Acute Encephalopathy Due to Polypharmacy Interactions With the Use of Paxlovid: A Case Report

Paxlovid is an oral therapy in the treatment of COVID-19. It has been authorized by the Food and Drug Administration (FDA) to be used under the Emergency Use Authorization Act (EUAA) for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) who are at high-risk for progression to severe COVID-19 and remains under extended review for New Drug Application (NDA). Paxlovid comprises two anti-viral medications: nirmatrelvir and ritonavir, which cause significant drug-drug interactions. In this case report, an elderly patient received Paxlovid and had medication interactions with benzodiazepines and narcotics leading to altered mental status.


Introduction
Since the beginning of the COVID-19 pandemic, many options to either prevent or treat the disease have been proposed and tried. Paxlovid represents a pharmaceutical breakthrough as it is the first oral therapy for the treatment of SARS-CoV-2. Being utilized under the Emergency Use Authorization Act (EUAA), Paxlovid is not approved by FDA. Nevertheless, it is the most recently developed medication for the treatment of mild to moderate COVID-19 infections among patients at risk of progressing to serious disease. Furthermore, it can be used in patients aged 12 years and older who weigh over 40 kg [1]. In our report, we focus on several important drug-drug interactions with Paxlovid.

Case Presentation
The patient is a 74-year-old female with a past medical history of hypertension and chronic obstructive pulmonary disease (COPD), is wheelchair-bound, and had denied a significant past psychiatric history. She was recently treated for Clostridioides difficile, UTI, and COVID-19 symptoms at an outside facility. The patient was treated for COVID-19 with Paxlovid and discharged home with antibiotics for C. diff and UTI. The patient was admitted to our facility within 24 hours of that discharge due to concerns of weakness and an altered mental status (AMS). The medical team had ruled out medical causes for her chief complaints and consulted psychiatry for the AMS. A preliminary chart review was conducted prior to assessing the patient in the medical unit. Her home medications consisted of diazepam, acetaminophen-codeine, tramadol, gabapentin, pravastatin, nystatin, albuterol sulfate, bisoprolol fumarate, cholecalciferol, fluticasone propionate-salmeterol, ipratropium-albuterol, magnesium oxide, tiotropium bromide, and triamterene hydrochlorothiazide. The patient was not on antibiotics at the time of her ER presentation. The patient's liver enzymes were significantly elevated as well, so the primary team was advised of the polypharmacological interactions and advised to either hold or discontinue medications that may be impacting the liver enzymes. The primary team held benzodiazepine, tramadol, codeine, and statins. The patient's mental status started to return to baseline within 24 hours of holding the medications. She was soon discharged home at her baseline.

Discussion
As previously mentioned, Paxlovid is comprised of two anti-viral protease inhibitor medications: nirmatrelvir and ritonavir. Nirmatrelvir has activity against SARS-CoV-2 main protease, which leads to decreased viral replication. Ritonavir, on the other hand, has no activity against COVID-19 but is instead used because it is a potent cytochrome P450 3A (CYP3A) inhibitor, which leads to increased levels of nirmatrelvir and delays its clearance [2,3]. Ritonavir is used as a pharmacokinetic enhancer or boosting agent and is required in this combination for nirmatrelvir to be able to reach its therapeutic levels to treat COVID-19 [3]. It should be noted that medications in this class are well-known for many significant drugdrug interactions.
The patient's age, duplicate narcotic medications, and her taking more than the recommended amounts of 1 2 prescription benzodiazepine put her at high risk for negative health outcomes. Both of Paxlovid's components have a known drug interaction to increase levels of diazepam through CYP3A4 inhibition as well as increasing tramadol serum concentration levels. Codeine may also have its levels altered by Paxlovid [3]. These interactions were most likely the primary cause of the patient's onset of confusion.
The National Health Institute (NIH) COVID treatment guidelines feature an extensive list of drug-drug interactions with Paxlovid (see Appendices) [4]. In addition, as of August 2022, the FDA released an updated checklist for potential risk factors and drug-drug interactions to be reviewed before administrating Paxlovid to patients ( Table 1) [5]. Although many medications can be safely taken while on Paxlovid, the drug-drug interaction list should still be referred to prior to and during treatment [4].

Conclusions
The introduction of Paxlovid as an oral therapy represents a significant step forward in the treatment of COVID-19. The main advantage of oral therapies over treatments completed in infusion centers allows the patient to save time and money. However, as it is a new medication with limited research and data, it will be the medical teams' responsibility to diligently monitor for significant drug-drug interactions when prescribing and administering Paxlovid and allow room for modifications as they see fit.

Appendices Prescribe Alternative COVID-19 Therapy
For these medications, management strategies are not possible or feasible, or the risks outweigh the potential benefits.

Continue Concomitant Medication and Monitor for Adverse Effects
Pre-emptive dose adjustment is not required but may be considered based on an individualized assessment of the patient's risk for adverse reactions.  Patients who are receiving higher doses of dexamethasone will be at a greater risk of AEs. k Patients should take ritonavir-boosted nirmatrelvir at least 3 hours after receipt of brincidofovir. l Ritonavir-boosted nirmatrelvir interacts with certain conjugated monoclonal antibodies, such as those conjugated to the drug monomethyl auristatin E (or vedotin). These include brentuximab vedotin, enfortumab vedotin, polatuzumab vedotin, and tisotumab vedotin.
Before coadministering ritonavir-boosted nirmatrelvir and any of these conjugated monoclonal antibodies, refer to the drug's FDA prescribing information and consult with the patient's specialist providers as needed. Key: AE = adverse effect; BPH = benign prostatic hyperplasia; CHA2DS2-VASc = congestive heart failure, hypertension, age, diabetes, stroke, vascular disease; CYP = cytochrome P450; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; LMWH = low-molecular-weight heparin; P-gp = P-glycoprotein

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.