Adverse drug reactions during long-term use of two targeted drugs in pediatric patients with cystic fibrosis in the Russian Federation
A. Yu. Voronkova,
E. K. Zhekaite,
I. R. Fatkhullina,
O. I. Golubtsova,
E. A. Enina,
I. P. Karimova,
M. V. Erzutova,
A. V. Orlov,
M. G. Rybalkina,
T. I. Safonova,
D. F. Sergienko,
I. P. Shulyak,
E. I. Kondratyeva https://doi.org/10.18093/0869-0189-2025-35-2-202-212
Abstract
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.
Supporting agencies: The research was performed within the state assignment “Comprehensive analysis of genophenotypic correlations in cystic fibrosis and primary ciliary dyskinesia”, no. 122032300396-1 by Federal State Budgetary Scientific Institution “Research Centre for Medical Genetics” of the Ministry of Science and Higher Education of the Russian Federation
About the Authors
A. Yu. Voronkova
Federal State Budgetary Scientific Institution “Research Centre for Medical Genetics”, Ministry of Science and Higher Education of the Russian Federation; State Budgetary Healthcare Institution of the Moscow region “Research Clinical Institute of Childhood”, Healthcare Ministry of Moscow Region
Russian Federation
Competing Interests:
Russian Federation
Anna Yu. Voronkova, Candidate of Medicine, Leading Researcher, Pediatrician
Scientific and Clinical Department of Cystic Fibrosis; Department of Cystic Fibrosis
115522; ul. Moskvorechye 1; 115093; Serpukhovskaya 62; Moscow
tel.: (495) 324-20-24
Scopus Author ID: 57189352251; Web of Science Researcher ID: M-7191–2014
Competing Interests:
The authors did not declare any conflicts of interests
E. K. Zhekaite
Federal State Budgetary Scientific Institution “Research Centre for Medical Genetics”, Ministry of Science and Higher Education of the Russian Federation; State Budgetary Healthcare Institution of the Moscow region “Research Clinical Institute of Childhood”, Healthcare Ministry of Moscow Region
Russian Federation
Competing Interests:
Russian Federation
Elena K. Zhekaite, Candidate of Medicine, Senior Researcher, Pediatrician
Department of Cystic Fibrosis
115522; ul. Moskvorechye 1; 115093; Serpukhovskaya 62; Moscow
tel.: (499) 324-15-01
Scopus ID: 57216849405; Web of Science Researcher ID: K-2207-2018
Competing Interests:
The authors did not declare any conflicts of interests
I. R. Fatkhullina
Federal State Budgetary Scientific Institution “Research Centre for Medical Genetics”, Ministry of Science and Higher Education of the Russian Federation; State Budgetary Healthcare Institution of the Moscow region “Research Clinical Institute of Childhood”, Healthcare Ministry of Moscow Region
Russian Federation
Competing Interests:
Russian Federation
Irina R. Fatkhullina, Head of the Department, pediatrician, research fellow, Researcher
Cystic Fibrosis Department; Department of Hereditary and Metabolic Diseases; Scientific and Clinical Department of Cystic Fibrosis
115522; ul. Moskvorechye 1; 115093; Serpukhovskaya 62; Moscow
tel.: (495) 111-03-03
Author ID: 1124891
Competing Interests:
The authors did not declare any conflicts of interests
O. I. Golubtsova
Budgetary institution of the Chuvash Republic “Republican Children’s Clinical Hospital” of the Ministry of Health of the Chuvash Republic
Russian Federation
Competing Interests:
Russian Federation
Olga I. Golubtsova, Candidate of Medicine, Head of the Department
Department of Pulmonology and Allergology
428020; ul. Fedora Gladkova 27; Cheboksary
tel: (8352) 55-01–26
Author ID: 657012
Competing Interests:
The authors did not declare any conflicts of interests
E. A. Enina
State Budgetary Healthcare Institution of the Stavropol Territory “Regional Children’s Clinical Hospital”; Federal State Budgetary Educational Institution of Higher Education “Stavropol State Medical University” of the Ministry of Health of the Russian Federation
Russian Federation
Competing Interests:
Russian Federation
Elena A. Enina, Candidate of Medicine, Head of the Department, Associate Professor
Department of Pulmonology; Hospital Pediatrics Department
355029; ul. Semashko 3; 355017; ul. Mira 310; Stavropol
tel.: (8652) 35-73-38
Author ID: 1227060
Competing Interests:
The authors did not declare any conflicts of interests
I. P. Karimova
State Autonomous Institution of Healthcare “Chelyabinsk Regional Children’s Clinical Hospital” of the Ministry of Healthcare of the Chelyabinsk Region
Russian Federation
Competing Interests:
Russian Federation
Irina P. Karimova, Candidate of Medicine, Head of the Department
Pulmonology Department
454087; ul. Blyukhera 42A; Chelyabinsk
tel.: (351) 232-80-80
Author ID: 981615
Competing Interests:
The authors did not declare any conflicts of interests
M. V. Erzutova
Federal State Budgetary Educational Institution of Higher Education “Privolzhsky Research Medical University”, Ministry of Healthcare of the Russian Federation
Russian Federation
Competing Interests:
Russian Federation
Marina V. Erzutova, Candidate of Medicine, Researcher
Gastroenterology Department
603950; pl. Minina i Pozharskogo 10/1; Nizhniy Novgorod
tel.: (831) 422-20-00
Author ID: 562065
Competing Interests:
The authors did not declare any conflicts of interests
A. V. Orlov
ederal State Budgetary Educational Institution of Higher Education “North-Western State Medical University named after I.I.Mechnikov”, Ministry of Health of the Russian Federation; Saint Petersburg State Budgetary Healthcare Institution “Children’s City Hospital of St. Olga”
Russian Federation
Competing Interests:
Russian Federation
Alexander V. Orlov, Candidate of Medicine, Infectious Disease Doctor, Pulmonologist, Associate Professor, Head of Department
Department of Pediatrics and Neonatology; Infectious Diseases (Boxed) Department No. 3
191015; ul. Kirochnaya 41; 194156; ul. Zemledel’cheskaya 2; Saint Petersburg
tel.: (812) 246-09-24
Author ID: 721638
Competing Interests:
The authors did not declare any conflicts of interests
M. G. Rybalkina
Federal State Budgetary Educational Institution of Higher Education “Orenburg State Medical University” of the Ministry of Healthcare of the Russian Federation
Russian Federation
Competing Interests:
Russian Federation
Marina G. Rybalkina, Candidate of Medicine, Associate Professor
Department of Pediatrics
460000; ul. Sovetskaya 6; Orenburg
tel.: (3532) 50-06-06 (ext. 814)
Author ID: 582162
Competing Interests:
The authors did not declare any conflicts of interests
T. I. Safonova
Budgetary Healthcare Institution of the Omsk region “Regional Children’s Clinical Hospital”
Russian Federation
Competing Interests:
Russian Federation
Tat’yana I. Safonova, Head of Department
Pulmonary Department
644001; ul. Kuibysheva 77; Omsk
tel.: (3812) 36-16-36
Author ID: 1274697
Competing Interests:
The authors did not declare any conflicts of interests
D. F. Sergienko
Federal State Budgetary Educational Institution of Higher Education “Astrakhan State Medical University”, Ministry of Healthcare of the Russian Federation
Russian Federation
Competing Interests:
Russian Federation
Diana F. Sergienko, Doctor of Medicine, Professor, Professor of the Department
Department of Faculty Pediatrics
414000; ul. Bakinskaya 121; Astrakhan
tel.: (512) 52-41-43
Author ID: 433729
Competing Interests:
The authors did not declare any conflicts of interests
I. P. Shulyak
State Autonomous Healthcare Institution of the Sverdlovsk Region “Regional Children’s Clinical Hospital”
Russian Federation
Competing Interests:
Russian Federation
Irina P. Shulyak, Pulmonologist
620149; ul. Serafimy Deryabinoy 34; Ekaterinburg
tel.: (343) 240-57-80
Competing Interests:
The authors did not declare any conflicts of interests
E. I. Kondratyeva
Federal State Budgetary Scientific Institution “Research Centre for Medical Genetics”, Ministry of Science and Higher Education of the Russian Federation; State Budgetary Healthcare Institution of the Moscow region “Research Clinical Institute of Childhood”, Healthcare Ministry of Moscow Region
Russian Federation
Competing Interests:
Russian Federation
Elena I. Kondratyeva, Doctor of Medicine, Professor, Deputy Director of the Center, Head of the Department
Cystic Fibrosis Center; Scientific and Clinical Department of Cystic Fibrosis; Department of Genetics of Diseases of the Respiratory System
115522; ul. Moskvorechye 1; 115093; Serpukhovskaya 62; Moscow
tel.: (495) 324-20-24
Scopus ID: 35196167800; Web of Science Researcher ID: АВВ-9783–2021
Competing Interests:
The authors did not declare any conflicts of interests
References
1. De Boeck K. Cystic fibrosis in the year 2020: a disease with a new face. Acta Paediatr. 2020; 109 (5): 893–899. DOI: 10.1111/apa.15155.
2. Marson F.A.L., Bertuzzo C.S., Ribeiro J.D. Classification of CFTR mutation classes. Lancet Respir. Med. 2016; 4 (8): e37–38. DOI: 10.1016/S2213-2600(16)30188-6.
3. Bell S.C., Mall M.A., Gutierrez H. et al. The future of cystic fibrosis care: a global perspective. Lancet Respir. Med. 2020; 8 (1): 65–124. DOI: 10.1016/S2213-2600(19)30337-6.
4. Wainwright C.E., Elborn J.S., Ramsey B.W. et al. Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N. Engl. J. Med. 2015; 373 (3): 220–231. DOI: 10.1056/nejmc1510466.
5. The State Register of Medicines. [Instructions for use of the medicinal product “Trikafta”]. Available at: https://grls.minzdrav.gov.ru/Grls_View_v2.aspx?routingGuid=bf582a60-1e93-441e-9062-e4bffc15d4d1 (in Russian).
6. The State Register of Medicines. [Instructions for use of the medicinal product “Orkambi”]. Available at: https://grls.minzdrav.gov.ru/Grls_View_v2.aspx?routingGuid=ff37d270-1afb-45ca-bbc7-521ff7e0ac41 (in Russian).
7. Dagenais R.V.E., Su V.C.H., Quon B.S. Real-World safety of CFTR modulators in the treatment of cystic fibrosis : a systematic review. J. Clin. Med. 2020; 10 (1): 23. DOI: 10.3390/jcm10010023.
8. Labaste A., Ohlmann C., Mainguy C. et al. Real-life acute lung function changes after Lumacaftor/Ivacaftor first administration in pediatric patients with cystic fibrosis. J. Cyst. Fibros. 2017; 16 (6): 709–712. DOI: 10.1016/j.jcf.2017.05.002.
9. Wark P.A.B., Cookson K., Thiruchelvam T. et al. Lumacaftor/Ivacaftor improves exercise tolerance in patients with cystic fibrosis and severe airflow obstruction. BMC Pulm. Med. 2019; 19 (1): 106. DOI: 10.1186/s12890-019-0866-y.
10. Heijerman H.G., McKone E.F., Downey D.G. et al. Efficacy and safety of the Elexacaftor plus Tezacaftor plus Ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial [published correction appears in Lancet. 2020; 395 (10238):1694]. Lancet. 2019; 394 (10212): 1940–1948. DOI: 10.1016/S0140-6736(19)32597-8.
11. Milla C.E., Ratjen F., Marigowda G. et al. Lumacaftor/Ivacaftor in patients aged 6–11 years with cystic fibrosis and Homozygous for F508del-CFTR. Am. J. Respir. Crit. Care Med. 2017; 195 (7): 912–920. DOI: 10.1164/rccm.201608-1754OC.
12. McNamara J.J., McColley S.A., Marigowda G. et al. Safety, pharmacokinetics, and pharmacodynamics of Lumacaftor and Ivacaftor combination therapy in children aged 2–5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study. Lancet Respir. Med. 2019; 7 (4): 325–35. DOI: 10.1016/s2213-2600(18)30460-0.
13. Arslan M. Chalmers S., Rentfrow K. et al. Suicide attempts in adolescents with cystic fibrosis on Elexacaftor/Tezacaftor/Ivacaftor therapy. J. Cyst. Fibros. 2023; 22 (3): 427–430. DOI: 10.1016/j.jcf.2023.01.015.
14. Sakon C., Vogt H., Brown C.D., Tillman E.M. A survey assessing the impact of COVID-19 and Elexacaftor/Tezacaftor/Ifavacaftor on both physical and mental health in adults with cystic fibrosis. Pediatr. Pulmonol. 2023; 58 (3): 662–664. DOI: 10.1002/ppul.26260.
Supplementary files
Review
For citations:
Voronkova A.Yu., Zhekaite E.K., Fatkhullina I.R., Golubtsova O.I., Enina E.A., Karimova I.P., Erzutova M.V., Orlov A.V., Rybalkina M.G., Safonova T.I., Sergienko D.F., Shulyak I.P., Kondratyeva E.I. Adverse drug reactions during long-term use of two targeted drugs in pediatric patients with cystic fibrosis in the Russian Federation. PULMONOLOGIYA. 2025;35(2):202-212. (In Russ.) https://doi.org/10.18093/0869-0189-2025-35-2-202-212
Views:
298
Email this article 