Amitriptyline × Fluvoxamine

Amitriptyline is cleared in the liver by several enzymes, mainly CYP2D6 and CYP2C19, and to a lesser extent CYP1A2 and CYP3A4 (amitriptyline SmPC). Fluvoxamine strongly inhibits CYP1A2 and CYP2C19 (fluvoxamine SmPC). The amitriptyline SmPC states that fluvoxamine raises amitriptyline plasma levels, and the FDA fluvoxamine label reports significantly increased levels of tricyclic antidepressants, amitriptyline included. Both drugs also enhance serotonin activity, so the combination raises the risk of serotonin syndrome (amitriptyline SmPC, FDA fluvoxamine label).

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: agitation, hallucinations, tremor, muscle rigidity, myoclonus, fever, sweating, tachycardia, labile blood pressure, nausea, vomiting, diarrhoea (FDA fluvoxamine label, amitriptyline SmPC).

Avoid the combination: the Spanish amitriptyline SmPC says so directly. If both drugs are still used, the fluvoxamine SmPC asks to consider lowering the amitriptyline dose when fluvoxamine is started, and the FDA fluvoxamine label advises monitoring tricyclic plasma levels and reducing the tricyclic dose if needed. Watch for serotonin syndrome at the start of treatment and after each dose increase. If it appears, stop amitriptyline and other serotonergic drugs at once and start supportive treatment (FDA amitriptyline label). Use amitriptyline with caution in marked bradycardia, decompensated heart failure and with QT-prolonging drugs; potassium or magnesium disturbances raise the risk of arrhythmia (amitriptyline SmPC).