Perfil de seguridad de nirmatrelvir-ritonavir: evidencia de eventos adversos por interacciones farmacológicas / Safety profile of nirmatrelvir-ritonavir: Evidence of adverse events due to drug-drug interactions

Objetivo: evaluar el perfil de seguridad de nirmatrelvir-ritonavir (NMV-r) en la práctica clínica real y analizar la relevancia clínica de las interacciones farmacológicas en el desarrollo de eventos adversos. Material y métodos: estudio observacional, retrospectivo en el que se evaluaron los datos de seguridad de pacientes tratados con NMV-r entre abril y julio de 2022. Se recopilaron datos demográficos y analíticos antes de comenzar el tratamiento. La duración del seguimiento fue de 28 días y se evaluó el número reacciones adversas reportadas, así como si fueron manejadas de forma ambulatoria o precisaron de asistencia sanitaria especializada y la presencia de deterioro de la función renal y hepática. Se revisó el tratamiento concomitante, identificando interacciones farmacológicas teóricas (IFT) cuya gravedad fue definida mediante la clasificación Lexi-interact. Resultados: el estudio incluyó 146 pacientes, 82 (56,16 %) eran mujeres, cuya mediana de edad fue de 65 años (22-95). El número de IFT detectadas y mantenidas durante el tratamiento con NMV-r fue de 164, siendo el porcentaje de pacientes con al menos una interacción de 62,33%. La mediana de IFT por paciente fue de uno (0-5). En 18 pacientes (11,84%) se reportó al menos un evento adverso (EA). Once EA se relacionaron potencialmente con alguna IFT, 7 pacientes requirieron contacto con asistencia hospitalaria para el manejo del EA, 8 pacientes presentaron deterioro de la función renal y 2 de la función hepática a los 28 días. Los principales grupos de fármacos implicados en la aparición de algún EA fueron los anticoagulantes orales, así como los calcio-antagonistas. Conclusiones: nuestros resultados muestran un elevado número de IFT detectadas entre NMV-r y otros fármacos, aunque la frecuencia de EA asociados fue baja. Este estudio proporciona un mayor conocimiento de los fármacos implicados en dichas interacciones y su potencial relación con la aparición de EA.(AU)

Objective: The aim of the study was to evaluate the safety profile of nirmatrelvir-ritonavir (NMV-r) in real clinical practice and to analyze the clinical relevance of drug-drug interactions in the development of adverse events. Methods: Observational, retrospective study in which safety data of patients treated with NMV-r between April and July 2022 in an outpatient setting were evaluated. The duration of follow-up was 28 days and the number of adverse reactions reported, as well as whether they were managed on an outpatient basis or required health care, and the presence of renal and hepatic function impairment were assessed. Concomitant treatment was reviewed, identifying theoretical drug-drug interactions (TDDIs) whose severity was defined using the Lexi-interact classification. Results: The study included 146 patients, 82 (56,16%) were women, whose median age was 65 years (22-95). The number of TDDIs detected and maintained during treatment with NMV-r was 164, with the percentage of patients with at least one interaction being 62,33%. The median number of TDDIs per patient was 1 (0-5). At least 1 adverse event (AE) was reported in 18 patients (11,84%). Eleven AEs were potentially related to any TDDI. Seven patients required contact with hospital assistance for AE management. Eight patients had impaired renal function and 2 had impaired liver function at 28 days. The main groups of drugs implicated in the occurrence of an AE were oral anticoagulants and calcium antagonists. Conclusions: Our results show a high number of TDDIs detected were detected between NMV-r and other drugs. This study provides greater knowledge of the drugs involved in such interactions and their potential relationship with the occurrence of adverse events.(AU)

Safety profile of nirmatrelvir-ritonavir: Evidence of adverse events due to DDIs / Perfil de seguridad de nirmatrelvir-ritonavir: evidencia de eventos adversos por interacciones farmacológicas

Objetivo: evaluar el perfil de seguridad de nirmatrelvir-ritonavir (NMV-r) en la práctica clínica real y analizar la relevancia clínica de las interacciones farmacológicas en el desarrollo de eventos adversos. Material y métodos: estudio observacional, retrospectivo en el que se evaluaron los datos de seguridad de pacientes tratados con NMV-r entre abril y julio de 2022. Se recopilaron datos demográficos y analíticos antes de comenzar el tratamiento. La duración del seguimiento fue de 28 días y se evaluó el número reacciones adversas reportadas, así como si fueron manejadas de forma ambulatoria o precisaron de asistencia sanitaria especializada y la presencia de deterioro de la función renal y hepática. Se revisó el tratamiento concomitante, identificando interacciones farmacológicas teóricas (IFT) cuya gravedad fue definida mediante la clasificación Lexi-interact. Resultados: el estudio incluyó 146 pacientes, 82 (56,16 %) eran mujeres, cuya mediana de edad fue de 65 años (22-95). El número de IFT detectadas y mantenidas durante el tratamiento con NMV-r fue de 164, siendo el porcentaje de pacientes con al menos una interacción de 62,33%. La mediana de IFT por paciente fue de uno (0-5). En 18 pacientes (11,84%) se reportó al menos un evento adverso (EA). Once EA se relacionaron potencialmente con alguna IFT, 7 pacientes requirieron contacto con asistencia hospitalaria para el manejo del EA, 8 pacientes presentaron deterioro de la función renal y 2 de la función hepática a los 28 días. Los principales grupos de fármacos implicados en la aparición de algún EA fueron los anticoagulantes orales, así como los calcio-antagonistas. Conclusiones: nuestros resultados muestran un elevado número de IFT detectadas entre NMV-r y otros fármacos, aunque la frecuencia de EA asociados fue baja. Este estudio proporciona un mayor conocimiento de los fármacos implicados en dichas interacciones y su potencial relación con la aparición de EA.(AU)

Objective: The aim of the study was to evaluate the safety profile of nirmatrelvir-ritonavir (NMV-r) in real clinical practice and to analyze the clinical relevance of drug-drug interactions in the development of adverse events. Methods: Observational, retrospective study in which safety data of patients treated with NMV-r between April and July 2022 in an outpatient setting were evaluated. The duration of follow-up was 28 days and the number of adverse reactions reported, as well as whether they were managed on an outpatient basis or required health care, and the presence of renal and hepatic function impairment were assessed. Concomitant treatment was reviewed, identifying theoretical drug-drug interactions (TDDIs) whose severity was defined using the Lexi-interact classification. Results: The study included 146 patients, 82 (56,16%) were women, whose median age was 65 years (22-95). The number of TDDIs detected and maintained during treatment with NMV-r was 164, with the percentage of patients with at least one interaction being 62,33%. The median number of TDDIs per patient was 1 (0-5). At least 1 adverse event (AE) was reported in 18 patients (11,84%). Eleven AEs were potentially related to any TDDI. Seven patients required contact with hospital assistance for AE management. Eight patients had impaired renal function and 2 had impaired liver function at 28 days. The main groups of drugs implicated in the occurrence of an AE were oral anticoagulants and calcium antagonists. Conclusions: Our results show a high number of TDDIs detected were detected between NMV-r and other drugs. This study provides greater knowledge of the drugs involved in such interactions and their potential relationship with the occurrence of adverse events.(AU)

[Translated article] Safety profile of nirmatrelvir-ritonavir: Evidence of adverse events due to DDIs.

OBJECTIVE: The aim of the study was to evaluate the safety profile of nirmatrelvir-ritonavir (NMV-r) in real clinical practice and to analyse the clinical relevance of drug-drug interactions in the development of adverse events. METHODS: Observational, retrospective study in which safety data of patients treated with NMV-r between April and July 2022 in an outpatient setting were evaluated. The duration of follow-up was 28 days and the number of adverse reactions reported, as well as whether they were managed on an outpatient basis or required health care, and the presence of renal and hepatic function impairment were assessed. Concomitant treatment was reviewed, identifying theoretical drug-drug interactions (TDDIs) whose severity was defined using the Lexi-interact classification. RESULTS: The study included 146 patients. 82 (56.16%) were women, whose median age was 65 years (22-95). the number of TDDIs detected and maintained during treatment with NMV-r was 164, with the percentage of patients with at least 1 interaction being 62.33%. The median number of TDDIs per patient was 1 (0-5). At least 1 adverse event (AE) was reported in 18 patients (11.84%). 11 AEs were potentially related to any TDDI. 7 patients required contact with hospital assistance for AE management. 8 patients had impaired renal function and 2 had impaired liver function at 28 days. The main groups of drugs implicated in the occurrence of an AE were oral anticoagulants and calcium antagonists. CONCLUSIONS: Our results show a high number of TDDIs detected were detected between NMV-r and other drugs. This study provides greater knowledge of the drugs involved in such interactions and their potential relationship with the occurrence of adverse events.

Safety profile of nirmatrelvir-ritonavir: Evidence of adverse events due to drug-drug interactions. / Perfil de seguridad de nirmatrelvir-ritonavir: evidencia de eventos adversos por interacciones farmacológicas.

OBJECTIVE: The aim of the study was to evaluate the safety profile of nirmatrelvir-ritonavir (NMV-r) in real clinical practice and to analyze the clinical relevance of drug-drug interactions in the development of adverse events. METHODS: Observational, retrospective study in which safety data of patients treated with NMV-r between April and July 2022 in an outpatient setting were evaluated. The duration of follow-up was 28 days and the number of adverse reactions reported, as well as whether they were managed on an outpatient basis or required health care, and the presence of renal and hepatic function impairment were assessed. Concomitant treatment was reviewed, identifying theoretical drug-drug interactions (TDDIs) whose severity was defined using the Lexi-interact classification. RESULTS: The study included 146 patients, 82 (56,16%) were women, whose median age was 65 years (22-95). The number of TDDIs detected and maintained during treatment with NMV-r was 164, with the percentage of patients with at least one interaction being 62,33%. The median number of TDDIs per patient was 1 (0-5). At least 1 adverse event (AE) was reported in 18 patients (11,84%). Eleven AEs were potentially related to any TDDI. Seven patients required contact with hospital assistance for AE management. Eight patients had impaired renal function and 2 had impaired liver function at 28 days. The main groups of drugs implicated in the occurrence of an AE were oral anticoagulants and calcium antagonists. CONCLUSIONS: Our results show a high number of TDDIs detected were detected between NMV-r and other drugs. This study provides greater knowledge of the drugs involved in such interactions and their potential relationship with the occurrence of adverse events.

Effectiveness and Adverse Events of Nirmatrelvir/Ritonavir Versus Molnupiravir for COVID-19 in Outpatient Setting: Multicenter Prospective Observational Study.

BACKGROUND: In this study, we aimed to compare the effectiveness and adverse reactions of nirmatrelvir/ritonavir and molnupiravir in high-risk outpatients with coronavirus disease 2019 (COVID-19). METHODS: This multicenter prospective observational study evaluated the rate of hospitalization, death, and adverse events within 28 days of oral antiviral agent prescription (molnupiravir, n = 240; nirmatrelvir/ritonavir, n = 240) to 480 nonhospitalized adult patients with COVID-19 from August 2, 2022 to March 31, 2023. RESULTS: Patients receiving molnupiravir had a higher prevalence of comorbidities (85.8% vs. 70.4%; P < 0.001) and a higher Charlson comorbidity index (2.8 ± 1.4 vs. 2.5 ± 1.5; P = 0.009) than those receiving nirmatrelvir/ritonavir. Three patients required hospitalization (nirmatrelvir/ritonavir group, n = 1 [0.4%]; molnupiravir group, n = 2 [0.8%]; P = 1.000). Nirmatrelvir/ritonavir was associated with a higher risk of adverse events than molnupiravir (odds ratio [OR], 1.96; 95% confidence interval [CI], 1.27-3.03), especially for patients aged 65 years and older (OR, 3.04; 95% CI, 1.71-5.39). The severity of adverse events in both groups was mild to moderate and improved after discontinuation of medication. In the molnupiravir group, age ≥ 65 years (OR, 0.43 95% CI, 0.22-0.86) and appropriate vaccination (OR, 0.37; 95% CI, 0.15-0.91) reduced the occurrence of adverse events. CONCLUSION: The rates of hospitalization and death were low and not significantly different between high-risk patients who received either nirmatrelvir/ritonavir or molnupiravir. Although adverse events were more frequent with nirmatrelvir/ritonavir than with molnupiravir, none were severe. Nirmatrelvir/ritonavir can be safely used to treat COVID-19, while molnupiravir could be considered as an alternative treatment option for high-risk groups.

Serotonin Syndrome Precipitated by Paxlovid Initiation.

A female in her early 40s taking buspirone, quetiapine, and daily kratom presented to the emergency department two days after starting a course of Paxlovid for a mild COVID-19 infection with diffuse tremors, ocular clonus, diaphoresis, and confusion consistent with serotonin syndrome (SS). The patient was treated with oral lorazepam, and her symptoms significantly improved within one hour without the need for additional dosing. To our knowledge, this is the first reported case of SS in a COVID-19-positive patient who was prescribed Paxlovid. Clinicians should be mindful of the potential interactions of Paxlovid with serotonergic agents, and they should consider reducing the dose of these agents or selecting other therapeutics to treat COVID-19 infection in these patients.

Clinical efficacy of nirmatrelvir and ritonavir combination for treating diabetic patients with COVID-19.

The aim of this study was to investigate the clinical efficacy of a combination of nirmatrelvir and ritonavir (NMV-r) for treating COVID-19 in patients with diabetes mellitus (DM). This retrospective cohort study used the TriNetX research network to identify adult diabetic patients with COVID-19 between January 1, 2020, and December 31, 2022. Propensity score matching was used to match patients who received NMV-r (NMV-r group) with those who did not receive NMV-r (control group). The primary outcome was all-cause hospitalization or death during the 30-day follow-up period. Two cohorts comprising 13 822 patients with balanced baseline characteristics were created using propensity score matching. During the follow-up period, the NMV-r group had a lower risk of all-cause hospitalization or death than the control group (1.4% [n = 193] vs. 3.1% [n = 434]; hazard ratio [HR], 0.497; 95% confidence interval [CI], 0.420-0.589). Compared with the control group, the NMV-r group also had a lower risk of all-cause hospitalization (HR, 0.606; 95% CI, 0.508-0.723) and all-cause mortality (HR, 0.076; 95% CI, 0.033-0.175). This lower risk was consistently observed in almost all subgroup analyses, which examined sex (male: 0.520 [0.401-0.675]; female: 0.586 [0.465-0.739]), age (age 18-64 years: 0.767 [0.601-0.980]; ≥65 years: 0.394 [0.308-0.505]), level of HbA1c (<7.5%: 0.490 [0.401-0.599]; ≥7.5%: 0.655 [0.441-0.972]), unvaccinated (0.466 [0.362-0.599]), type 1 DM (0.453 [0.286-0.718]) and type 2 DM (0.430 [0.361-0.511]). NMV-r can help reduce the risk of all-cause hospitalization or death in nonhospitalized patients with DM and COVID-19.

Clinical effectiveness of oral antiviral agents in older patients with COVID-19 based on real-world data.

Several randomized controlled trials and real-world cohort studies have demonstrated the efficacies of nirmatrelvir plus ritonavir (NMV-r) and molnupiravir (MOV) in at-risk patients with COVID-19; however, the effectiveness of antisevere acute respiratory syndrome-coronavirus 2 treatments on older patients (≥65 years) remains unclear. This retrospective cohort study aimed to assess the clinical effectiveness of the oral antiviral agents, MOV and NMV-r, in older patients (≥65 years) infected with severe acute respiratory syndrome-coronavirus 2. Nonhospitalized older patients with COVID-19 between January 1, 2022, and December 31, 2022, were recruited from the TriNetX Research Network. Propensity score matching (PSM) was used to match patients who received either NMV-r or MOV treatment with those who did not receive any oral antiviral agents. Hazard ratios (HRs) for composite all-cause hospitalization or death during the 30-day follow-up period were calculated. PSM revealed two cohorts with 28 824 patients each having balanced baseline characteristics. The antiviral group was associated with significantly lower risk of the primary composite outcome of all-cause hospitalization or death than the control group (241 vs. 801; HR, 0.307; 95% confidence interval (CI), 0.27-0.36) during the follow-up period. For the secondary outcome, the antiviral group had a significantly lower risk of all-cause hospitalization (288 vs. 725; HR, 0.322; 95% CI, 0.28-0.37) and mortality (16 vs. 94; HR, 0.176; 95% CI, 0.10-0.30) than the control group. Moreover, the reduced risk of all-cause hospitalization or death remained consistent in patients receiving NMV-r (HR, 0.279; 95% CI, 0.24-0.33) and MOV (HR, 0.279; 95% CI, 0.21-0.38). Our results revealed that NMV-r and MOV decreased the all-cause hospitalization and death rates among older patients with COVID-19, supporting the use of antivirals in this vulnerable population.

Efficacy of nirmatrelvir and ritonavir for post-acute COVID-19 sequelae beyond 3 months of SARS-CoV-2 infection.

The effect of nirmatrelvir plus ritonavir (NMV-r) on post-acute COVID-19 sequelae beyond 3 months of SARS-CoV-2 infection remains unknown. This retrospective cohort study utilized data from the TriNetX Research Network. We identified nonhospitalized adult patients with COVID-19 receiving a diagnosis between January 1 and July 31, 2022. Propensity score matching (PSM) was used to create two matched cohorts: NMV-r and non-NMV-r groups, respectively. We measured the primary outcomes using a composite of all-cause emergency room (ER) visits or hospitalization and a composite of post-COVID-19 symptoms according to the WHO Delphi consensus, which also stated that post COVID-19 condition occurs usually 3 months from the onset of COVID-19, during the follow-up period between 90 days after the index diagnosis of COVID-19 and the end of follow-up (180 days). Initially, we identified 12 247 patients that received NMV-r within 5 days of diagnosis and 465 135 that did not. After PSM, 12 245 patients remained in each group. During the follow-up period, patients treated with NMV-r had a lower risk of all-cause hospitalization and ER visits compared with untreated patients (659 vs. 955; odds ratio [OR], 0.672; 95% confidence interval [CI], 0.607-0.745; p < 0.0001). However, the overall risk of post-acute COVID-19 symptoms did not significantly differ between the two groups (2265 vs. 2187; OR, 1.043; 95% CI, 0.978-1.114; p = 0.2021). The reduced risk of all-cause ER visits or hospitalization in the NMV-r group and the similarities in the risk of post-acute COVID-19 symptoms between the two groups were consistent in the subgroups stratified by sex, age, and vaccination status. Early NMV-r treatment of nonhospitalized patients with COVID-19 was associated with reduced risk of hospitalization and ER visits during the period of 90-180 days after diagnosis compared with no NMV-r treatment; however, post-acute COVID-19 symptoms and mortality risk did not differ significantly between the groups.

Optimizing the use of nirmatrelvir/ritonavir in solid organ transplant recipients with COVID-19: A review of immunosuppressant adjustment strategies.

The coronavirus disease 2019 (COVID-19) pandemic has caused a significant burden of morbidity and mortality worldwide, with solid organ transplant recipients (SOTRs) being particularly vulnerable. Nirmatrelvir and ritonavir have demonstrated the potential for reducing the risk of hospitalization and death in patients with mild-to-moderate COVID-19. However, ritonavir has a strong drug-drug interaction with CYP3A-dependent drugs such as calcineurin inhibitors, potentially leading to rapid increases in blood concentration. As SOTRs are commonly prescribed immunosuppressants, co-administration with nirmatrelvir/ritonavir requires careful consideration. To address this issue, we conducted a literature review to evaluate the use and adverse effects of nirmatrelvir/ritonavir in SOTRs and explore feasible immunosuppressant adjustment regimens. Our findings suggest that nirmatrelvir/ritonavir could be a feasible treatment option for COVID-19 in SOTRs, provided that appropriate immunosuppressive drug management is in place during co-administration. Although prescribing the novel anti-SARS-CoV-2 drug to transplant recipients poses challenges, potential strategies to overcome these issues are discussed. Further studies are needed to determine the optimal dosing strategies of nirmatrelvir/ritonavir, immunosuppressant adjustment, and monitoring in this patient population.

Nirmatrelvir/Ritonavir Prescription Rate and Outcomes in Coronavirus Disease 2019: A Single Center Study.

BACKGROUND: Nirmatrelvir/ritonavir was Korea's first oral antiviral agent to treat coronavirus disease 2019 (COVID-19). We analyzed the nirmatrelvir/ritonavir prescription rate and treatment outcomes in treatment-eligible patients with COVID-19 receiving home-based care. MATERIALS AND METHODS: We retrospectively collected data of patients with COVID-19-eligible for nirmatrelvir/ritonavir treatment from January 14, 2022, to February 15, 2022. We analyzed the prescription rate of nirmatrelvir/ritonavir, the reasons for non-prescription, and patient outcomes. RESULTS: A total of 414 patients were included, of whom 44.2% were male, and the mean age was 64.6 (standard deviation [SD] = 8.5). Approximately 73.2% (n = 303) of patients were not prescribed nirmatrelvir/ritonavir. More than fourth-fifths of the patients refused nirmatrelvir/ritonavir treatment (n = 262, 86.5%). The mean symptom duration was significantly shorter in the prescription group (5.2 days [SD = 2.3] vs. 4.4 days [SD = 1.9], P = 0.001). A total of 6 (1.4%) patients were hospitalized, and none of the patients who received nirmatrelvir/ritonavir required admission. Among the patients prescribed nirmatrelvir/ritonavir (n = 111), 17 (15.3%) patients experienced side effects, and 5 (4.5%) patients discontinued nirmatrelvir/ritonavir due to side effects. CONCLUSION: The nirmatrelvir/ritonavir prescription rate was low, with more than fourth-fifths of non-prescriptions being due to patient refusal. Symptom resolution was faster, and no life-threatening side effects were reported. Accurate information about drug safety must be provided to patients to make informed decisions regarding nirmatrelvir/ritonavir treatment.