Theophylline is a bronchodilator used in chronic asthma and COPD, when other treatments are not enough. It has a narrow therapeutic window — high levels cause serious effects (vomiting, arrhythmias, seizures) and require regular blood tests.
Also known as: aminofilina, aminophylline, Uniphyllin
Mucolytic + methylxanthine: no clinically significant pharmacokinetic interaction.
Acetylcysteine does not significantly affect theophylline metabolism. Possible additive therapeutic effect (mucolytic + bronchodilator).
No dose adjustment required.
DailyMed/FDA; EMC-UK
Combining theophylline with salbutamol has additive effects (tremor, tachycardia, hypokalaemia).
Salbutamol (beta2-agonist) and theophylline both raise cAMP — the former by direct beta2 receptor activation, the latter by phosphodiesterase inhibition — and the pharmacodynamic effect is additive. Theophylline "increases release of endogenous catecholamines" and the label links this to an "increased risk of ventricular arrhythmias"; salbutamol "may produce significant hypokalaemia... with the potential to produce adverse cardiovascular effects". The combination is common in practice (severe asthma/COPD), but high doses of both add up tachycardia, tremor, nausea and potassium loss, with arrhythmia risk mainly in elderly or cardiac patients. Use the lowest effective doses, monitor serum potassium and symptoms (palpitations, tremor, anxiety) and reduce theophylline if toxicity signs appear.
Salbutamol + theophylline: additive beta-adrenergic stimulation — tachycardia, tremor, hypokalaemia and arrhythmia risk. Monitor potassium and cardiovascular symptoms.
Both drugs stimulate adenylate cyclase / raise cAMP and may potentiate the β2 effect and potassium loss.
Monitor tremor, palpitations and check potassium in at-risk patients.
Symptomatic hypokalaemia, arrhythmias.
Monitor serum potassium and heart rhythm, especially in patients with cardiovascular disease.
DailyMed (FDA) — approved Theophylline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e64036a-ee3e-42e7-9e59-881f88a4e298 ; approved Salbutamol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3236f82c-14e9-dfd4-e063-6294a90ac43d — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Decongestant + theophylline: additive stimulation and hypokalaemia.
Theophylline and pseudoephedrine (a sympathomimetic, isomer of ephedrine) are both CNS and cardiovascular stimulants. The theophylline label documents the combination with ephedrine as having "synergistic CNS effects, with increased frequency of nausea, nervousness, and insomnia" — the same class as pseudoephedrine. Together they increase the risk of tachycardia, palpitations, tremor, anxiety and insomnia, and in susceptible patients may precipitate arrhythmias or seizures (theophylline lowers the seizure threshold). The combination is frequent in over-the-counter cold/flu products — always ask the patient about decongestants. Use with caution, prefer topical decongestants or a reduced theophylline dose, and watch for adrenergic symptoms, especially in the elderly and cardiac patients.
Pseudoephedrine + theophylline: additive CNS and cardiovascular stimulation — nausea, nervousness, insomnia, tachycardia and tremor. Use with caution.
Additive stimulant effects (tachycardia, tremor) and possible potassium loss.
Potassium and adrenergic symptoms.
Palpitations, tremor, insomnia.
Watch for cardiovascular symptoms; monitor potassium in at-risk patients.
DailyMed (FDA) — approved Pseudoephedrine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=78faa497-6743-b85b-e053-2a91aa0ae822 ; approved Theophylline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e64036a-ee3e-42e7-9e59-881f88a4e298 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Epinephrine + theophylline: additive cardiac effects and hypokalaemia.
The epinephrine label explicitly documents the "drugs potentiating the hypokalaemic effects of epinephrine — potassium-depleting diuretics, corticosteroids and theophylline" and recommends "observing for the development of cardiac arrhythmias" with these combinations. Conversely, theophylline "increases release of endogenous catecholamines", with an "increased risk of ventricular arrhythmias" (theophylline label), and lowers the seizure threshold. The combination is mainly relevant in hospital settings (epinephrine infusion + theophylline/aminophylline) and in patients with ischaemic heart disease or pre-existing hypokalaemia. Monitor serum potassium, ECG and signs of toxicity (tremor, palpitations, arrhythmias); correct hypokalaemia and reduce doses whenever possible.
Epinephrine + theophylline: theophylline potentiates epinephrine hypokalaemia and both increase arrhythmia risk. Monitor potassium and cardiac rhythm.
Both are β-adrenergic stimulants; they increase the risk of tachycardia, tremor and hypokalaemia.
Serum potassium and ECG.
Tachyarrhythmias, tremor, symptomatic hypokalaemia.
Monitor potassium and heart rhythm, especially in cardiovascular patients.
DailyMed (FDA) — approved Epinephrine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5726eeca-db88-ba8e-e063-6294a90a927d ; approved Theophylline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e64036a-ee3e-42e7-9e59-881f88a4e298 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Methylxanthine + anticoagulant: theophylline may slightly potentiate warfarin effect.
Theophylline may partially compete for CYP1A2/CYP2C9 metabolism of warfarin, slightly increasing INR. The effect is generally modest but clinically relevant in patients with INR already at the upper limit. Monitor INR during the first 2-3 weeks.
Theophylline may slightly potentiate warfarin effect. Monitor INR.
Theophylline may partially compete for CYP1A2/CYP2C9 metabolism of warfarin, slightly increasing INR.
INR.
Monitor INR during the first 2-3 weeks after theophylline initiation/change.
DailyMed/FDA; EMC-UK
Methylxanthine + CYP1A2 inhibitor: fluconazole increases theophylline levels 30-50%. Risk of toxicity.
Theophylline has a narrow therapeutic index (10-20 μg/mL) and is primarily metabolised by CYP1A2 (70%). Fluconazole moderately inhibits CYP1A2, increasing theophylline levels 30-50%. Above 20 μg/mL, risk of nausea, vomiting, and tachycardia. Above 30 μg/mL, risk of seizures and potentially fatal ventricular arrhythmias. The Prontuário Terapêutico recommends: reduce theophylline dose by 25-50%, monitor levels weekly, and discontinue if >20 μg/mL. Alternative: switch fluconazole to voriconazole (less CYP1A2 inhibition) or itraconazole.
Fluconazole inhibits CYP1A2, increasing theophylline levels 30-50%. Risk of toxicity (seizures, arrhythmias).
Theophylline is metabolised by CYP1A2 (70%). Fluconazole moderately inhibits CYP1A2, increasing theophylline levels 30-50%. The therapeutic index is narrow (10-20 μg/mL) — even moderate increases may cause toxicity.
Theophylline levels, signs of toxicity (nausea, vomiting, tachycardia, seizures).
Seizures, arrhythmias, death (levels >30 μg/mL).
Reduce theophylline dose by 25-50%. Monitor theophylline levels weekly during co-administration.
DailyMed/FDA; EMC-UK
Methylxanthine + potent CYP inhibitor: ritonavir may significantly increase theophylline levels.
Ritonavir is a potent CYP3A4 inhibitor and may inhibit CYP1A2. Theophylline is a CYP1A2 (70%) and CYP3A4 (15%) substrate. The resulting effect is unpredictable — depends on the patient's CYP phenotype and doses. Cases of theophylline toxicity with ritonavir have been documented. There are no specific guidelines for this combination. Recommendation: avoid. If unavoidable, reduce theophylline by 50%, monitor levels 2x/week, and have IV theophylline available for emergencies.
Ritonavir inhibits CYP3A4/1A2 — unpredictable effect on theophylline levels. Avoid combination.
Ritonavir inhibits CYP3A4 and may inhibit CYP1A2, increasing theophylline levels. The effect is unpredictable and may be significant.
Theophylline levels, ECG, signs of toxicity.
Severe theophylline toxicity.
Avoid combination if possible. If necessary, reduce theophylline dose by 50% and monitor levels weekly.
DailyMed/FDA; EMC-UK
Carbamazepine induces hepatic metabolism and may lower theophylline levels; the interaction is bidirectional and variable.
Carbamazepine is a potent inducer of CYP1A2, CYP3A4, and UGT. Theophylline is a CYP1A2 substrate (70%). Co-administration reduces theophylline levels 20-40%, potentially compromising asthma/COPD control. Adjust theophylline dose based on levels (target: 10-20 μg/mL). Monitor monthly. Carbamazepine may also induce metabolism of other concomitant drugs.
Carbamazepine induces CYP1A2, reducing theophylline 20-40%. Adjust dose based on levels.
Carbamazepine is an enzyme inducer (CYP3A4), accelerating theophylline clearance.
Monitor theophylline efficacy and signs of seizures or toxicity.
Loss of asthma control (subtherapeutic theophylline) or toxicity when carbamazepine is stopped.
Monitor levels of both drugs when starting, adjusting or stopping either one.
DailyMed (FDA) — approved Theophylline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e64036a-ee3e-42e7-9e59-881f88a4e298 ; approved Carbamazepine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=97e6e175-75e8-437b-b457-ddb1ae4e857d — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
CYP1A2 inducer + CYP1A2 substrate: phenytoin reduces theophylline levels 20-30%.
Phenytoin moderately induces CYP1A2, reducing theophylline levels 20-30%. The effect is less than with carbamazepine. Adjust theophylline dose based on levels.
Phenytoin induces CYP1A2, reducing theophylline 20-30%. Adjust dose based on levels.
Phenytoin induces CYP1A2, reducing theophylline levels. The effect is moderate.
Theophylline levels.
Adjust theophylline dose based on levels.
DailyMed/FDA; EMC-UK
CYP1A2 inhibitor + CYP1A2 substrate: fluoxetine may increase theophylline levels 10-20%.
Fluoxetine weakly inhibits CYP1A2. The effect on theophylline levels is generally modest (10-20%), clinically significant only at high fluoxetine doses (>40 mg/day) or in CYP2D6 poor metabolisers. Monitor levels if high dose.
Fluoxetine weakly inhibits CYP1A2, increasing theophylline 10-20%. Effect generally modest.
Fluoxetine weakly inhibits CYP1A2, potentially slightly increasing theophylline levels. The effect is generally modest.
Theophylline levels.
Monitor theophylline levels if high-dose fluoxetine.
DailyMed/FDA; EMC-UK
Ciprofloxacin reduces theophylline clearance and may increase its toxicity.
Ciprofloxacin is an inhibitor of CYP1A2, the enzyme that metabolises theophylline, and can raise theophylline serum concentrations by about 40% (per the theophylline label) and precipitate toxicity (nausea, vomiting, tachycardia, tremor, seizures, arrhythmias). The theophylline label recommends monitoring serum levels and adjusting the dose when ciprofloxacin is started or stopped, and watching for signs of toxicity (the ciprofloxacin label reports serious and fatal reactions with the combination). The interaction is particularly relevant in COPD/asthma patients on chronic theophylline.
Ciprofloxacin + theophylline: ciprofloxacin inhibits CYP1A2 and can raise theophylline (~40%), with a risk of toxicity. Monitor levels.
Ciprofloxacin inhibits CYP1A2, raising theophylline concentrations.
Monitor signs of theophylline toxicity (nausea, tremor, tachycardia, seizures).
Seizures, serious arrhythmias.
Reduce the theophylline dose or monitor levels during ciprofloxacin treatment.
DailyMed (FDA) — approved Theophylline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e64036a-ee3e-42e7-9e59-881f88a4e298 ; approved Ciprofloxacin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c527d138-e32c-418f-9573-a3d8a796279f — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Clarithromycin inhibits theophylline metabolism and may raise its levels, with a risk of toxicity (nausea, tachycardia, seizures).
Theophylline is metabolised by CYP1A2 and CYP3A4; clarithromycin inhibits CYP3A4 and can raise its concentrations, with risk of toxicity (nausea, vomiting, tachycardia, tremor and, in severe cases, seizures and arrhythmias). Theophylline has a narrow therapeutic window, so monitor its plasma levels and reduce the dose if needed during the combination.
Theophylline + clarithromycin: clarithromycin inhibits theophylline metabolism and may raise its levels, with risk of toxicity. Monitor theophylline levels.
Clarithromycin inhibits CYP1A2/CYP3A4, reducing the clearance of theophylline, which has a narrow therapeutic margin.
Monitor nausea, vomiting, tachycardia, tremor and neurological signs (seizures).
Tachycardia, arrhythmias, repeated vomiting, seizures.
Monitor theophylline levels and reduce the dose if needed; consider an alternative antibiotic.
DailyMed (FDA) — approved Theophylline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e64036a-ee3e-42e7-9e59-881f88a4e298 ; approved Clarithromycin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d836ae7e-fdbf-4dcb-a90d-ede1dcbc3e67 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Theophylline + verapamil: verapamil decreases theophylline metabolism, increasing its levels and the toxicity risk (QUADRO 2).
Verapamil inhibits CYP1A2, the main enzyme metabolising theophylline, potentially increasing theophylline concentrations by 20-25% or more. QUADRO 2 of Annex 7 lists theophylline among drugs interacting with calcium channel blockers. Theophylline toxicity presents with nausea, vomiting, tachycardia, tremors, insomnia and, at high levels, seizures and arrhythmias. The risk is higher in smokers who stop tobacco, the elderly or those with heart failure. When starting verapamil, consider reducing the theophylline dose and monitor serum levels and toxicity signs; prefer other calcium channel blockers when possible.
Theophylline + verapamil: verapamil inhibits theophylline metabolism — toxicity risk (nausea, tachycardia, seizures); reduce dose and monitor.
Verapamil (calcium channel blocker) inhibits theophylline hepatic metabolism — increased plasma levels (QUADRO 2, Theophylline: "Drugs that decrease theophylline metabolism: ... Verapamil").
Monitor theophylline toxicity symptoms (nausea, tachycardia, tremor).
Theophylline toxicity (tachycardia, tremor, seizures) after starting verapamil.
Monitor theophylline levels when starting verapamil; consider reducing the theophylline dose.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (Theophylline)
Theophylline + phenobarbital: phenobarbital induces theophylline metabolism, decreasing its levels and bronchodilator effect (QUADRO 2).
Phenobarbital is a CYP1A2 and CYP3A4 inducer, accelerating theophylline metabolism and reducing its plasma concentrations and bronchodilator effect. QUADRO 2 of Annex 7 records this interaction in the barbiturate section. Clinical relevance is greater in asthmatic or COPD patients whose control worsens after starting phenobarbital, possibly requiring a theophylline dose increase. Conversely, if phenobarbital is stopped, theophylline levels rise and toxicity may appear. Monitor clinical response and, if available, theophylline levels; adjust the dose when starting, adjusting or stopping the barbiturate.
Theophylline + phenobarbital: enzyme induction by phenobarbital — reduced theophylline concentrations and bronchodilator effect; monitor.
Barbiturates induce the hepatic microsomal enzymes that metabolise theophylline — decreased plasma levels and activity after 10-12 days (QUADRO 2, Barbiturates: "Theophylline: decreased plasma levels and activity after 10-12 days").
Monitor the bronchodilator response (worsening asthma/COPD).
Worsening asthma/COPD or subtherapeutic theophylline levels with phenobarbital.
Monitor theophylline levels and adjust the dose when starting/stopping phenobarbital.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (Barbiturates)
Theophylline + rifampicin: rifampicin increases theophylline metabolism, reducing its effect (QUADRO 2).
Rifampicin is a potent CYP1A2 and CYP3A4 inducer, potentially reducing theophylline concentrations by 30-50% and compromising bronchodilator control. QUADRO 2 of Annex 7 records this interaction in the rifampicin section. The reduced effect may appear within days and persist for weeks after stopping rifampicin. Asthmatic or COPD patients may worsen clinically and require substantial theophylline dose increases; when rifampicin is stopped, the opposite risk (toxicity) applies. Monitor theophylline levels when available and respiratory function; warn the patient about worsening bronchospasm.
Theophylline + rifampicin: enzyme induction by rifampicin — marked reduction of theophylline concentrations and effect; monitor and adjust dose.
Rifampicin is a potent inducer of microsomal enzymes — increased theophylline metabolism and reduced effect (QUADRO 2, Rifampicin: "Theophylline: increased theophylline metabolism; reduced theophylline effect").
Monitor theophylline levels and clinical response during rifampicin.
Worsening asthma/COPD or subtherapeutic levels with rifampicin.
Increase the theophylline dose under level monitoring when starting rifampicin.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (Rifampicin)
Xanthine-rich foods may add to the stimulant effect of theophylline, increasing risk of insomnia and tachycardia.
Limit tea, coffee, and chocolate consumption during theophylline treatment.
Caffeine is a methylxanthine with additive effects to theophylline (CNS stimulation, tachycardia, tremor).
Limit coffee, tea and caffeinated drinks during theophylline treatment.
EMC-UK (MHRA) — approved Theophylline SmPC: https://www.medicines.org.uk/emc/product/100851/smpc
Alcohol may alter theophylline metabolism and potentiate central nervous system effects.
Limit alcohol intake during treatment.
EMC-UK (MHRA) — approved Theophylline SmPC: https://www.medicines.org.uk/emc/product/100851/smpc
Renal clearance of theophylline may be reduced in severe renal impairment.
eGFR <30: reduce dose by 25%. Monitor levels.
DailyMed/FDA; EMC-UK
Theophylline may lower the seizure threshold, especially at high levels.
Use with caution and keep serum levels within the therapeutic range.
EMC-UK (MHRA) — approved Theophylline SmPC: https://www.medicines.org.uk/emc/product/100851/smpc
Theophylline clearance is reduced in hepatic disease, with a risk of accumulation and toxicity.
Reduce the dose and monitor serum theophylline levels.
EMC-UK (MHRA) — approved Theophylline SmPC: https://www.medicines.org.uk/emc/product/100851/smpc
Dose reduction in hepatic impairment.
Reduce the dose in hepatic impairment.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 3, Drugs and hepatic impairment: Dose reduction in hepatic impairment.
Theophylline may be used in pregnancy if needed, with tight monitoring of levels.
Keep serum levels in the low therapeutic range; monitor fetal tachycardia.
Excreted into breast milk in small amounts; use with caution.
No specific additional contraception.
EMC-UK (MHRA) — approved Theophylline SmPC: https://www.medicines.org.uk/emc/product/100851/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Bronchodilator (methylxanthine). Bronchodilation occurs over serum concentrations of 5 to 20 mcg/mL; clinically important improvement generally requires peaks above 10 mcg/mL, and above 20 mcg/mL the frequency and severity of adverse reactions increase. It increases the force of contraction of the diaphragmatic muscles. Recommended target: peaks of 10 to 15 mcg/mL.
Smooth muscle relaxation of the airways by inhibition of two phosphodiesterase isozymes (PDE III and, to a lesser extent, PDE IV); the non-bronchodilator prophylactic effects involve distinct molecular mechanisms, not PDE III inhibition or adenosine receptor antagonism. Some adverse effects are mediated by PDE III inhibition and adenosine receptor antagonism.
Rapid and complete oral absorption (solution or immediate-release tablets); peak serum concentrations 1 to 2 hours after dosing (5 mg/kg: about 10 mcg/mL). No appreciable pre-systemic elimination. Food and antacids do not significantly alter absorption of immediate-release forms.
About 90% of the dose is metabolised in the liver (demethylation to 1- and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid; about 6% N-methylated to caffeine); CYP1A2 catalyses demethylation to 3-methylxanthine. Non-linear kinetics — clearance decreases and half-life increases at higher concentrations. Clearance is reduced by 50% or more in hepatic failure, heart failure and the elderly; increased in smokers.
Mean half-life of 8.7 hours in healthy non-smoking adults (6.1 to 12.8); 3.4 hours in children aged 1 to 4 years; 30 hours in premature neonates; 32 hours in cirrhosis; prolonged in heart failure (clearance reduced by 50% or more). Steady state in 30 to 65 hours (mean 40 hours) in adults.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
