Drug-drug:

• Concurrent use with MAO inhibitors may result in serious potentially fatal reactions (MAO inhibitors should be stopped at least 14 days before imipramine therapy. Imipramine should be stopped at least 14 days before MAO inhibitor therapy).
• Concurrent use with MAO-inhibitor like drugs, such as linezolid or methylene blue may ↑ risk of serotonin syndrome; concurrent use contraindicated; do not start therapy in patients receiving linezolid or methylene blue; if linezolid or methylene blue need to be started in a patient receiving trimipramine, immediately discontinue trimipramine and monitor for signs/symptoms of serotonin syndrome for 2 wk or until 24 hr after last dose of linezolid or methylene blue, whichever comes first (may resume trimipramine therapy 24 hr after last dose of linezolid or methylene blue).
• Trimipramine is metabolized in the liver by the cytochrome P450 2D6 enzyme, and its action may be affected by drugs that compete for metabolism by this enzyme, including other antidepressants, phenothiazines, carbamazepine, class 1C antiarrhythmics including propafenone, and flecainide; when used concurrently dose of one or the other or both may be necessary. Concurrent use of other drugs that inhibit the activity of the enzyme, including cimetidine, quinidine, amiodarone, and ritonavir, may result in ↑ effects of trimipramine.
• Concurrent use with SSRIs may result in toxicity and should be avoided (fluoxetine should be stopped 5 wk before starting trimipramine).
• Concurrent use with clonidine may result in hypertensive crisis and should be avoided.
• Concurrent use with levodopa may result in delayed or absorption of levodopa or hypertension.
• Blood levels and effects may be ↓ by rifamycins (rifampin, rifapentine, and rifabutin).
• Concurrent use with moxifloxacin↑ risk of adverse cardiovascular reactions.
• ↑CNS depression with other CNS depressants including alcohol, antihistamines, clonidine, opioids, and sedative/hypnotics.
• Barbiturates may alter blood levels and effects.
• ↑adrenergic and anticholinergic side effects with other agents having adrenergic or anticholinergic properties.
• Levels and risk of toxicity may be ↑ by phenothiazines or oral contraceptives.
• Nicotine may ↑ metabolism and alter effects.
• Drugs that affect serotonergic neurotransmitter systems, including SSRIs, SNRIs, fentanyl, buspirone, tramadol and triptans↑ risk of serotonin syndrome.

Drug-Natural Products:

• Use with St. John's wort↑ of serotonin syndrome.
• Concomitant use of kava-kava, valerian, or chamomile can ↑ CNS depression.
• ↑anticholinergic effects with jimson weed and scopolia.