Pharmacokinetic Interaction Causing Alprazolam Accumulation During COVID-19 Treatment
Patient Background
A 42-year-old female with a long-standing history of severe generalized anxiety disorder had been maintained on alprazolam 1 mg orally twice daily for several years with stable symptom control. She had no history of renal or hepatic impairment and was otherwise medically stable.
Clinical Presentation
Three days after being diagnosed with COVID-19, the patient was prescribed Paxlovid (nirmatrelvir/ritonavir) for a five-day treatment course. She continued her usual alprazolam regimen without dose adjustment.
Within 48–72 hours, she developed marked drowsiness, confusion, slurred speech, dizziness, and gait instability. Her husband reported near-fall episodes and an inability to remain alert during normal activities. She presented to the emergency department with excessive sedation, mild ataxia, and dysarthria, though she remained arousable. Vital signs were stable, and laboratory investigations, including renal function and electrolytes, were unremarkable.
Clinical Issue Identified
The patient’s presentation was consistent with benzodiazepine toxicity secondary to a drug–drug interaction. Ritonavir, a pharmacokinetic booster component of Paxlovid, is a potent inhibitor of cytochrome P450 3A4 (CYP3A4)—the primary enzyme responsible for the hepatic metabolism of alprazolam.
Inhibition of CYP3A4 resulted in reduced clearance and rapid accumulation of alprazolam, leading to supratherapeutic plasma concentrations. The clinical consequences included excessive sedation, impaired coordination, cognitive dysfunction, and increased fall risk, all of which were evident in this patient. The temporal relationship between Paxlovid initiation and symptom onset strongly supported this mechanism.
Pharmacist Intervention and Clinical Management
Immediate Medication Management
Hold alprazolam immediately to prevent further accumulation and toxicity.
Avoid flumazenil given the patient’s chronic benzodiazepine use and seizure risk.
Supportive Care and Monitoring
Provide close neurological monitoring until sedation resolves.
Implement fall precautions and ensure a safe environment.
Monitor respiratory status due to the risk of hypoventilation with benzodiazepine toxicity
Interaction Mitigation Strategy
- Educate the patient and caregivers regarding the interaction between ritonavir and benzodiazepines.
If anxiolytic therapy is required during future Paxlovid courses, consider:
- Temporary dose reduction or discontinuation of alprazolam
- Substitution with benzodiazepines less dependent on CYP3A4 metabolism (e.g., lorazepam, oxazepam)
Follow-Up and Long-Term Planning
Resume alprazolam cautiously after completion of Paxlovid and adequate ritonavir washout, if clinically necessary.
Document the interaction clearly in the medical record to prevent recurrence.
Reinforce the importance of medication review prior to initiating antivirals or other enzyme inhibitors
Clinical Rationale and Ramifications
This case highlights the clinical consequences of unrecognized pharmacokinetic drug–drug interactions, particularly involving strong CYP3A4 inhibitors such as ritonavir. Failure to adjust or withhold alprazolam resulted in acute benzodiazepine toxicity, placing the patient at risk for falls, respiratory depression, and cognitive impairment.
Given the widespread use of Paxlovid in outpatient COVID-19 management, clinicians must remain vigilant when prescribing it to patients receiving chronic benzodiazepine therapy. Proactive medication reconciliation and anticipatory dose adjustments can prevent serious adverse events.
This case underscores the critical role of pharmacist-led medication review, especially during acute care transitions. Recognizing enzyme-mediated interactions before therapy initiation is essential to ensure patient safety and avoid preventable harm.