Theophylline

Mechanism

Theophylline at toxic doses causes seizures by itself. Bupropion lowers the seizure threshold. High risk even at therapeutic theophylline concentrations.

Symptoms

Seizures (generalised tonic-clonic or focal), agitation, tremor, insomnia. Patients with prior epilepsy or eating disorders are at particular risk.

Management

Avoid the combination, especially in COPD or asthma patients. Alternative antidepressants: sertraline or escitalopram. Alternative bronchodilators: inhaled β2-agonists with anticholinergics.

Mechanism

Carbamazepine induces CYP1A2, which partly metabolises theophylline. Theophylline plasma levels fall by 25–50%; bronchodilator effect weakens.

Symptoms

Recurrence of asthma or COPD symptoms: dyspnoea, wheezing.

Management

During carbamazepine therapy, increase theophylline by 50% with level monitoring at 1–2 weeks. Alternative anticonvulsants without induction: levetiracetam, lamotrigine.

Mechanism

Carvedilol blocks β2-adrenergic receptors (non-selective beta-blocker) and causes bronchoconstriction in asthma or COPD. Theophylline becomes less effective in these conditions.

Symptoms

Recurrence of asthma or COPD symptoms: dyspnoea, wheezing, need for additional short-acting β2-agonist doses. In severe asthma: risk of severe bronchospasm.

Management

Avoid the combination in asthma and severe COPD. In heart failure with mild COPD, a selective beta-blocker (bisoprolol, metoprolol) is preferred. Alternative to theophylline: long-acting inhaled β2-agonists with anticholinergics.

Mechanism

Ciprofloxacin strongly inhibits CYP1A2 – the main theophylline metabolic route. Theophylline plasma levels rise 2- to 3-fold. Theophylline has a narrow therapeutic window, so any rise is clinically significant.

Symptoms

Nausea, tachycardia, tremor, insomnia, agitation. At levels above 30 mg/L: seizures and ventricular arrhythmias. Older patients and chronic kidney disease: earlier symptoms.

Management

Avoid the combination. Alternative antibiotics: a cephalosporin or levofloxacin (weaker CYP1A2 inhibition). If ciprofloxacin is needed, halve theophylline and check level at 3–5 days.

Mechanism

Clarithromycin blocks CYP1A2 and CYP3A4 – theophylline metabolic routes. Theophylline plasma levels rise 2- to 3-fold. Theophylline has a narrow therapeutic window.

Symptoms

Nausea, tachycardia, tremor, insomnia, agitation. At levels above 30 mg/L: seizures and ventricular arrhythmias.

Management

Avoid the combination. Alternative antibiotics without CYP1A2/CYP3A4 inhibition: a cephalosporin, amoxicillin-clavulanate, or doxycycline. If clarithromycin is needed, halve theophylline and check level at 3 days.

Mechanism

Fluvoxamine is the most potent CYP1A2 inhibitor among SSRIs, and CYP1A2 is the main theophylline metabolic route. Theophylline plasma levels rise 3-fold. Theophylline has a narrow therapeutic window.

Symptoms

Nausea, tachycardia, tremor, insomnia, agitation. At levels above 30 mg/L: seizures and ventricular arrhythmias. Older patients and chronic kidney disease: earlier symptoms.

Management

Avoid the combination. Alternative antidepressants without CYP1A2 effect: sertraline, escitalopram, or agomelatine. If fluvoxamine is needed, reduce theophylline 3-fold and check level at 3–5 days.

Mechanism

Rifampicin strongly induces CYP1A2 – the main theophylline metabolic route. Theophylline plasma levels fall by 30–50%; bronchodilator effect weakens.

Symptoms

Recurrence of asthma or COPD symptoms: dyspnoea, wheezing, need for additional short-acting β2-agonist doses.

Management

During anti-TB therapy, increase theophylline 1.5- to 2-fold with level monitoring at 1 week. Alternative bronchodilators: long-acting inhaled β2-agonists (formoterol, salmeterol) with anticholinergics.