From the FDA Drug Label
Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment.
Fluoxetine may increase phenytoin levels, leading to elevated plasma anticonvulsant concentrations and potential clinical anticonvulsant toxicity.
- Key points to consider:
- Elevated plasma concentrations: Concomitant use of fluoxetine and phenytoin may result in increased phenytoin levels.
- Clinical anticonvulsant toxicity: Patients may experience clinical anticonvulsant toxicity due to elevated phenytoin levels.
- Monitoring required: Close monitoring of patients is necessary when initiating concomitant fluoxetine treatment in those on stable doses of phenytoin. 1
From the Research
Prozac (fluoxetine) can significantly increase phenytoin levels in the blood when taken together, posing a risk of phenytoin toxicity due to fluoxetine's inhibition of the CYP2C9 liver enzyme that metabolizes phenytoin, as supported by a study published in 2021 2. When these medications are combined, phenytoin levels may rise due to fluoxetine's inhibition of the CYP2C9 liver enzyme. This interaction typically begins within a few weeks of starting Prozac and can lead to phenytoin toxicity with symptoms including:
- Dizziness
- Unsteady gait
- Slurred speech
- Confusion
- Nystagmus Patients taking both medications should have their phenytoin levels monitored closely, especially when starting, stopping, or changing the dose of Prozac. A phenytoin dose reduction may be necessary, but should be individualized based on blood level monitoring, as phenytoin has a narrow therapeutic window, meaning the difference between effective and toxic doses is small, as noted in a study published in 1997 3. The mechanism of fluoxetine-mediated CYP2D6 inhibition is also relevant, as fluoxetine and its active metabolite, norfluoxetine, are strong affinity substrates of CYP2D6 and can inhibit the metabolism of other sensitive CYP2D6 substrates, as discussed in a study published in 2021 2. Additionally, fluoxetine is a CYP2C9 substrate and a mechanism-based inhibitor of CYP2C19, which can further contribute to the increased phenytoin levels, as reported in a study published in 2002 4. It is essential to be aware of the P450 enzymes involved in drug metabolism to minimize and prevent these interactions, as highlighted in a study published in 1997 5. Patients should report any signs of toxicity to their healthcare provider immediately.