Safety of Using Gepants with CGRP Monoclonal Antibodies for Migraine
There is limited but supportive evidence that using a gepant for acute migraine treatment in a patient already taking galcanezumab (CGRP-targeting monoclonal antibody) is safe and well-tolerated, making it a reasonable option for this patient experiencing breakthrough migraines.
Evidence for Combination Therapy
Recent real-world evidence supports the safety of combining CGRP-targeting therapies:
A 2024 retrospective study of 234 patients receiving both CGRP monoclonal antibodies and gepants found only three adverse events, which were mild and transient, not requiring treatment discontinuation 1.
A 2024 prospective study (COURAGE) demonstrated that ubrogepant was effective as an acute treatment when used with CGRP monoclonal antibodies, with 80.4% of patients achieving meaningful pain relief at 4 hours after the first attack 2.
A smaller 2020 study of 13 patients using rimegepant with various CGRP monoclonal antibodies (including galcanezumab) found no safety issues, with only mild to moderate adverse events reported 3.
Clinical Decision-Making Algorithm
For this 28-year-old woman with:
- 75% reduction in monthly migraine days with galcanezumab
- Breakthrough migraines in the week before next dose
- Previous failure of conventional acute treatments
The decision pathway should be:
Assess current response pattern
- Patient has good overall response (75% reduction)
- Breakthrough migraines occur predictably before next dose
Consider treatment options
- Continue galcanezumab as it provides significant benefit
- Add gepant for acute treatment of breakthrough migraines
- Monitor for any adverse effects from combination therapy
Guidelines and Evidence Gaps
Current guidelines acknowledge limitations in the evidence:
The 2025 American College of Physicians guideline notes that CGRP antagonists-gepants have "very little comparative evidence for prioritized outcomes" and that there are "evidence gaps" regarding newer migraine medications 4.
The 2024 VA/DoD headache guideline acknowledges that "robust head-to-head evidence is largely unavailable" for comparative efficacy of newer headache pharmacotherapies 4.
Important Considerations and Caveats
Cost implications: Gepants are significantly more expensive than traditional acute treatments, with annualized costs ranging from $4,959 to $5,994 for oral formulations 4.
Monitoring: Regular assessment of treatment efficacy and adverse effects is essential when combining these medications.
Alternative approaches: If combination therapy is ineffective or not tolerated, consider:
- Adjusting the dosing schedule of galcanezumab
- Trying a different class of acute treatment
- Exploring non-pharmacological options like neuromodulation devices
Conclusion
While the American College of Physicians notes limited comparative evidence for gepants 4, the most recent real-world studies suggest that combining CGRP monoclonal antibodies with gepants is safe and can be effective 1, 2, 3. For this patient who has failed multiple conventional acute treatments but responds well to galcanezumab, adding a gepant for breakthrough migraines is a reasonable therapeutic option.