With: Monoamine oxidase inhibitors (MAOIs) and related drugs (e.g., phenelzine, tranylcypromine, isocarboxazid, selegiline, rasagiline, linezolid, methylene blue)
Risk: Serious reactions including very high blood pressure, serotonin toxicity, and other life-threatening effects.
Action: Contraindicated. Allow at least 14 days between stopping an MAOI and starting amoxapine, and at least 14 days between stopping amoxapine and starting an MAOI or high-risk serotonergic MAO-B inhibitor.
With: Other serotonergic agents (SSRIs, SNRIs, other TCAs, many triptans, tramadol, some opioids, St John’s wort, dextromethorphan, etc.)
Risk: Increased serotonin with potential for serotonin syndrome (agitation, tremor, clonus, fever, autonomic instability).
Action: Use cautiously. Avoid unnecessary combinations and monitor closely for symptoms of serotonin toxicity.
With: Other drugs that lower seizure threshold (e.g., bupropion, tramadol, typical antipsychotics, some fluoroquinolones)
Risk: Higher risk of seizures.
Action: Avoid high-risk combinations when possible or use the lowest effective doses with careful monitoring.
With: CNS depressants (alcohol, benzodiazepines, opioids, sedating antihistamines, sleep medicines, muscle relaxants)
Risk: Additive sedation, impaired coordination, falls, and in severe cases, slowed or stopped breathing.
Action: Avoid or minimize combined use. If combination cannot be avoided, use the smallest effective doses and monitor closely.
With: Strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine, some antipsychotics)
Risk: Possible increase in amoxapine levels, leading to more side effects.
Action: Consider lower amoxapine doses and monitor for toxicity (sedation, confusion, tremor, heart rhythm changes).
With: Anticholinergic medications (e.g., oxybutynin, some antipsychotics, first-generation antihistamines)
Risk: Increased dry mouth, constipation, urinary retention, blurred vision, and confusion.
Action: Limit combined anticholinergic load where possible; monitor especially in older adults.