Methylxanthine bronchodilator
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
Carbamazepine induces hepatic metabolism and may lower theophylline levels; the interaction is bidirectional and variable.
Carbamazepine induces CYP1A2 and CYP3A4, pathways of theophylline metabolism, and can reduce its concentrations by about 50%, compromising asthma/COPD control. Theophylline has a narrow therapeutic window, so monitor its plasma levels and adjust the dose (often upwards) while the combination lasts; consider an antiepileptic without enzyme induction if respiratory control is difficult.
Carbamazepine + theophylline: carbamazepine induces theophylline metabolism and lowers its levels by ~50%, with loss of bronchodilator effect. Monitor theophylline 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)
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)
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)
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
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
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.
