Co-Administration of Roflumilast (Daliresp) and Phenytoin
Co-administering roflumilast and phenytoin is contraindicated and should be avoided. Phenytoin is a strong CYP450 enzyme inducer that significantly reduces roflumilast exposure, potentially eliminating its therapeutic effectiveness in COPD management 1.
Mechanism of Drug Interaction
Roflumilast metabolism depends critically on CYP3A4 and CYP1A2 enzymes for N-oxidation to its active metabolite, roflumilast N-oxide. 1 Phenytoin, as a potent CYP450 inducer, accelerates this metabolism and dramatically reduces plasma concentrations of both roflumilast and its active metabolite 1.
- The FDA label explicitly states that "the use of strong cytochrome P450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) with roflumilast is not recommended" 1
- Strong CYP inducers result in reduced roflumilast exposure, which may decrease therapeutic effectiveness 1
- This interaction is classified as a "red light" contraindication in hepatitis C treatment guidelines using similar drug interaction principles, where phenytoin co-administration with drugs metabolized by CYP3A4 is contraindicated 2
Clinical Implications
If a patient requires both medications, alternative anticonvulsants that do not induce CYP450 enzymes should be considered. 2
- Phenytoin cannot be simply dose-adjusted to overcome this interaction—the induction effect is too profound 1
- The interaction affects both the parent compound and the active N-oxide metabolite, which has a long half-life and is responsible for roflumilast's once-daily dosing efficacy 3
- Loss of roflumilast efficacy means loss of exacerbation reduction in severe COPD patients with chronic bronchitis, the specific population for whom this drug is indicated 4, 5
Alternative Management Strategies
For seizure management in patients requiring roflumilast:
- Consider non-enzyme-inducing anticonvulsants such as levetiracetam, gabapentin, or lamotrigine (at stable doses) that do not significantly affect CYP450 enzymes 2
- If phenytoin is absolutely necessary for seizure control, roflumilast should be discontinued and alternative COPD therapies pursued 1
For COPD management in patients requiring phenytoin:
- Escalate to LAMA/LABA/ICS triple therapy if the patient has high exacerbation risk (≥2 moderate or ≥1 severe exacerbation in the past year) 2
- Consider adding macrolide maintenance therapy (azithromycin) if appropriate, ensuring no QT prolongation concerns or drug interactions with phenytoin 2
- N-acetylcysteine may be considered as an alternative add-on therapy for patients with chronic bronchitic phenotype 2
Monitoring Considerations
If phenytoin must be initiated in a patient currently taking roflumilast:
- Discontinue roflumilast before starting phenytoin 1
- Monitor for increased COPD exacerbations after roflumilast discontinuation 4
- Reassess COPD control within 2-4 weeks and optimize alternative maintenance therapies 2
Common pitfall: Attempting to increase roflumilast dose to overcome the interaction is ineffective and not recommended, as the enzymatic induction effect cannot be overcome by dose escalation 1.