Adverse drug reactions during long-term use of two targeted drugs in pediatric patients with cystic fibrosis in the Russian Federation

In the Russian Federation, patients with cystic fibrosis (CF) under 19 years of age receive targeted therapy with two drugs: lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor. Currently, a large volume of information has accumulated regarding possible adverse drug reactions (ADRs) during long-term targeted therapy in children with CF. The aim of the study was to investigate the ADR profile associated with long-term use of CFTR modulators in children with CF. Methods. Data on the targeted therapy were taken from the Russian registry of CF patients (2021 – 2024). The data of 392 patients at the start of therapy with lumacaftor/ivacaftor, 196 patients after 1 year, and 36 patients after 2 years were analyzed. The data of 220 patients at the start of therapy with elexacaftor/tezacaftor/ivacaftor, 214 patients after 1 year, and 43 patients after 2 years were analyzed. Early adverse reactions were assessed within 30 days from the start of therapy. Change in the adverse reaction profile was assessed after 360 and 720 days. Results. The number of adverse reactions in patients receiving lumacaftor/ivacaftor was 51.27 % for 1 month. It decreased more than 2-fold (20.4 %) by the end of the 1st year (p1–2 < 0.001) due to a decrease in the number of patients with cough, shortness of breath, elevated alanine aminotransferase (ALT) / aspartate aminotransferase (AST) levels, and diarrhea. After 2 years, the incidence of adverse reactions was 55.5 % (p2–3 < 0.001), the number of patients with subfebrile body temperature/fever increased (p2–3 < 0.001; p1–3 < 0.001), the rate of fatigue increased to 11.1 % (p2–3 = 0.029), and the rate of sleep disturbance increased (from 0.25% at the start to 11.1 % after 2 years of therapy; p1–3 < 0.001; p2–3 < 0.001). The average incidence of adverse reactions per patient was 2.27 ± 0.45 for lumacaftor/ivacaftor. The total incidence of ADRs with elexacaftor/tezacaftor/ivacaftor combination therapy was 48.2 % at the start, 19.6 % after 1 year (p1–2 < 0.001), and increased to 41.9 % after 2 years (p2–3 < 0.001) due to subfebrile body temperature/fever – from 1.9 to 6.9 % (p1–3 = 0.032), headache – from 2.3 to 11.6 % (p1–3 = 0.003), and fatigue – up to 13.9 % (p1–3 < 0.001; p2–3 = 0.002). The average incidence of ADRs per patient was 2.56 ± 0.71 with elexacaftor/tezacaftor/ivacaftor combination therapy. More ADRs were observed at the start of therapy with lumacaftor/ivacaftor compared to elexacaftor/tezacaftor/ivacaftor (p = 0.019). The frequency of elevated ALT/AST levels at the start of therapy with lumacaftor/ivacaftor was higher than for elexacaftor/tezacaftor/ivacaftor (p = 0.02). Rash was observed more often at the start of therapy with elexacaftor/tezacaftor/ivacaftor (p < 0.001), fatigue – at the start of lumacaftor/ivacaftor (p = 0.011). No difference in the ADR profile was found after 2 years of therapy. Conclusion. A higher number of ADRs was associated with lumacaftor/ivacaftor compared to elexacaftor/tezacaftor/ivacaftor. Over time, the main adverse drug reactions associated with respiratory and gastrointestinal symptoms resolve, but the number of patients complaining of fatigue, sleep disturbances, headaches, subfebrile temperature and fever increases, requiring active follow-up and adjustment of the therapy if necessary.