20.500.12556/RUL-181439 Neželeni učinki izbranih visoko učinkovitih zdravil za zdravljenje multiple skleroze: analiza poročil iz farmakovigilančne baze EudraVigilance Adverse effects of selected highly effective medicines for the treatment of multiple sclerosis: analysis of reports from the pharmacovigilance database EudraVigilance Multipla skleroza je kronična avtoimunska bolezen osrednjega živčevja, za katero so značilne vnetne demielinizacijske lezije in postopna nevrodegeneracija. Z uvedbo visoko učinkovitih zdravil, ki spreminjajo potek bolezni, se je prognoza bolnikov z multiplo sklerozo bistveno izboljšala. Kljub visoki učinkovitosti pa so ta zdravila povezana s povečanim tveganjem za resne neželene učinke, zlasti okužbe, zato je njihovo spremljanje v realnem okolju ključnega pomena. Namen magistrske naloge je bil analizirati neželene učinke (NU) izbranih visoko učinkovitih zdravil za zdravljenje multiple skleroze – ofatumumaba (Kesimpta), alemtuzumaba (Lemtrada), kladribina (Mavenclad), okrelizumaba (Ocrevus) in natalizumaba (Tysabri in Tyruko) na podlagi poročil iz evropske farmakovigilančne baze EudraVigilance. Analiza je vključevala porazdelitev poročil po spolu, starosti in letih, podrobno obravnavo skupine infekcijske in parazitske bolezni po klasifikaciji MedDRA, ter pogostost poročanja na različnih nivojih MedDRA. Za oceno povezav med posameznimi zdravili in določenimi okužbami je bila izvedena analiza nesorazmernosti z izračunom razmerja obetov poročanja (ROR). Skupno je bilo analiziranih več kot 15.000 poročil in 38.000 NU od prihoda zdravila na trg do 22. marca 2025. Pri vseh zdravilnih učinkovinah so bili najpogosteje poročani NU iz skupin infekcijske in parazitske bolezni, bolezni živčevja in preiskave (tj. povišana ali znižana raven jetrnih encimov, kreatinina v krvi, abnormalni izvidi elektrokardiograma, povišana telesna temperatura ipd.). Pri ofatumumabu, alemtuzumabu, kladribinu in okrelizumabu so med najbolj pogosto poročanimi okužbe zgornjih in spodnjih dihal, okužbe s herpes virusom in okužbe sečil. Največ NU je bilo poročanih za natalizumab, ki je tudi najdlje na trgu. Analiza nesorazmernosti, katero smo izvajali na treh nivojih (PT, HLT, SMQ), je potrdila že znane in klinično uveljavljene varnostne signale, kot so progresivna multifokalna levkoencefalopatija pri natalizumabu (ROR 55,29; 95 % IZ 35,82-85,37), listerioza pri alemtuzumabu (ROR 36,24; 95 % IZ 4,46-294,69) ter okužbe s herpesvirusi (ROR 2,08; 95% IZ 1,70-2,50), specifično herpes zoster (ROR 2,12; 95 % IZ 1,61-2,79) pri kladribinu. Hkrati so bili zaznani okrepljeni signali za nekatere resne okužbe pri okrelizumabu, in sicer okužbe osrednjega živčevja in hrbtenjače (ROR 2,27; 95 % IZ 1,41-3,64), specifično meningitis (ROR 2,64; 95% IZ 1,04-6,71). Ofatumumab je najmanj časa na trgu, posledično ima tudi najmanj signalov. Ugotovitve magistrske naloge poudarjajo pomen stalnega farmakovigilančnega spremljanja sodobnih terapij za multiplo sklerozo ter prispevajo k boljšemu razumevanju njihovega varnostnega profila v klinični praksi. Multiple sclerosis is a chronic autoimmune disease of the central nervous system, characterized by inflammatory demyelinating lesions and progressive neurodegeneration. With the introduction of highly effective drugs that modify the course of the disease, the prognosis of patients with multiple sclerosis has significantly improved. Despite their high efficacy, these drugs are associated with an increased risk of serious side effects, especially infections, so their monitoring in a real-world setting is of key importance. The purpose of the master's thesis was to analyze the side effects of selected highly effective drugs for the treatment of multiple sclerosis - ofatumumab (Kesimpta), alemtuzumab (Lemtrada), cladribine (Mavenclad), ocrelizumab (Ocrevus) and natalizumab (Tysabri and Tyruko) based on reports from the European pharmacovigilance database EudraVigilance. The analysis included the distribution of reports by gender, age and years, a detailed discussion of the group of infectious and parasitic diseases according to the MedDRA classification, and the frequency of reporting at different MedDRA levels. A disproportionality analysis was performed to assess the association between individual drugs and specific infections by calculating the reporting odds ratio (ROR). In total, more than 15,000 reports and 38,000 adverse reactions were analyzed from the time the drug was launched on the market until March 22, 2025. For all active substances, the most frequently reported adverse reactions were from the groups of infectious and parasitic diseases, nervous system disorders and investigations (i.e. elevated or decreased levels of liver enzymes, blood creatinine, abnormal electrocardiogram results, elevated body temperature, etc.). For ofatumumab, alemtuzumab, cladribine and ocrelizumab, the most frequently reported were upper and lower respiratory tract infections, herpes virus infections and urinary tract infections. The most adverse effects were reported for natalizumab, which has also been on the market the longest. The disproportionality analysis, which was performed at three levels (PT, HLT, SMQ), confirmed already known and clinically established safety signals, such as progressive multifocal leukoencephalopathy with natalizumab (ROR 55.29; 95% CI 35.82-85.37), listeriosis with alemtuzumab (ROR 36.24; 95% CI 4.46-294.69), and herpesvirus infections (ROR 2.08; 95% CI 1.70-2.50), specifically herpes zoster (ROR 2.12; 95% CI 1.61-2.79) with cladribine. At the same time, enhanced signals were detected for some serious infections with ocrelizumab, namely infections of the central nervous system and spinal cord (ROR 2.27; 95% CI 1.41-3.64), specifically meningitis (ROR 2.64; 95% CI 1.04-6.71). Ofatumumab has been on the market for the shortest time, and consequently has the fewest signals. The findings of the master's thesis emphasize the importance of continuous pharmacovigilance monitoring of modern therapies for multiple sclerosis and contribute to a better understanding of their safety profile in clinical practice. multipla skleroza visoko učinkovita zdravila neželeni učinki EudraVigilance okužbe analiza nesorazmernosti multiple sclerosis highly effective drugs adverse effects EudraVigilance infections disproportionality analysis true false false [Ž. Županc] Slovenski jezik Angleški jezik Magistrsko delo/naloga 2026-04-08 08:46:17 2026-04-08 08:46:30 2026-05-05 11:07:23 0000-00-00 00:00:00 2026 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 1970-01-01 615.2:616.8(043.2) 124967 275052803 31887.pdf 31887.pdf 1 43DAD486B4372290AA71623AEC98DA2D 6136978256c78dc2fbc38e90b88b3a7da3dc7afd05bf13cc171fd6d1ee29b84d 7f0dd111-3316-11f1-b0ab-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=231888 Fakulteta za farmacijo 0 0 0