Which antidepressant interacts adversely with theophylline?

Fluvoxamine is the Antidepressant that Interacts Adversely with Theophylline

Fluvoxamine is the antidepressant that has the most significant and potentially dangerous interaction with theophylline, causing substantial increases in theophylline levels that can lead to toxicity.

Mechanism of Interaction

Fluvoxamine is a potent inhibitor of the cytochrome P450 1A2 (CYP1A2) enzyme, which is primarily responsible for theophylline metabolism. This interaction has several important clinical implications:

• Fluvoxamine potently inhibits all pathways of theophylline biotransformation with an inhibitor constant (Ki) of 0.07-0.29 μM 1
• This inhibition can increase theophylline concentrations by up to 300% 2
• The interaction is unique to fluvoxamine among SSRIs - other antidepressants show either weak or no inhibition of theophylline metabolism 1, 3

Clinical Consequences

When fluvoxamine is combined with theophylline, several serious adverse effects can occur:

• Theophylline toxicity symptoms may develop rapidly (within days to a week)
• Clinical manifestations include headaches, nausea, vomiting, tremors, and potentially more serious cardiovascular effects 4
• A case report documented an 11-year-old boy experiencing severe headaches, tiredness, and vomiting when fluvoxamine was added to his theophylline regimen, with theophylline levels nearly doubling from 14.2 mg/L to 27.4 mg/L 4

Comparison with Other Antidepressants

Other SSRIs have significantly less impact on theophylline metabolism:

• Citalopram has been specifically studied and shown not to affect theophylline pharmacokinetics 5
• Fluoxetine, paroxetine, and sertraline do not significantly inhibit CYP1A2 and therefore have minimal effect on theophylline metabolism 6, 1

Clinical Management Recommendations

If a patient requires both theophylline and an antidepressant:

1. Avoid fluvoxamine completely in patients taking theophylline
2. Consider alternative antidepressants:
   • Citalopram/escitalopram may have the least effect on CYP450 isoenzymes compared with other SSRIs 7
   • Sertraline has minimal interaction with theophylline 1
3. If fluvoxamine must be used (which is rarely justified):
   • Reduce theophylline dose substantially before starting fluvoxamine
   • Monitor theophylline levels frequently (every few days initially)
   • Watch for signs of theophylline toxicity: nausea, vomiting, headache, insomnia, fine tremor, and potentially cardiac arrhythmias

Special Considerations

• Elderly patients are at higher risk for adverse effects from this interaction due to decreased drug clearance
• Patients with hepatic impairment may experience more pronounced effects
• Smoking status affects theophylline metabolism (smoking induces CYP1A2), adding another variable to consider

This drug interaction is specifically mentioned in the FDA-approved theophylline labeling, highlighting its clinical significance 2. The American Thoracic Society guidelines also specifically warn about the interaction between theophylline and fluvoxamine 7.