 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.
Levonorgestrel; Ethinyl Estradiol; 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.
Levonorgestrel; Ethinyl Estradiol; 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.
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.
Lidocaine; Epinephrine: (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity. (Moderate) Theophylline may potentiate the hypokalemic effects of epinephrine.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Lorazepam: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
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.
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.
Methacholine: (Major) Discontinue use of oral theophylline 12 to 48 hours before a methacholine challenge test. Theophylline inhibits the airway response to methacholine.
Methamphetamine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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 sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
Midodrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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) Monitor theophylline concentrations and watch for decreased efficacy of theophylline if coadministration with modafinil is necessary; a theophylline dose increase may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and modafinil is a CYP1A2 inducer.
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) Monitor for reduced aminophylline efficacy during concomitant use of nabilone. Concomitant use may decrease theophylline concentrations, the active component of aminophylline. Chronic cannabis smoking has been observed to enhance theophylline clearance; nabilone is a synthetic cannabinoid that may have a similar effect on theophylline concentrations. (Minor) Monitor for reduced theophylline efficacy during concomitant use of nabilone. Concomitant use may decrease theophylline concentrations. Chronic cannabis smoking has been observed to enhance theophylline clearance; nabilone is a synthetic cannabinoid that may have a similar effect on theophylline concentrations.
Naproxen; Pseudoephedrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Neuromuscular blockers: (Moderate) A higher neuromuscular blocker dose may be required to achieve neuromuscular block with concomitant aminophylline use. Aminophylline may antagonize neuromuscular blocking effects, possibly due to phosphodiesterase inhibition. (Moderate) A higher neuromuscular blocker dose may be required to achieve neuromuscular block with concomitant theophylline use. Theophylline may antagonize neuromuscular blocking effects, possibly due to phosphodiesterase inhibition.
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.
Nirmatrelvir; 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.
Norepinephrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Norethindrone Acetate; Ethinyl Estradiol; 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.
Norethindrone; 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.
Norethindrone; Ethinyl Estradiol; 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.
Norgestimate; 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.
Obeticholic Acid: (Moderate) Monitor theophylline concentrations and watch for an increase in theophylline-related adverse reactions if coadministration with obeticholic acid is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and obeticholic acid is a CYP1A2 inhibitor. (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.
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.
Osilodrostat: (Moderate) Monitor theophylline concentrations and watch for an increase in theophylline-related adverse reactions if coadministration with osilodrostat is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and osilodrostat is a moderate CYP1A2 inhibitor.
Oxazepam: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
Pacritinib: (Moderate) Monitor theophylline concentrations and watch for an increase in theophylline-related adverse reactions if coadministration with pacritinib is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and pacritinib is a CYP1A2 inhibitor.
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.
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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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.
Phenobarbital; Hyoscyamine; Atropine; 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.
Phentermine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Phentermine; Topiramate: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Phenylephrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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.
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 sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity. (Moderate) Theophylline may potentiate the hypokalemic effects of epinephrine.
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.
Promethazine; Phenylephrine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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.
Propranolol; Hydrochlorothiazide, HCTZ: (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. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Pseudoephedrine; Triprolidine: (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. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
Quazepam: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
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 sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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.
Remimazolam: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
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.
Riociguat: (Contraindicated) Coadministration of riociguat and phosphodiesterase inhibitors, including nonspecific phosphodiesterase inhibitors (e.g., theophylline, aminophylline) is contraindicated due to the risk of hypotension.
Ritlecitinib: (Moderate) Monitor theophylline concentrations and watch for an increase in theophylline-related adverse reactions if coadministration with ritlecitinib is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and ritlecitinib is a CYP1A2 inhibitor.
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.
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).
Ropeginterferon 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.
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) Monitor drug concentrations and watch for decreased efficacy of aminophylline or theophylline if coadministration with sarilumab is necessary; a dosage increase of these methylxanthines may be necessary. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index may have fluctuations in drug levels and therapeutic effect when sarilumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. In vitro,sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Aminophylline and Theophylline are CYP1A2 substrates and narrow therapeutic index drugs.
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.
Segesterone Acetate; 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.
Semaglutide: (Moderate) Consider increased clinical or laboratory monitoring for aminophylline if administered with oral semaglutide as the absorption of aminophylline may be altered. Semaglutide delays gastric emptying and therefore has the potential to affect absorption of other orally administered medications, particularly those with a narrow therapeutic index, such as aminophylline, a prodrug for theophylline. Administer oral semaglutide separately from other oral medications. Monitor theophylline levels as clinically indicated. This interaction does not occur with subcutaneous semaglutide or with IV aminophylline. (Moderate) Consider increased clinical or laboratory monitoring for theophylline if administered with oral semaglutide as the absorption of theophylline may be altered. Semaglutide delays gastric emptying and therefore has the potential to affect absorption of other orally administered medications, particularly those with a narrow therapeutic index, such as theophylline. Administer oral semaglutide separately from other oral medications. Monitor theophylline levels as clinically indicated. This interaction does not occur with subcutaneous semaglutide or with IV theophylline.
Serdexmethylphenidate; Dexmethylphenidate: (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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) Monitor drug concentrations and watch for decreased efficacy of aminophylline or theophylline if coadministration with siltuximab is necessary; a dosage increase of these methylxanthines may be 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 compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index 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. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Aminophylline and Theophylline are CYP1A2 substrates and narrow therapeutic index drugs.
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.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor theophylline concentrations and watch for decreased efficacy of theophylline if coadministration with taurursodiol is necessary; a theophylline dose increase may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and taurursodiol is a CYP1A2 inducer.
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.
Stiripentol: (Moderate) Consider a dose adjustment of aminophylline when coadministered with stiripentol. Coadministration may alter plasma concentrations of aminophylline resulting in an increased risk of adverse reactions and/or decreased efficacy. Aminophylline is a sensitive CYP1A2 substrate. In vitro data predicts inhibition or induction of CYP1A2 by stiripentol potentially resulting in clinically significant interactions. (Moderate) Consider a dose adjustment of theophylline when coadministered with stiripentol. Coadministration may alter plasma concentrations of theophylline resulting in an increased risk of adverse reactions and/or decreased efficacy. Theophylline is a sensitive CYP1A2 substrate. In vitro data predicts inhibition or induction of CYP1A2 by stiripentol potentially resulting in clinically significant interactions.
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.
Sympathomimetics: (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
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.
Temazepam: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
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.
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.
Tirzepatide: (Moderate) Consider increased clinical or laboratory monitoring for aminophylline if administered with tirzepatide as the absorption of aminophylline may be altered. Ttirzepatide delays gastric emptying and therefore has the potential to affect absorption of other orally administered medications, particularly those with a narrow therapeutic index, such as aminophylline, a prodrug for theophylline. Monitor theophylline levels as clinically indicated. This interaction does not occur with IV aminophylline. (Moderate) Consider increased clinical or laboratory monitoring for theophylline if administered with tirzepatide as the absorption of theophylline may be altered. Ttirzepatide delays gastric emptying and therefore has the potential to affect absorption of other orally administered medications, particularly those with a narrow therapeutic index, such as theophylline. Monitor theophylline levels as clinically indicated. This interaction does not occur with IV theophylline.
Tobacco: (Major) Advise patients to avoid smoking tobacco while taking aminophylline. Smoking tobacco may reduce aminophylline exposure and decrease efficacy. Theophylline is a CYP1A2 substrate and smoking tobacco induces CYP1A2. (Major) Advise patients to avoid smoking tobacco while taking theophylline. Smoking tobacco has been observed to decrease theophylline exposure by 50% to 100% and may result in loss of efficacy. Theophylline is a CYP1A2 substrate and smoking tobacco induces CYP1A2.
Tocilizumab: (Moderate) Monitor drug concentrations and watch for decreased efficacy of aminophylline or theophylline if coadministration with tocilizumab is necessary; a dosage increase of these methylxanthines may be necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Aminophylline and Theophylline are CYP1A2 substrates and narrow therapeutic index drugs.
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: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
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.
Viloxazine: (Contraindicated) Concomitant use of viloxazine and aminophylline is contraindicated due to the increased risk for aminophylline-related adverse effects and exposure. Theophylline is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor. (Contraindicated) Concomitant use of viloxazine and theophylline is contraindicated due to the increased risk for theophylline-related adverse effects and exposure. Theophylline is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor.
Vonoprazan; Amoxicillin; 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.
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. (Moderate) Monitor theophylline concentrations and watch for an increase in theophylline-related adverse reactions if coadministration with zileuton is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and zileuton is a CYP1A2 inhibitor.
How Supplied
Aminophylline/Theophylline, Dextrose Intravenous Inj Sol: 1mL, 25mg, 200-5%, 400-5%, 800-5%
Elixophyllin/Theophylline, Anhydrous Oral Sol: 15mL, 80mg
Quibron T/SR/Theo X/Theochron/Theo-Dur/Theolair SR/Theophylline/Theophylline, Anhydrous/Uni-Dur/Uniphyl Oral Tab ER: 100mg, 200mg, 300mg, 400mg, 450mg, 600mg
Theo-24 Oral Cap ER: 100mg, 200mg, 300mg, 400mg
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):
Adults18 to 60 years: Adults requiring more than 600 mg/day total of theophylline require close monitoring to individualize dosage. It is recommended not to exceed 400 mg/day PO in patients with risk factors for decreased clearance or in whom recommended serum concentration monitoring is not possible.
60 years and older: Do not exceed 400 mg/day PO, as reduced clearance of theophylline is expected.
400 mg/day PO.
Adolescents16 to 17 years: Individualize dosage; 400 mg/day PO, if risk factors for decreased clearance are present or recommended serum concentration monitoring is not possible.
13 to 15 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.
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.
InfantsIndividualize dosage; infant dosing is based on age/weight.
NeonatesIndividualize dosage; loading doses of 8 mg/kg IV or PO have been used.
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.
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.
Pregnancy And Lactation
Theophylline and aminophylline have not been proven to be teratogenic in humans; however, there are no adequate controlled trials of the drugs during pregnancy.[44288] [44293] [46999] Decreased theophylline clearance has been reported during the third trimester of pregnancy. Theophylline is considered an alternative therapy for mild persistent asthma and adjunctive treatment for moderate to severe persistent asthma during pregnancy according to the Guidelines of the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group. Inhaled corticosteroids are the preferred asthma maintenance treatment during pregnancy due to the potential toxicities of theophylline and the propensity for drug interactions that can reduce theophylline clearance.[31822] If theophylline or aminophylline must be used, it is recommended that serum theophylline concentrations be regularly monitored and maintained between 5 to 12 mcg/mL. Use during pregnancy may lead to potentially dangerous serum theophylline and caffeine concentrations and/or symptoms of theophylline toxicity in newborns; an exposed infant should be closely monitored at birth. The 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.[31822] In studies in which pregnant mice, rats and rabbits were dosed during the period of organogenesis, theophylline produced teratogenic effects.[44288] [44293] [46999]
Use theophylline with caution during breast-feeding. Theophylline is excreted in breast milk in concentrations similar to the serum concentration of the mother. Breastfed 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. Close monitoring is recommended, particularly in a newborn. Theophylline or aminophylline are not preferred therapy for asthma in the lactating woman; these drugs are considered alternative therapy to inhaled corticosteroids for mild persistent asthma and an adjunctive medication for moderate to severe asthma during lactation according to the 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 to 12 mcg/mL.