Fremanezumab 225mg/1.5ml solution for injection pre-filled disposable devices

Migraine is a leading cause of global disability, and conventional preventive therapies often suffer from poor tolerability and low adherence. Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs: erenumab, fremanezumab, galcanezumab, and eptinezumab) represent a targeted therapeutic advance, but long-term adherence and safety remain under investigation. Following PRISMA guidelines, we systematically searched PubMed, Embase, CENTRAL, Scopus, and Web of Science (2018-2024) for randomized controlled trials, real-world studies, and systematic reviews reporting adherence, tolerability, or discontinuation outcomes in adults with episodic or chronic migraine. Eleven studies (n > 50,000) met the inclusion criteria. Pooled 12-month adherence was approximately 55% (vs. ~35% for oral preventives), while discontinuation due to adverse events ranged from 5.9%-20%, most commonly constipation and injection-site reactions (relative risk, 1.32-1.55); serious adverse events were rare (<5%). Responder rates (≥50% reduction in monthly migraine days) improved from 44% at three months to 64% at 12 months, with network meta-analyses suggesting greater efficacy compared with topiramate and OnabotulinumtoxinA, though direct head-to-head RCTs remain lacking. Overall, anti-CGRP mAbs demonstrate favorable adherence, sustained tolerability, and comparative advantages over conventional therapies, but further research is needed to assess long-term safety beyond 12 months, cost-effectiveness, and use in special populations such as pregnancy.

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BackgroundDespite advances in migraine management, some patients fail to respond to preventive treatments for migraine. We aimed to assess the comparative effects of available pharmacological prophylaxis in adults with a treatment failure history.MethodsWe searched Medline, Embase, Cochrane Central, PsycINFO, Web of Science, and Scopus up to July 2025. Pairs of reviewers independently screened titles, abstracts, and full-text articles to identify randomized controlled trials of prophylactic pharmacological interventions that enrolled adults diagnosed with chronic or episodic migraine and a prior preventive treatment failure. We performed a frequentist random-effects network meta-analysis and used the GRADE approach to assess the certainty of evidence.ResultsWe included 18 randomized trials (7281 participants). Compared to placebo, low certainty evidence suggest fremanezumab [mean difference (MD) -3.30 (95% CI: -4.11 to -2.49)], eptinezumab [MD -3.35 (95% CI: -4.38 to -2.32)], galcanezumab [MD -2.73 (95% CI: -3.43 to -2.03)], atogepant [MD -2.30 (95% CI: -3.47 to -1.13)], and erenumab [MD -2.20 (95% CI: -2.72 to -1.68)] may be among the most effective in reducing the monthly migraine headache days. Low to moderate certainty evidence suggests that, compared with placebo, galcanezumab [relative risk (RR) 1.94 (95% CI: 1.52 to 2.48)], fremanezumab [RR 3.98 (95% CI: 2.40 to 6.59)], atogepant [RR 2.80 (95% CI: 1.73 to 4.54)], erenumab [RR 2.56 (95% CI: 2.01 to 3.26)], and eptinezumab [RR 2.35 (95% CI: 1.61 to 3.42)] may increase the likelihood of achieving a 50% response rate.ConclusionEvidence for migraine patients with prior preventive treatment failure is limited. Low- to moderate-certainty data suggest that CGRP-targeted therapies may provide some benefit and are generally tolerable, but the available evidence is driven by a few industry-sponsored trials. Additional independent, well-powered studies with longer follow-up are needed to strengthen the evidence base.Registration numberPROSPERO (CRD42024547860).

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OBJECTIVE: To evaluate the long-term safety (≥12 months) of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) or its receptor in migraine prevention by synthesising evidence from clinical trials and real-world studies. We focus on drug discontinuation due to adverse events and the type and frequency of adverse events. This is the first review to analyse the effects of the long-term use of all anti-CGRP (receptor) mAbs, aiming to provide novel insights for clinical practice and future treatment strategies. METHODS: We systematically searched PubMed, Cochrane Library, and ClinicalTrials.gov for studies with ≥12 months of anti-CGRP (receptor) mAb use between January 2013 and April 2025. A random-effects meta-analysis of proportions (logit transformation, inverse variance weighting, restricted maximum likelihood) was performed to estimate pooled discontinuation and adverse event rates. Risk of bias was assessed using the ROBINS-I score. RESULTS: From a total of 1,499 records, 14 met the inclusion criteria and were eligible for data analysis. These 14 records corresponded to 11 individual studies with observational durations all exceeding 12 months. Seven studies investigated erenumab, two eptinezumab, and one each fremanezumab and galcanezumab. All studies were judged to have a severe risk of bias due to their underlying design. The overall pooled proportion of treatment discontinuation for any reason among patients receiving anti-CGRP (receptor) mAbs was 23%, whereas the pooled proportion of discontinuation specifically due to adverse events was substantially lower at 3%. Time-trend analysis showed that adverse event–related discontinuation remained low (70%) but did not further increase with prolonged follow-up. CONCLUSION: Evidence on long-term use of anti-CGRP (receptor) mAbs over 12 months remains limited, but our analysis indicates good tolerability with consistently low adverse event-related discontinuation, no emergent safety signals, and largely non-serious, stable adverse event profiles. However, heterogeneity and study-level bias warrant cautious interpretation, highlighting the need for long-term clinical studies and continued real-world surveillance (e.g. registries). CLINICAL TRIAL NUMBER: Not applicable.

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Context: Migraine is a highly prevalent and disabling neurological condition, affecting approximately one billion people worldwide. It is the second most common type of primary headache. Among the existing therapeutic options, many demonstrate limited efficacy and significant side effects. Fremanezumab, a monoclonal antibody that selectively blocks CGRP, has been studied as a promising alternative for migraine prevention, as it acts directly on the pathophysiological mechanisms of the disease. Objective: This systematic review aims to gather and analyze the results of randomized clinical trials evaluating the efficacy and safety of fremanezumab as a prophylactic strategy for migraine in adults. Methods: Searches were conducted in the PubMed, Cochrane CENTRAL, and LILACS databases, covering publications from 2015 to 2025 in English, Portuguese, or Spanish. After independent and double-blinded screening of 511 records, 3 randomized clinical trials were included. Results: In all analyzed studies, fremanezumab demonstrated superiority over placebo, with reductions ranging from 3.7 to 4.6 headache days per month and higher response rates (≥ 50% reduction), observed in up to 41% of treated patients. The most common adverse events were injection site reactions and nasopharyngitis, which were generally mild. The included studies showed good methodological quality and demonstrated benefits of fremanezumab in both treatment-responsive and treatment-refractory patients. Conclusion: Fremanezumab appears to be an effective and safe option for the prophylaxis of episodic and chronic migraine. Nonetheless, longer-duration studies with more diverse populations and economic evaluations are needed to support its widespread, evidence-based adoption in clinical practice.

Abstract licence: CC BY-NC-ND 4.0

ObjectiveCalcitonin gene-related peptide (CGRP) inhibitors, including monoclonal antibodies (mAbs) and small-molecule antagonists (gepants), have transformed migraine treatment. Although clinical trials established their efficacy and initial safety, post-marketing surveillance is essential for understanding their real-world safety profile in a broader population. Therefore, this study aims to systematically review and synthesize findings from published pharmacovigilance studies that analyze potential safety signals for CGRP inhibitors using major international databases, including the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), the World Health Organization's (WHO's) VigiBase, and EudraVigilance, in order to establish a comprehensive real-world safety profile to guide clinical practice.MethodsA systematic search was conducted in major electronic databases for studies published up to September 2025. Study selection, data extraction, and quality assessment were performed by two independent researchers. We included original research articles analyzing FAERS, VigiBase, or EudraVigilance for AEs associated with erenumab, galcanezumab, fremanezumab, eptinezumab, rimegepant, ubrogepant, atogepant, or zavegepant. Data on key signals of disproportionate reporting (SDRs) and quantitative measures of disproportionality were extracted and synthesized thematically.ResultsThe search identified 30 eligible studies. For mAbs, consistent SDRs included injection site reactions, alopecia (e.g., fremanezumab reporting odds ratio (ROR) ranging from 2.73 to 6.9), constipation (primarily for erenumab, RORs ranging from 4.92 to 17.94), and a range of cardiovascular events. For gepants, common SDRs included nausea and fatigue or somnolence, with highly specific SDRs for severe constipation for atogepant (ROR025 = 19.99) and dysgeusia for zavegepant (ROR025 = 212.07), linked to its nasal administration. A critical divergence was observed for rare but serious cerebrovascular events: SDRs for reversible cerebral vasoconstriction syndrome (RCVS [erenumab ROR 9.43, 95% confidence interval {CI} 4.5-19.8]) and cervical artery dissection (CeAD [galcanezumab ROR 14.0, 95% CI 6.22-31.4]) were associated with certain mAbs. Conversely, no such SDRs have been detected for gepants to date, although this distinction requires confirmation as real-world exposure increases. However, a class-level SDR for cerebrovascular diseases as a whole was identified for CGRP inhibitors as a group (ROR 1.22, 95% CI 1.12-1.33). Also notable were shared SDRs for Raynaud's phenomenon and alopecia across both subclasses. Finally, concerning safety in pregnancy, the data are complex: while comprehensive class-level analyses did not identify a disproportionality signal compared to triptans, some analyses of individual drugs have identified reporting patterns that warrant cautious interpretation, underscoring the need for further dedicated pharmacovigilance studies to fully clarify the safety profile in this population.ConclusionsThis systematic review confirms that CGRP inhibitors have a manageable yet complex safety profile. It distinguishes rare, serious cerebrovascular events (RCVS, CeAD) associated with some mAbs but not with gepants, as well as shared adverse effects such as Raynaud's phenomenon and alopecia. Significant heterogeneity in safety profiles-from erenumab's pronounced constipation SDR to zavegepant's unique dysgeusia-challenges the view of CGRP inhibitors as a monolithic category. These findings provide a clear rationale for personalized risk assessment, enabling clinicians to tailor treatment to individual patient profiles.

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Calcitonin gene-related peptide (CGRP) monoclonal antibodies have emerged as effective preventive treatments for episodic and chronic migraine, but concerns have been raised regarding their potential cardiovascular safety profile, particularly the risk of hypertension. This systematic review aimed to assess the occurrence of hypertension in patients receiving CGRP monoclonal antibodies for migraine prevention. A comprehensive search of PubMed, Embase, Scopus, and Cochrane Library was conducted for studies published between January 2015 and June 2025. Five studies met the inclusion criteria, encompassing 75,065 patients across randomized controlled trials, observational studies, and real-world cohort analyses. The evidence suggests a differential risk profile between CGRP receptor antagonists and ligand-targeting antibodies, with erenumab (receptor antagonist) demonstrating greater blood pressure increases compared to fremanezumab. In patients with baseline hypertension, anti-CGRP treatment was associated with a slight annual increase in antihypertensive medication requirements, while normotensive patients showed minimal blood pressure changes. Clinical trials reported low incidence rates of hypertension adverse events, though post-marketing surveillance identified 362 hypertension events in over 245,000 patient-years of exposure. The temporal pattern suggests cumulative rather than immediate effects, with a small proportion of normotensive patients requiring antihypertensive treatment after erenumab initiation. These findings indicate that while the overall risk of hypertension appears modest, clinically meaningful effects on blood pressure regulation may occur, particularly in patients with pre-existing hypertension. Regular cardiovascular monitoring is recommended for patients receiving CGRP monoclonal antibodies, especially those with baseline cardiovascular risk factors.

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