safetyriskБезопасность и риск фармакотерапииSafety and Risk of Pharmacotherapy2312-78212619-1164Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/2312-7821-2019-7-2-84-92safetyrisk-137Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESАнализ информации об осложнениях фармакотерапии и оценка возможности выявления сигнала о нежелательных реакциях при применении препаратов интерферона бетаInterferon Beta: Analysis of Information on Adverse Reactions and Evaluation of Possibility of Signal Identificationhttps://orcid.org/0000-0003-0925-0623ЗатолочинаК. Э.ZatolochinaK. E.

Затолочина Карина Эдуардовна, кандидат медицинских наук 

 

Karina E. Zatolochina, Candidate of Medical Sciences 

w00100@yandex.ruhttps://orcid.org/0000-0002-7844-7043СнегиреваИ. И.SnegirevaI. I.

Снегирева Ирина Илларионовна, кандидат медицинских наук 

Irina I. Snegireva, Candidate of Medical Sciences

SnegirevaII@expmed.ruhttps://orcid.org/0000-0003-2665-796XКазаковА. С.KazakovA. S.

Казаков Александр Сергеевич, кандидат медицинских наук 

Alexander S. Kazakov, Candidate of Medical Sciences

KazakovAS@expmed.ruhttps://orcid.org/0000-0002-3706-7271ЛепахинВ. К.LepakhinV. K.

Лепахин Владимир Константинович, доктор медицинских наук, профессор, член-корреспондент РАН 

Vladimir K. Lepakhin, Doctor of Medical Sciences, Full Professor, Corresponding Member of the Russian Academy of Sciences 

Lepakhin@expmed.ruФедеральное государственное автономное образовательное учреждение высшего образования «Российский университет дружбы народов»РоссияPeoples' Friendship University of RussiaRussian FederationФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian FederationФедеральное государственное автономное образовательное учреждение высшего образования «Российский университет дружбы народов» Федеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияPeoples' Friendship University of Russia; Scientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation201926032019728492Copyright © Затолочина К.Э., Снегирева И.И., Казаков А.С., Лепахин В.К., 20192019Затолочина К.Э., Снегирева И.И., Казаков А.С., Лепахин В.К.Zatolochina K.E., Snegireva I.I., Kazakov A.S., Lepakhin V.K.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.risksafety.ru/jour/article/view/137

Рассеянный склероз является одним  из наиболее распространенных неврологических заболеваний людей трудоспособного возраста. Для  предотвращения обострений и прогрессирования рассеянного склероза на протяжении последних 20 лет широко применяются препараты, изменяющие течение рассеянного склероза. Статья посвящена проблемам безопасности терапии рассеянного склероза препаратами интерферона бета.  Цель работы: анализ  информации о нежелательных реакциях, развившихся на  фоне  применения препаратов интерферона бета,  и оценка возможности выявления сигнала о редких нежелательных реакциях на основании данных спонтанной отчетности. Проведен ретроспективный анализ сообщений о нежелательных реакциях, развившихся после  применения интерферона бета-1а, интерферона бета-1b. Полученные результаты подтверждают известные риски развития нежелательных реакций (общих расстройств и нарушений в месте введения препарата, неврологических нарушений, нарушений со стороны скелетно-мышечной системы и психики) и неэффективности данной группы препаратов. Выводы: выявлено недостаточное репортирование о случаях нежелательных реакций при  применении препаратов интерферона бета, установлен высокий удельный вес сообщений от фармацевтических компаний. Информация о серьезных нежелательных реакциях при  применении интерферона бета-1а присутствовала в 52,9 % поступивших спонтанных сообщений, при  применении интерферона бета-1b — в 29,4 %. Все нежелательные реакции были  предвиденными. Результаты исследования подтвердили возможность выявления сигналов, связанных с возникновением очень  частых, частых, а также нечастых нежелательных реакций, таких как тромбоцитопения.

Multiple sclerosis is  one  of  the  most common neurological diseases of  working age population. The last 20 years widely use drugs that change the  course of multiple sclerosis. The article is devoted to the  problems of the  safety of treatment of multiple sclerosis with interferon beta  drugs. The aim of the study was to analyze the  adverse drug reactions (ADRs)  of interferon beta  medicines and  the  assessment of the  possibility of identify signals on rare adverse drug reactions based  on spontaneous reporting data. A retrospective analysis of reports of ADRs that occur after the  use of interferon beta-1a, interferon beta-1b was performed. The results confirm the known risks of developing ADRs of this group of drugs: general disorders and administration site conditions, nervous system disorders, musculoskeletal and  connective tissue disorders and psychiatric disorders. Under-reporting of ADR  was  identified, high level  reporting rate from manufacturers was  detected. A significant number of received spontaneous reports contained information about serious ADRs  (52.9 % — for  interferon beta-1a; 29.4 % — for  interferon beta-1b). All ADRs corresponded to those specified in the  instructions for  medical use of drugs. The results of the  study confirmed the  possibility of identifying signals associated with the  occurrence of very common, common, and uncommon ADRs, such  as thrombocytopenia.

интерферон бетанежелательная реакциярассеянный склерозсигналтромботическая микроангиопатияinterferon betaadverse reactionmultiple sclerosissignalthrombotic microangiopathyРабота выполнена без спонсорской поддержки.The study was performed without external funding.ReferencesRae-Grant A, Day GS, Marrie RA, Rabinstein A, Cree BAC, Gronseth GS, et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17);777–88. https://doi.org/10.1212/WNL.0000000000005347Rae-Grant A, Day GS, Marrie RA, Rabinstein A, Cree BAC, Gronseth GS, et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17);777–88. https://doi.org/10.1212/WNL.0000000000005347Ekstein D, Linetsky E, Abramsky O, Karussis D. Polyneuropathy associated with interferon beta treatment in patients with multiple sclerosis. Neurology. 2005;65(3):456–8. https://doi.org/10.1212/01.wnl.0000171858.82527.4cEkstein D, Linetsky E, Abramsky O, Karussis D. Polyneuropathy associated with interferon beta treatment in patients with multiple sclerosis. Neurology. 2005;65(3):456–8. https://doi.org/10.1212/01.wnl.0000171858.82527.4cTremlett HL, Yoshida EM, Oger J. Liver injury associated with the beta-interferons for MS: a comparison between the three products. Neurology. 2004;62(4):628–31. https://doi.org/10.1212/WNL.62.4.628Tremlett HL, Yoshida EM, Oger J. Liver injury associated with the beta-interferons for MS: a comparison between the three products. Neurology. 2004;62(4):628–31. https://doi.org/10.1212/WNL.62.4.628Francis GS, Grumser Y, Alteri E, Micaleff A, O’Brien F, Alsop J, et al. Hepatic reactions during treatment of multiple sclerosis with interferon-β-1a: incidence and clinical significance. Drug Saf. 2003;26(11):815–27. https://doi.org/10.2165/00002018-200326110-00006Francis GS, Grumser Y, Alteri E, Micaleff A, O’Brien F, Alsop J, et al. Hepatic reactions during treatment of multiple sclerosis with interferon-β-1a: incidence and clinical significance. Drug Saf. 2003;26(11):815–27. https://doi.org/10.2165/00002018-200326110-00006The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45(7):1277–85. https://doi.org/10.1212/WNL.45.7.1277The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45(7):1277–85. https://doi.org/10.1212/WNL.45.7.1277Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996;39(3):285–94. https://doi.org/10.1002/ana.410390304Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996;39(3):285–94. https://doi.org/10.1002/ana.410390304PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352(9139):1498–504. https://doi.org/10.1016/S0140-6736(98)03334-0PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352(9139):1498–504. https://doi.org/10.1016/S0140-6736(98)03334-0PRISMS (Prevention of Relapses and Disability by Interferon-β-1a Subcutaneously in Multiple Sclerosis) Study Group, University of British Columbia MS/MRI Analysis Group. PRISMS-4: long-term efficacy of interferon-β-1a in relapsing MS. Neurology. 2001;56(12):1628–36. https://doi.org/10.1212/WNL.56.12.1628PRISMS (Prevention of Relapses and Disability by Interferon-β-1a Subcutaneously in Multiple Sclerosis) Study Group, University of British Columbia MS/MRI Analysis Group. PRISMS-4: long-term efficacy of interferon-β-1a in relapsing MS. Neurology. 2001;56(12):1628–36. https://doi.org/10.1212/WNL.56.12.1628Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006;67(7):1242–49. https://doi.org/10.1212/01.wnl.0000237641.33768.8dKappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006;67(7):1242–49. https://doi.org/10.1212/01.wnl.0000237641.33768.8dJacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000;343:898–904. https://doi.org/10.1056/NEJM200009283431301Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000;343:898–904. https://doi.org/10.1056/NEJM200009283431301Patten SB, Francis G, Metz LM, Lopez-Bresnahan M, Chang P, Curtin F. The relationship between depression and interferon beta-1a therapy in patients with multiple sclerosis. Mult Scler. 2005;11(2):175–81. https://doi.org/10.1191/1352458505ms1144oaPatten SB, Francis G, Metz LM, Lopez-Bresnahan M, Chang P, Curtin F. The relationship between depression and interferon beta-1a therapy in patients with multiple sclerosis. Mult Scler. 2005;11(2):175–81. https://doi.org/10.1191/1352458505ms1144oaAlba Palé L, León Caballero J, Samsó Buxareu B, Salgado Serrano P, Pérez Solà V. Systematic review of depression in patients with multiple sclerosis and its relationship to interferonβ treatment. Mult Scler Relat Disord. 2017;17:138–43. https://doi.org/10.1016/j.msard.2017.07.008Alba Palé L, León Caballero J, Samsó Buxareu B, Salgado Serrano P, Pérez Solà V. Systematic review of depression in patients with multiple sclerosis and its relationship to interferonβ treatment. Mult Scler Relat Disord. 2017;17:138–43. https://doi.org/10.1016/j.msard.2017.07.008Solaro C, Gamberini G, Masuccio FG. Depression in multiple sclerosis: epidemiology, aetiology, diagnosis and treatment. CNS Drugs. 2018;32(2):117–33. https://doi.org/10.1007/s40263-018-0489-5Solaro C, Gamberini G, Masuccio FG. Depression in multiple sclerosis: epidemiology, aetiology, diagnosis and treatment. CNS Drugs. 2018;32(2):117–33. https://doi.org/10.1007/s40263-018-0489-5Nikfar S, Rahimi R, Abdollahi M. A meta-analysis of the efficacy and tolerability of interferon-β in multiple sclerosis, overall and by drug and disease type. Clin Ther. 2010;32(11):1871–88. https://doi.org/10.1016/j.clinthera.2010.10.006Nikfar S, Rahimi R, Abdollahi M. A meta-analysis of the efficacy and tolerability of interferon-β in multiple sclerosis, overall and by drug and disease type. Clin Ther. 2010;32(11):1871–88. https://doi.org/10.1016/j.clinthera.2010.10.006Bertolotto A, Gilli F, Sala A, Capobianco M, Malucchi S, Milano E, et al. Persistent neutralizing antibodies abolish the interferon β bioavailability in MS patients. Neurology. 2003;60(4):634–9. https://doi.org/10.1212/01.WNL.0000046662.03894.C5Bertolotto A, Gilli F, Sala A, Capobianco M, Malucchi S, Milano E, et al. Persistent neutralizing antibodies abolish the interferon β bioavailability in MS patients. Neurology. 2003;60(4):634–9. https://doi.org/10.1212/01.WNL.0000046662.03894.C5Sorensen PS, Koch-Henriksen N, Ross C, Clemmesen KM, Bendtzen K, Danish Multiple Sclerosis Study Group. Appearance and disappearance of neutralizing antibodies during interferon-beta therapy. Neurology. 2005;65(1):33–9. https://doi.org/10.1212/01.WNL.0000166049.51502.6ASorensen PS, Koch-Henriksen N, Ross C, Clemmesen KM, Bendtzen K, Danish Multiple Sclerosis Study Group. Appearance and disappearance of neutralizing antibodies during interferon-beta therapy. Neurology. 2005;65(1):33–9. https://doi.org/10.1212/01.WNL.0000166049.51502.6AHunt D, Kavanagh D, Drummond I, Weller B, Bellamy C, Overell J, et al. Thrombotic microangiopathy associated with interferon beta. N Engl J Med. 2014;370(13):1270–1. https://doi.org/10.1056/NEJMc1316118Hunt D, Kavanagh D, Drummond I, Weller B, Bellamy C, Overell J, et al. Thrombotic microangiopathy associated with interferon beta. N Engl J Med. 2014;370(13):1270–1. https://doi.org/10.1056/NEJMc1316118Olea T, Díaz-Mancebo R, Picazo ML, Martínez-Ara J, Robles A, Selgas R. Thrombotic microangiopathy associated with use of interferon-beta. Int J Nephrol Renovasc Dis. 2012;5:97–100. https://doi.org/10.2147/IJNRD.S30194Olea T, Díaz-Mancebo R, Picazo ML, Martínez-Ara J, Robles A, Selgas R. Thrombotic microangiopathy associated with use of interferon-beta. Int J Nephrol Renovasc Dis. 2012;5:97–100. https://doi.org/10.2147/IJNRD.S30194Kavanagh D, McGlasson S, Jury A, Williams J, Scolding N, Bellamy C, et al. Type I interferon causes thrombotic microangiopathy by a dosedependent toxic effect on the microvasculature. Blood. 2016;128(24):2824–33. https://doi.org/10.1182/blood-2016-05-715987Kavanagh D, McGlasson S, Jury A, Williams J, Scolding N, Bellamy C, et al. Type I interferon causes thrombotic microangiopathy by a dosedependent toxic effect on the microvasculature. Blood. 2016;128(24):2824–33. https://doi.org/10.1182/blood-2016-05-715987Koudriavtseva T, Plantone D, Renna R, Mandoj C, Giannarelli D, Mainero C. Interferon-β therapy and risk of thrombocytopenia in multiple sclerosis patients. Neurol Sci. 2015;36(12):2263–8. https://doi.org/10.1007/s10072-015-2348-1Koudriavtseva T, Plantone D, Renna R, Mandoj C, Giannarelli D, Mainero C. Interferon-β therapy and risk of thrombocytopenia in multiple sclerosis patients. Neurol Sci. 2015;36(12):2263–8. https://doi.org/10.1007/s10072-015-2348-1Segal JB, Powe NR. Prevalence of immune thrombocytopenia: analyses of administrative data. J Thromb Haemost. 2006;4(11):2377–83. https://doi.org/10.1111/j.1538-7836.2006.02147.xSegal JB, Powe NR. Prevalence of immune thrombocytopenia: analyses of administrative data. J Thromb Haemost. 2006;4(11):2377–83. https://doi.org/10.1111/j.1538-7836.2006.02147.xPapani R, Duarte AG, Lin YL, Kuo YF, Sharma G. Pulmonary arterial hypertension associated with interferon therapy: a population-based study. Multidiscip Respir Med. 2017;12:1. https://doi.org/10.1186/s40248-016-0082-zPapani R, Duarte AG, Lin YL, Kuo YF, Sharma G. Pulmonary arterial hypertension associated with interferon therapy: a population-based study. Multidiscip Respir Med. 2017;12:1. https://doi.org/10.1186/s40248-016-0082-zСнегирева ИИ, Пастернак ЕЮ, Затолочина КЭ, Дармостукова МА, Аляутдин РН, Поливанов ВА. Проблема взаимозаменяемости интерферонов системного действия для лечения рассеянного склероза. Безопасность и риск фармакотерапии. 2017;5(4):161–9.Snegireva II, Pasternak EYu, Zatolochina KE, Darmostukova MA, Alyautdin RN, Polivanov VA. Problems of interchangeability of systemic interferons for treatment of multiple sclerosis. Safety and risk of pharmacotherapy. Bezopasnost’ i risk farmakoterapii = Safety and Risk of Pharmacotherapy. 2017;5(4):161–9 (In Russ.)Солдатов АА, Авдеева ЖИ, Олефир ЮВ, Меркулов ВА, Бондарев ВП. Безопасность биологических препаратов. Сообщение 2. Проблемы безопасности биоподобных препаратов. БИОпрепараты. Профилактика, диагностика, лечение. 2016;16(2):78–89.Soldatov AA, Avdeeva ZhI, Olefir YuV, Merkulov VA, Bondarev VP. The safety of biological preparations. Part 2. Safety issues of biosimilars. BIOpreparaty. Profilaktika, diagnostika, lechenie = BIOpreparations. Prevention, Diagnosis, Treatment. 2016;16(2):78–89 (In Russ.)Хабиров ФА, Бабичева НН, Хайбуллин ТИ, Аверьянова ЛА, Гранатов ЕВ, Ахмедова ГМ. Опыт применения биоаналога интерферона бета-1b для лечения рассеянного склероза. Журнал неврологии и психиатрии им. С.С. Корсакова. Спецвыпуски. 2012;112(9):113–22.Khabirov FA, Babicheva NN, Khaibullin TI, Averyanova LA, Granatov EV, Akhmedova GM. Biosimilar of interferon-beta 1b in the treatment of multiple sclerosis and the own experience in the use of ronbetal. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. Special issues = S.S. Korsakov Journal of Neurology and Psychiatry. Special issues. 2012;112(9):113–22 (In Russ.)Tóthfalusi L, Endrényi L, Chow SC. Statistical and regulatory considerations in assessments of interchangeability of biological drug products. Eur J Health Econ. 2014;15(Suppl 1):5–11. https://doi.org/10.1007/s10198-014-0589-1Tóthfalusi L, Endrényi L, Chow SC. Statistical and regulatory considerations in assessments of interchangeability of biological drug products. Eur J Health Econ. 2014;15(Suppl 1):5–11. https://doi.org/10.1007/s10198-014-0589-1

The authors declare that there are no conflicts of interest present.