Amitriptyline × Fluoxetine

The combination works along three lines. Kinetics: fluoxetine strongly inhibits CYP2D6, which clears amitriptyline, so amitriptyline levels can rise markedly (labels of both drugs). The FDA fluoxetine label gives data for imipramine and desipramine: their stable plasma levels rose 2- to 10-fold, and the effect lasted 3 weeks or longer after fluoxetine was stopped. Serotonin: both drugs enhance it and together raise the risk of serotonin syndrome. Heart and seizures: both can prolong the QT interval, and the combination can raise seizure risk (labels of both drugs).

Signs of amitriptyline excess: drowsiness, dry mouth, constipation, urinary retention, dilated pupils, fast heartbeat, dizziness on standing and confusion. High levels can cause arrhythmias, QT prolongation, seizures and marked hypotension (amitriptyline SmPC). Serotonin syndrome as described in the FDA fluoxetine label: agitation, hallucinations, delirium, tremor, rigidity, myoclonus, hyperreflexia, fever, sweating, tachycardia, labile blood pressure, nausea, vomiting, diarrhoea.

The combination is acceptable only with careful dosing. While the patient takes fluoxetine and for 5 weeks after it is stopped, amitriptyline is started or adjusted within the lowest therapeutic range (fluoxetine SmPC). The FDA fluoxetine label warns that the tricyclic dose may need to be reduced and its plasma level monitored for a while, including after fluoxetine was recently stopped. When fluoxetine is added to amitriptyline, consider a lower amitriptyline dose and monitoring of its level (amitriptyline SmPC). Watch for serotonin syndrome at the start of treatment and after each dose increase; if it appears, stop both drugs at once and start supportive treatment (FDA labels of both drugs). In stable heart disease consider an ECG before starting fluoxetine; with risk factors for QT prolongation consider periodic ECGs as well; stop fluoxetine if signs of arrhythmia appear (fluoxetine labels). Low potassium or magnesium raises the risk of arrhythmia, so take it into account when prescribing (labels of both drugs).