Fluoxetine × Selegiline

Selegiline selectively inhibits monoamine oxidase type B (MAO-B), the enzyme mainly responsible for dopamine breakdown in the brain (selegiline SmPC). The US Food and Drug Administration (FDA) label for selegiline in Parkinson's disease adds that this inhibition is irreversible, that selectivity for MAO-B may be incomplete even at the recommended dose, and that it is lost above it (selegiline SmPC: above 10 mg a day). Fluoxetine is a selective serotonin reuptake inhibitor (SSRI). Both fluoxetine and its active metabolite norfluoxetine have a very long elimination half-life (selegiline and fluoxetine SmPCs). With serotonin breakdown slowed and reuptake blocked, serotonin builds up in the synapse. The selegiline SmPC contraindicates the combination with SSRIs because of the risk of serotonin syndrome and names fluoxetine. The FDA label for the selegiline patch reports serious, sometimes fatal central nervous system toxicity when nonselective MAO inhibitors are combined with serotonergic drugs. The FDA label for selegiline in Parkinson's disease reports fatal and non-fatal cases of serotonin syndrome in patients treated with antidepressants together with selegiline. Because fluoxetine is cleared so slowly, the risk persists for weeks after it is stopped. That is why the documents require a 5-week gap before selegiline is started.

For the combination with selective serotonin reuptake inhibitors (SSRIs), the selegiline SmPC lists confusion, hypomania, hallucinations and manic episodes, agitation, myoclonus, hyperreflexia, incoordination, shivering, tremor, seizures, ataxia, sweating, diarrhoea, fever and hypertension. All of these can be part of serotonin syndrome. The fluoxetine SmPC describes the reaction with a monoamine oxidase (MAO) inhibitor as hyperthermia, rigidity, myoclonus, autonomic instability with rapid swings in vital signs, and mental changes ranging from confusion and irritability to extreme agitation, delirium and coma. The US Food and Drug Administration (FDA) label for the selegiline patch adds tachycardia, labile blood pressure, nausea and vomiting.

The combination is contraindicated. The selegiline SmPC names fluoxetine among the drugs selegiline must not be used with (section 4.3) and bans selegiline with all selective serotonin reuptake inhibitors (SSRIs) (section 4.5). The US Food and Drug Administration (FDA) label for the selegiline patch contraindicates fluoxetine (section 4). The FDA fluoxetine label contraindicates monoamine oxidase (MAO) inhibitors intended to treat psychiatric disorders (section 4.1). The fluoxetine SmPC itself only asks for caution and closer follow-up with selegiline, but the stricter documents take precedence. When switching from selegiline to fluoxetine, allow at least 14 days after stopping selegiline (selegiline SmPC, section 4.5; FDA label for selegiline in Parkinson's disease; FDA fluoxetine label). When switching from fluoxetine to selegiline, allow at least 5 weeks after the last dose of fluoxetine, because fluoxetine and norfluoxetine are cleared so slowly (selegiline SmPC, sections 4.3 and 4.5; FDA label for the selegiline patch; FDA fluoxetine label). The FDA label for selegiline in Parkinson's disease allows an even longer gap after prolonged or high-dose fluoxetine. If a patient is already taking both, stop both immediately at the first signs of serotonin syndrome and start supportive treatment (FDA label for the selegiline patch; FDA fluoxetine label). The fluoxetine SmPC allows cyproheptadine or dantrolene for such a reaction. No selegiline dose reduction is needed for fluoxetine's inhibition of CYP3A4. The FDA label for the selegiline patch requires no dose adjustment with CYP3A4 inhibitors, and in the FDA label for selegiline in Parkinson's disease itraconazole did not change selegiline pharmacokinetics.