A case of extrapyramidal side effects due to possible paliperidone: voriconazole interaction

Background It is thought that paliperidone, an active metabolite of risperidone, has limited potential for pharmacokinetic drug–drug interactions (DDIs) due to minimal metabolism by cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2D6 (CYP2D6). However, DDIs have been reported and include a theoretical interaction between paliperidone and voriconazole based on interactions between risperidone and strong CYP3A4 inhibitor azoles. Aim To describe the first recorded DDI between paliperidone and voriconazole leading to extrapyramidal side effects (EPSEs). Clinical details A 34‐year‐old male presented with febrile neutropenia presumed due to clozapine. Clozapine was ceased and paliperidone commenced with voriconazole added to the patient's empiric piperacillin/tazobactam therapy due to a suspected fungal infection. Two days after starting voriconazole, the patient developed hypertonia and hyperreflexia in all limbs, thought most likely to be antipsychotic induced EPSEs. Paliperidone was withheld and EPSEs resolved. Outcomes The patient had previously tolerated long‐term paliperidone at higher doses, prior to transitioning to clozapine. The development of EPSEs occurred two days post azole initiation, indicating a probable paliperidone adverse drug reaction (ADR) due to strong CYP3A4 inhibition by voriconazole. This case appears to be the first documented report of this previous theoretical DDI in practice. Further studies, including therapeutic drug monitoring, are required to confirm findings. Conclusion Paliperidone may be affected by pharmacokinetic drug–drug interactions and patients should be monitored for ADRs when CYP3A4 inhibitors are concomitantly administered.