An interim analysis of an ongoing phase 2/3 single-arm, open-label clinical trial (CARAVAN study; N= 53) on safety, tolerability, pharmacokinetics, and efficacy of remdesivir in patients aged <18 years with coronavirus disease 2019 (COVID-19) was presented in the 29th Conference on Retroviruses and Opportunistic Infections (February 12-16, 2022). Pediatric patients were placed into 5 cohorts (cohorts 1, 2, 3, 4, and 8) based on age and weight. Cohorts 1 and 8 included children weighing ≤ 40 kg who received 200 mg on Day 1 followed by 100 mg daily whereas cohorts 2-4 included children weighing <40 kg who received weight-based dosing of 5mg/kg on Day 1 followed by 2.5 mg/kg daily. The interim results demonstrated that remdesivir was generally well tolerated in the pediatric population hospitalized with COVID-19. The most common reported adverse event was constipation (17%), followed by acute kidney injury (11%), hyperglycemia (9%), pyrexia (9%), and increased alanine transaminase (8%). There were no reports of bradycardia presented in this interim analysis. The estimated completion date of the study is February 2023. [1]
A 2021 letter to editor described the observation of sinus bradycardia in children treated with remdesivir for COVID-19 in several pediatric case reports. An 11-year-old male with advanced neuronal ceroid lipofuscinoses type 2 experienced COVID-19 pneumonia and developed episodes of sinus bradycardia (heart rate dropped to 59 beats per minutes [bpm] from 90 to 100 bpm at baseline) on day 3 and day 4 of receiving remdesivir. Another 13-year-old male with primordial dwarfism also had symptoms of pneumonia and was in demand of oxygen. On day 5 of receiving remdesivir, his heart rate dropped from > 100 bpm at baseline to 56 bpm. Both patients survived, although suffered from further residual lung damage aggravating their chronic disease. A third 7-year-old female with dystrophy, mild microcephaly, and hypothyroidism developed critical COVID-19 disease for which remdesivir was initiated. The patient experienced severe sinus bradycardia (38 bpm) on day 5 of remdesivir treatment despite having confirmation of remdesivir and its metabolite being within target levels. However, she also had severe myocarditis leading to extracorporeal life support, hemofiltration, catecholamine use, and multiple other drugs that could be responsible for bradycardia. She succumbed to fulminant COVID-19. Another letter to the editor also reported that 3 out 4 children who were treated with remdesivir in a single-center hospital with normal cardiologic evaluation developed asymptomatic sinus bradycardia. Remedivir was only discontinued in an infant whereas the other two older children completed the 5-day therapy period. Having an uncomplicated course, all three patients were discharged after a median of 5 days (range 4-7). The authors emphasized the importance of continuous cardiac monitoring as well as therapeutic drug monitoring in pediatric patients, especially those with pre-existing cardiac conditions. [2], [3]
A 2021 article described while the available literature regarding the incidence of arrhythmia in children with COVID-19 is limited to case reports, some small case series reported up to 16% arrhythmia in children who were treated with remdesivir; however, the arrhythmia was reported to be mild or less harmful in nature compared to ones reported in adult cases. Given the limited data on the association of bradycardia and remdesivir utilized in children with COVID-19, performing electrocardiographic monitoring in all children with COVID-19, especially those with a cardiac underlying condition is warranted. [4], [5]
A 2019 case report and review of literature described a post-marketing study that found that patients who received remdesivir had a 1.7-fold increased odds of developing bradycardia than those treated with other COVID-19 therapies. Several pediatric cases reported remdesivir-induced bradycardia (see Tables 1-2). Several adult case reports also exist confirming the potential for remdesivir-induced bradycardia. As the safety and effectiveness of remdesivir treatment in pediatric patients <12 years had not been assessed in depth at the time of the review, the authors noted that pediatricians should be aware of this potential cardiovascular effect of remdesivir administration. [6]