Potential Adverse Effects of CGRP Inhibitors
CGRP inhibitors (erenumab, galcanezumab, and fremanezumab) are generally well-tolerated with mostly mild adverse effects, primarily including injection site reactions, constipation (especially with erenumab), and mild systemic symptoms. 1, 2
Common Adverse Effects
Injection Site Reactions
- Pain, swelling, erythema, and pruritus at injection sites are among the most frequently reported adverse events 3
- These reactions are typically mild to moderate in severity and self-limiting
Gastrointestinal Effects
- Constipation is particularly common with erenumab (reported rate of 4.90 per 1000 patients) but less frequent with fremanezumab (0.46) and galcanezumab (0.76) 3
- Nausea may occur (2.94,0.91, and 1.09 per 1000 patients for erenumab, fremanezumab, and galcanezumab, respectively) 3
Other Common Adverse Effects
- Mild paresthesia
- Reduced physical activity
- Rash
- Dizziness 1
Immunogenicity
- Anti-drug antibody development has been reported:
- 6.2% in patients receiving erenumab 70 mg monthly (with 2 showing neutralizing activity)
- 2.6% in patients receiving erenumab 140 mg monthly (none with neutralizing activity)
- In long-term studies, antibody development was observed in 11.1% of patients on erenumab 2
- The clinical significance of these antibodies remains unclear due to limited data 2
Special Considerations
Cardiovascular Concerns
- Theoretical concerns exist regarding CGRP inhibitors' potential to inhibit vasodilation, which could pose risks in patients with cardiovascular disease 4
- Post-marketing studies have shown increased risk for development or worsening of hypertension with erenumab, leading to revised prescribing information with warnings and precautions 1
- However, cardiovascular events did not rank among the top ten adverse events for any CGRP inhibitor in real-world monitoring 3
Older Adults
- Evidence suggests similar efficacy and tolerability in patients aged ≥65 years compared to younger patients
- Side effect incidence may be slightly lower in older adults (22% vs 28% in younger patients) 5
Serious Adverse Events
- The frequency of serious adverse events is low, with ≤2% of reported adverse events categorized as serious across all CGRP monoclonal antibodies 3
- No specific pattern of serious adverse events has been identified in clinical trials or post-marketing surveillance
Drug Interactions
- CGRP inhibitors are not metabolized by cytochrome P450 enzymes, making interactions with medications that are substrates, inducers, or inhibitors of these enzymes unlikely 2
- Studies have shown no effect on the pharmacokinetics of:
- Combined oral contraceptives containing ethinyl estradiol and norgestimate
- Sumatriptan 2
- Concomitant use of rimegepant (a CGRP receptor antagonist) with CGRP monoclonal antibodies appears to be well-tolerated, with no significant safety issues identified in small studies 6
Monitoring Recommendations
- Patients should be monitored for:
- Injection site reactions
- Constipation, particularly with erenumab
- Changes in blood pressure, especially in those with pre-existing hypertension
- Development of new or worsening headache (reported as an adverse event with all three medications) 3
Clinical Perspective
The American College of Physicians notes that CGRP monoclonal antibodies have more favorable adverse event profiles compared to some traditional migraine preventives like topiramate, with fewer discontinuations due to adverse events 1. However, these medications are substantially more expensive than traditional options, with annual costs ranging from $7,071 to $22,790 compared to $67-$393 for first-line alternatives 1, 4.
The American Headache Society now considers CGRP-targeting therapies to be first-line options for migraine prevention, citing evidence that their efficacy and tolerability are equal to or greater than previous first-line therapies, with rare serious adverse events 7.