Fluoxetine × Metoprolol

Fluoxetine is a strong inhibitor of the CYP2D6 enzyme (fluoxetine SmPC), and metoprolol is a CYP2D6 substrate (metoprolol SmPC). Strong CYP2D6 inhibitors, including fluoxetine, roughly double metoprolol concentrations, and metoprolol loses its cardioselectivity (US metoprolol label). The risk of marked bradycardia, hypotension and AV block rises.

Bradycardia, dizziness, fainting, a drop in blood pressure on standing. The metoprolol SmPC treats a heart rate below 50–55 beats per minute as significant. In heart failure: worsening breathlessness and oedema.

In heart failure the combination is contraindicated: the Spanish fluoxetine SmPC contraindicates fluoxetine with metoprolol used for this indication because of the risk of excessive bradycardia (fluoxetine SmPC). For other indications, the FDA advises combining metoprolol with a CYP2D6 inhibitor only when this cannot be avoided, and then monitoring the patient closely (US metoprolol label). Drugs metabolised by CYP2D6 are started or titrated at the lowest dose in patients on fluoxetine, and this also applies for 5 weeks after fluoxetine is stopped (fluoxetine SmPC). If the patient already takes metoprolol, its dose may need to be reduced when fluoxetine is started (metoprolol SmPC). If the heart rate falls below 50–55 beats per minute, reduce the metoprolol dose gradually or withdraw it slowly (metoprolol SmPC).