Ravulizumab is a long-acting C5 complement inhibitor that binds with high affinity and specificity to the human terminal complement protein C5, thereby preventing its cleavage into C5a and C5b and inhibiting the formation of the membrane attack complex (MAC). Dysregulated activation of the complement system is a key pathological mechanism shared by various autoimmune diseases. For instance, in generalized myasthenia gravis (gMG), anti-acetylcholine receptor (AChR) antibodies activate the classical complement pathway, leading to MAC deposition that disrupts the postsynaptic membrane structure at the neuromuscular junction (NMJ) and results in muscle weakness (1–3). Similar complement-mediated tissue damage mechanisms are observed in paroxysmal nocturnal hemoglobinuria (PNH), systemic lupus erythematosus, atypical hemolytic uremic syndrome (aHUS), and acute organ transplant rejection (4–8). Based on this mechanism of action, ravulizumab is currently approved for the treatment of generalized myasthenia gravis, paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and neuromyelitis optica spectrum disorder (NMOSD).

Structurally, ravulizumab is a humanized monoclonal antibody. Compared to eculizumab, ravulizumab incorporates four key amino acid substitutions in the Fc region. This structural modification significantly enhances its affinity for the neonatal Fc receptor (FcRn) and slows the dissociation rate of the ravulizumab-C5 complex within the endosomal system. Consequently, the plasma half-life of ravulizumab is extended to approximately four times that of eculizumab. This optimization provides the structural basis for the sustained efficacy of ravulizumab and offers convenience for long-term disease management (9).

Ravulizumab initially received approval from FDA in December 2018 for the treatment of PNH. PNH is an ultra-rare, acquired hematopoietic stem cell disorder characterized by a mutation in the PIG-A gene. This mutation results in the production of blood cells that are susceptible to complement-mediated intravascular hemolysis. The clinical manifestations of PNH arise from uncontrolled complement activation, and the complement protein C5 is considered an ideal therapeutic target for inhibiting the complement system in PNH (6).

Ravulizumab received FDA approval in April 2022 for the treatment of gMG in adult patients who are AChR antibody-positive. Myasthenia gravis is an autoimmune disorder characterized by muscle weakness and fatigability, caused by autoantibodies targeting components of the neuromuscular junction (10). In the Phase III CHAMPION-MG trial, intravenous ravulizumab demonstrated statistically significant and clinically meaningful improvements compared to placebo at Week 26, as measured by changes in the Myasthenia Gravis-Activities of Daily Living (MG-ADL) score and the Quantitative Myasthenia Gravis (QMG) score in these patients (11).

Furthermore, ravulizumab received FDA approval in September 2021 for the treatment of aHUS. aHUS is a rare thrombotic microangiopathy (TMA) caused by dysregulation of the complement system, characterized primarily by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (12–14). Results from a randomized controlled trial investigating ravulizumab for aHUS demonstrated that improvements in hematologic parameters, renal function, and quality of life were sustained for over two years following treatment initiation (15).

As the clinical use of ravulizumab expands, understanding its adverse reaction profile in real-world practice becomes increasingly important. However, the adverse events (AEs) identified in published clinical trials are derived from specific disease populations and thus may only reflect the safety profile within those subsets. Therefore, this study was conducted to address this gap by providing a comprehensive analysis of the safety profile of ravulizumab, thereby offering additional evidence to guide healthcare professionals.

This study compiled adverse event reports extracted from the US FDA Adverse Event Reporting System (FAERS) database from the fourth quarter of 2018 to the second quarter of 2025. Reports listing ravulizumab as the primary suspect (PS) drug were included. Data extraction and cleaning were performed using R software version 4.4.1. The initial dataset contained 11,653,790 reports. Following FDA recommendations (16), 1,771,030 duplicate reports were excluded. The PRIMARYID, CASEID, and FDA_DT fields were extracted from the DEMO table of the raw data and subsequently sorted. For reports sharing the same CASEID, the entry with the latest FDA_DT was retained. For reports with identical CASEID and FDA_DT values, the entry with the highest PRIMARYID was kept. Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 27.0 (17), based on Preferred Terms (PT) and System Organ Classes (SOC). Figure 1 illustrates the flowchart for identifying ravulizumab-associated adverse events in the FAERS database.

This study analyzed adverse events associated with ravulizumab recorded in the FAERS database from the fourth quarter of 2018, following its initial FDA approval and subsequent post-marketing phase. The findings not only confirm various adverse reactions previously documented in the prescribing information—including fatigue, asthenia, headache, malaise, dyspnea, back pain, feeling abnormal, and diplopia—but also identify additional AEs not currently included in the label, such as anemia, dysphagia, urinary tract infection, and somnolence.

Our study demonstrates that the top 10 most frequently reported AEs associated with ravulizumab are largely consistent with those listed in its prescribing information, thereby confirming that fatigue, asthenia, and headache are common AEs for this medication.

Ravulizumab shares a mechanism of action similar to eculizumab, specifically binding to the complement protein C5. This binding inhibits the generation of the anaphylatoxin C5a and the terminal complement component C5b, which is essential for forming the membrane attack complex (C5b-9) (24). Structural modifications, however, confer a prolonged duration of action to ravulizumab, allowing for an extended dosing interval of every 8 weeks compared to eculizumab. A comparative study of AEs for these two agents in myasthenia gravis (MG) suggests that while their mechanisms are similar, their clinical adverse event profiles are not identical. Eculizumab use is clearly associated with adverse events like Neisseria meningitidis bacteremia and septicemia, as documented in clinical studies and real-world settings (25–27). Our analysis identified 39 reports of Neisseria meningitidis infections associated with ravulizumab, indicating a similar risk profile for this specific, serious infection between the two drugs. This potentially fatal reaction underscores the critical importance of meningococcal vaccination prior to initiating therapy with either agent (28).

However, differences emerge for other AEs. Eculizumab treatment for MG has been associated with nasopharyngitis, gastric cancer, and embolic stroke. In contrast, ravulizumab therapy for MG has been linked to psoriatic arthropathy and peripheral vascular disease (29). Furthermore, the AE profile of these drugs varies significantly depending on the treated condition. Among the five AEs mentioned above (meningococcal infections, nasopharyngitis, gastric cancer, embolic stroke, psoriatic arthropathy, peripheral vascular disease), only nasopharyngitis has been reported in the context of treating PNH, aHUS, or NMOSD; the others have not been documented for these indications. This highlights that healthcare professionals must carefully consider the specific disease being treated and its associated AE profile when making therapeutic decisions.

Data extracted from the FAERS database indicate that fatigue is the most frequently reported AE associated with ravulizumab. However, its high reporting frequency may be attributed to several factors. Its characteristic clinical presentation facilitates accurate identification and documentation by healthcare providers, whereas concurrent non-drug-related symptoms may be incorrectly attributed to ravulizumab therapy. Anemia, identified as an AE not currently included in the drug label, may be linked to multiple factors. In patients with PNH, anemia could primarily result from bone marrow failure but may also arise from extravascular hemolysis (EVH) (30). EVH occurs due to C3b opsonization of PNH red blood cells, leading to their removal from circulation and subsequent destruction in the reticuloendothelial system. Furthermore, through sensitivity analysis, we mitigated the potential confounding effects of medications commonly used concomitantly with ravulizumab in standard clinical practice, such as prednisone, pyridostigmine, eculizumab, and intravenous immunoglobulin. Notably, pyridostigmine is a specific medication for MG treatment, and its frequent co-reporting reflects the greater utilization of ravulizumab in MG patients compared to other indications. This observation confirms that the characteristics of the data we extracted from FAERS align with real-world clinical practice.

Regarding the adverse reactions reported in published clinical studies, the incidence of adverse events associated with ravulizumab appears relatively high. In one randomized controlled trial (RCT) investigating ravulizumab for the treatment of MG, over 90% of participants reported treatment-emergent adverse events. Headache was reported in 23.1% of subjects, and diarrhea occurred in 17.2%. Concerning serious adverse events (SAEs), 16 SAEs were reported in 11 out of 169 participants, including pyelonephritis, pancreatitis, erysipelas, and Neisseria meningitidis bacteremia (31). Another RCT comparing ravulizumab and eculizumab for treating PNH similarly reported adverse events in 87.6% of patients. In the ravulizumab group, the most frequent AEs were headache (26.8%), nasopharyngitis (21.6%), and upper respiratory tract infection (18.6%) (32). The incidence of SAEs in this study was approximately 4%, which is lower than that observed in the MG trial. In a separate RCT evaluating ravulizumab for aHUS, the incidence of adverse events reached 100%. Headache, diarrhea, and vomiting were the most commonly reported AEs, while the SAE incidence was approximately 24% (33)—significantly higher than the rates observed in the MG and PNH trials. These findings suggest that the safety profile of ravulizumab may vary considerably across different indications. Therefore, during treatment, careful patient assessment tailored to the specific clinical context is essential to determine the most appropriate management strategy.

This study has several limitations that warrant consideration. First, as the FAERS database primarily relies on voluntary reporting by healthcare professionals and consumers, the potential for selection bias exists. Notably, in RCTs, physicians explicitly inform patients of potential AEs, enhancing reporting of even mild reactions, while real-world AEs are typically reported only when causing significant discomfort. This discrepancy may bias our results, as FAERS (a real-world database) may underreport mild AEs compared to RCTs. Second, the database lacks standardized grading for the severity of AEs and does not systematically differentiate between drug-induced AEs and those attributable to underlying comorbidities or concomitant medications. Although such differentiation is inherently challenging, this limitation complicates the accurate assessment of causality and severity, as disease-related symptoms may be reported as AEs. Consequently, clinical judgment remains essential for appropriate evaluation. Third, FAERS data reflect point-in-time reports following treatment and lack longitudinal follow-up information, which restricts the ability to assess long-term drug safety in real-world settings. Furthermore, the database exhibits significant geographic bias, with the majority of case reports originating from the United States, thereby limiting the generalizability of the findings to global populations and diverse clinical contexts. These inherent limitations underscore the necessity for complementary prospective studies to validate the pharmacovigilance signals identified in this analysis.

This pharmacovigilance study utilized the FAERS database to evaluate the real-world safety profile of ravulizumab. The analysis confirmed that frequently reported AEs, such as fatigue, asthenia, headache, malaise, dyspnea, back pain, feeling abnormal, and diplopia, were consistent with those described in the drug label. Importantly, several clinically significant AEs not currently listed in the prescribing information were identified, including anemia, dysphagia, urinary tract infection, and somnolence. These findings enhance healthcare professionals’ awareness of potential ravulizumab-associated toxicities, enabling more comprehensive risk assessment and informed management of potential adverse reactions when making treatment decisions for patients.