Adverse Drug Reactions with Drugs Used in Multiple Sclerosis: An Analysis from the Italian Pharmacovigilance Database

Abstract

Given the importance of inflammation at the onset of multiple sclerosis (MS), therapy is mainly based on the use of anti-inflammatory drugs including disease modifying therapies (DMTs). Considering the recent approval of some DMTs, pharmacovigilance becomes a fundamental tool for the acquisition of new safety data. The aim of the study was to analyze adverse drug reactions (ADRs) related to the use of drugs approved for MS. All national publicly-available aggregated ADR reports recorded from 2002 to 2020 into the Reports of Adverse Reactions of Medicines (RAM) system and all complete Sicilian data reported into the Italian spontaneous reporting system (SRS) database having as suspected drugs interferon β-1a (IFN β-1a), interferon β-1b (IFN β-1b), peginterferon β-1a (PEG-IFN β-1a), glatiramer acetate (GA), natalizumab (NTZ), fingolimod (FNG), teriflunomide (TRF), dimethyl fumarate (DMF), alemtuzumab (Alem), ocrelizumab (OCZ), or cladribine (Cladr), were collected. Descriptive analyses of national, publicly-available aggregated data and full-access regional data were performed to assess demographic characteristics and drug-related variables followed by a more in-depth analysis of all Sicilian ADRs with a case-by-case assessment and a disproportionality analysis of unexpected ADRs. A total of 13,880 national reports have been collected from 2002 to 2020: they were mainly not serious ADRs (67.9% vs. 26.1%) and related to females (71.7% vs. 26.3%) in the age group 18–65 years (76.5%). The most reported ADRs were general and administration site conditions (n = 6,565; 47.3%), followed by nervous (n = 3,090; 22.3%), skin (n = 2,763; 19.9%) and blood disorders (n = 2,180; 15.7%). Some unexpected Sicilian ADRs were shown, including dyslipidemia for FNG (n = 10; ROR 28.5, CI 14.3–59.6), NTZ (n = 5; 10.3, 4.1–25.8), and IFN β-1a (n = 4; 8.7, 3.1–24.1), abortion and alopecia for NTZ (n = 9; 208.1, 73.4–590.1; n = 3; 4.9, 1.5–15.7), and vitamin D deficiency for GA (n = 3; 121.2, 30.9–475.3). Moreover, breast cancer with DMF (n = 4, 62.8, 20.5–191.9) and hypothyroidism with Cladr (n = 3; 89.2, 25.9–307.5) were also unexpected. The reporting of drugs-related ADRs in MS were mostly reported in the literature, but some unknown ADRs were also found. However, further studies are necessary to increase the awareness about the safety profiles of new drugs on the market.

Adverse Events Associated With Disease-Modifying Drugs for Multiple Sclerosis

“… 37 Nonetheless, although most of the Italian findings were consistent with the literature, we were able to confirm some of the unexpected signals identified, including, for example, the risk of thyroid disorders for teriflunomide which was significantly elevated in our population-based study. 36 Reassuringly, the higher potential risk of dyslipidemia for fingolimod, natalizumab, and β-interferon reported in the Italian study was not observed in our study. 36 …”

“… 36 Reassuringly, the higher potential risk of dyslipidemia for fingolimod, natalizumab, and β-interferon reported in the Italian study was not observed in our study. 36 …”

“…One Italian study analyzed 13,880 physician-reported MS DMD-related adverse reactions to the National Pharmacovigilance Database (2002–2020). 36 Although these voluntarily reporting systems can provide important safety signals, a systematic review found that most serious or severe adverse events (95%) are never reported. 37 Nonetheless, although most of the Italian findings were consistent with the literature, we were able to confirm some of the unexpected signals identified, including, for example, the risk of thyroid disorders for teriflunomide which was significantly elevated in our population-based study.…”

A bibliometric analysis of research progress on pharmacovigilance and cancer from 2002 to 2021

“…Moreover, most patients continue to exhibit MS symptoms long after stopping therapy, which may be related to the long half-life of ICIs and the sustained immune response ( 50 ). Unexpectedly, some drugs approved for MS may have cancer risks, such as dimethyl fumarate, fingolimod, natalizumab and glatiramer acetate, which may be related to the occurrence of lung cancer, prostate cancer and breast cancer ( 51 ). It is still debated whether autoimmune disorders are contraindications to ICIs therapy, since some patients may still benefit from immune-based cancer treatments.…”

Effectiveness and Safety Profiles of Biological Therapies in Inflammatory Bowel Disease: Real Life Data from an Active Pharmacovigilance Project

“…Although both the efficacy and safety of these drugs have been established in many clinical trials [ 65 , 66 , 67 , 68 ], the benefit/risk profile remains controversial due to the different persistence rates based on the risk of immunogenicity and SADRs, such as the onset of infections and neoplasms. Consequently, the key strength of this study is that real-world analyses increase awareness on biologic use in IBD; moreover, active pharmacovigilance plays a crucial role in detecting ADRs and SADRs [ 69 , 70 ] and post-marketing activities are essential to implement the safety profile of these new treatments, thereby reducing any under-reporting phenomena and resulting in therapy optimization in clinical practice [ 18 , 71 ]. The choice of a specific biologic on the index date may be related to the patient’s medical history, but, in effect, depends on regional directives that regulate biologic and biosimilar prescriptions.…”