15 Frequently Asked Questions About CGRP Monoclonal Antibodies and Gepants (4)

15 Frequently Asked Questions About CGRP Monoclonal Antibodies and Gepants

Medically reviewed by: Dr. Deena Kuruvilla

Calcitonin Gene-Related Peptide (CGRP) Inhibitors such as Gepants and CGRP monoclonal antibodies (CGRP mAbs) are frequently talked about in the migraine community. But, what are the differences and what should you know about them? We’ve gathered the 15 most frequently asked questions to provide you with important information you should know about these medications.

Calcitonin gene-related peptide, or CGRP, is a protein naturally produced throughout the body. It acts as a messenger to help nerve cells talk to each other and other areas of the body. During a migraine attack, nerve endings in the brain release various chemicals, including CGRP, which causes pain, inflammation, and dilation of blood vessels. Recently, medications were designed to block the CGRP protein or its receptor to reduce inflammation and pain.

Monoclonal antibodies (also called mAbs) are lab produced proteins that have a specific target in the body. CGRP mAbs are preventive treatments designed specifically to treat migraine in adults. There are four FDA-approved monoclonal antibodies including erenumab (Aimovig), fremanezumab (Ajovy), galcanezumab (Emgality) and eptinezumab (Vyepti). Erenumab binds to the CGRP receptor while fremanezumab, galcanezumab and eptinezumab bind to the CGRP protein.

Gepants are used for the acute and/or preventive treatment of migraine in adults. They are small molecules that block CGRP from binding to its receptors. 

There are four FDA-approved gepants:

  1. Rimegepant (Nurtec): Acute or preventive treatment
  2. Ubrogepant (Ubrelvy): Acute treatment
  3. Zavegepant (Zavzpret): Acute treatment
  4. Atogepant (Qulipta): Preventive treatment

The American Headache Society recently published a position statement regarding CGRP-blocking medications for migraine prevention: “The CGRP-targeting therapies should be considered as a first-line approach for migraine prevention along with previous first-line treatments without a requirement for prior failure of other classes of migraine preventive treatment.”1 This updated statement provides a summary of the research to help people with migraine gain access to these important medications. There have been barriers established by insurance companies that limit access to these newer, more expensive treatments.

Depending on the specific medication, gepants and CGRP mAbs are taken either orally, by injection/shot, intravenously (IV), or via a nasal spray. Some can be used for acute or preventive treatment.

Gepants

  • Rimegepant (Nurtec): 75 mg orally disintegrating tablet placed under the tongue. It is used at the onset of an attack for acute treatment and/or every other day for the prevention of episodic migraine.
  • Ubrogepant (Ubrelvy): 50 or 100 mg tablet used at the onset of an attack. Another dose can be taken at least two hours apart from the initial dose (up to 200 mg in 24 hours). There is some evidence to suggest that it may be effective during the early signs of an attack also known as the prodrome phase.2
  • Atogepant (Qulipta): 10 mg, 30 mg or 60 mg tablet used daily for migraine prevention.
  • Zavegepant (Zavzpret): 10 mg nasal spray in one nostril at the onset of an attack (maximum 1 dose per 24 hours). The safety is not known if used more than 8 times per month.

CGRP Monoclonal Antibodies

  • Erenumab (Aimovig): 70 mg or 140 mg subcutaneous injection administered monthly for migraine prevention.
  • Fremanezumab (Ajovy): 225 mg monthly or 675 mg (3 consecutive injections) every 3 months (quarterly) administered by a subcutaneous injection for migraine prevention.
  • Galcanezumab (Emgality): The first dose requires a “loading dose” of 240 mg or two subcutaneous injections of 120 mg. Afterwards, one, 120 mg injection is used monthly for migraine prevention. 
  • Eptinezumab (Vyepti): 100 mg or 300 mg intravenous infusion administered every three months for migraine prevention.

CGRP Monoclonal Antibodies

  • Erenumab (Aimovig): Constipation, increased blood pressure (hypertension), injection site reactions, oral ulcers and alopecia (hair loss).
    • People should seek an alternative CGRP medication if they have constipation or a latex allergy. Another option may be considered for people with pre-existing high blood pressure.
  • Eptinezumab (Vyepti): Stuffy nose and scratchy throat, allergic reactions.
  • Galcanezumab (Emgality) and Fremanezumab (Ajovy): Injection site reactions.

Gepants

  • Nausea, indigestion, stomach pain, sleepiness and allergic reaction are all possible side effects but vary based on the medication. For zavegepant (Zavzpret) nasal spray, other potential side effects include nasal discomfort or unusual taste.

Gepants are known to interact with medications that block an enzyme found in the liver and intestine known as CYP3A4.

  • A few examples of these medications include certain antibiotics (ex. clarithromycin, erythromycin), anti-cancer agents (ex. tamoxifen and irinotecan), anti-HIV agents (ex. ritonavir and delavirdine), antihypertensives (ex. dihydralazine, verapamil and diltiazem), sex steroids, etc.3
  • Cannabinol (CBD) is also metabolized by the CYP3A4 enzyme. Use should be avoided when taking rimegepant (Nurtec), atogepant (Qulipta) or ubrogepant (Ubrelvy).
  • Rimegepant, atogepant and ubrogepant interact with nirmatrelvir/ritonavir (Paxlovid).4 The dose may be adjusted or temporarily stopped.4

While there are no known drug to drug interactions with CGRP monoclonal antibodies, preventive CGRP mAbs and preventive gepants should not be used at the same time.

Yes! For CGRP monoclonal antibodies, erenumab (Aimovig) works differently than fremanezumab (Ajovy), galcanezumab (Emgality), and eptinezumab (Vyepti). A study was conducted on switching from erenumab (Aimovig) to galcanezumab (Emgality) or fremanezumab (Ajovy) or vice versa, depending on the ineffective medication.5 The authors of the study support the proposal to switch when the first anti-CGRP monoclonal antibody is not effective.5 In clinical practice, some people try multiple CGRP monoclonal antibodies.

There have been no clinical trials studying the efficacy of switching gepants if one is not successful. In clinical practice, healthcare providers may trial multiple gepants.

Although this has not been studied in a large clinical trial, there are anecdotal reports.6 A provider may prescribe a gepant for acute treatment with a CGRP monoclonal antibody if a person has insufficient effects or contraindications to other acute treatments (ex. triptans, dihydroergotamine, etc.). 

There was a small study of 13 individuals who used rimegepant acutely with erenumab (Aimovig), fremanezumab (Ajovy) or galcanezumab (Emgality) and no safety issues were identified.7

A case report of two individuals found that 75 mg of rimegepant (Nurtec) may be effective for acute treatment while using erenumab (Aimovig) for preventive treatment.8

A study of 40 individuals looked at the how the body interacts with ubrogepant (Ubrelvy) and either erenumab (Aimovig) or galcanezumab (Emgality) and found no safety concerns when administered together.9

There is limited research on combining atogepant (Qulipta) for migraine prevention and ubrogepant (Ubrelvy) for the acute treatment of migraine. One study found no new safety concerns when administering atogepant and ubrogepant together.10 However, high doses of ubrogepant may interact with atogepant and therefore providers may use a smaller dose of ubrogepant when needed.10

Success looks different for everyone. Unfortunately, there is no cure for migraine and while the new medications are effective for many people, headaches and/or migraine attacks can still occur. According to the American Headache Society, a preventive medication is considered a “success” in any of the following instances:11

  • A decrease in the number of headache or migraine days by 50%
  • A significant decrease in attack duration or severity
  • An improved response to acute treatment
  • A reduction in migraine-related disability or psychological distress
  • An improvement in functioning

Some people are “super responders” to the new medications where they have a 75% or greater reduction in headache or migraine days.

The long-term safety of these medications has not been established. Since the CGRP monoclonal antibodies entered the market in 2018 and the gepants in 2019, more research is needed.

There is not enough data to know if the CGRP monoclonal antibodies or gepants are safe to use during pregnancy or breastfeeding. Health care providers typically recommend stopping CGRP monoclonal antibodies 5-6 months before attempting to get pregnant, while gepants should be discontinued 5-7 days beforehand.

Rimegepant was studied in a phase 1 trial to determine the excretion of a single dose in healthy lactating women (without migraine) who were 2 weeks to 6 months postpartum.12 The study found that the excretion into human milk was very low.12 More studies are needed.

Due to the strict regulations regarding testing medications on pregnant people, many pharmaceutical companies have pregnancy registries to understand the effects of medications on pregnant people and the outcomes for newborn babies. If you and your provider determine that you will continue to take your current CGRP medication while pregnant, consider signing up for the registry associated with the medication.

There is not enough information at this time to know if CGRP monoclonal antibodies or gepants are safe in children or adults over 65 years old. Typically people over 65 years old are excluded from clinical trials. However, clinical trials are underway for children.

For people living with chronic migraine, more than one preventive treatment may be necessary. It is thought that onabotulinumtoxinA (BOTOX) works differently than CGRP monoclonal antibodies and are thought to have a synergistic effect when used together. For people who are interested in the technical reasoning, onabotulinumtoxinA is thought to reduce activation of the C-fiber pain receptors and the CGRP monoclonal antibodies are thought to prevent activation of the Aδ pain receptors.13

A recent observational study from Italy found that Anti-CGRP monoclonal antibodies were more effective in reducing monthly headache days, MIDAS (disability scores) and monthly acute medication intake than onabotulinumtoxinA at 6 and 12 months.14

Gepants are not known to cause medication overuse headache.

Unfortunately, there can be obstacles to obtaining these medications. There is limited availability in many countries around the world. In addition, their cost may be prohibitive for some people whose insurance either doesn’t cover these medications or the copayments are too expensive. Some manufacturers offer savings programs via their websites for people in the U.S. with commercial insurance. 

The introduction of multiple classes of CGRP-inhibiting medications marks a significant advancement in migraine treatment for many people, offering hope and potentially a better quality of life. However, further research is required to better understand their long-term safety, efficacy in special populations and compatibility with other treatments.

  1. headachejournal.onlinelibrary.wiley.com/doi/full/10.1111/head.14692
  2. www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01683-5/abstract
  3. pubmed.ncbi.nlm.nih.gov/15762770/#:~:text=Clinically%20important%20mechanism%2Dbased%20CYP3A4,diltiazem)%2C%20sex%20steroids%20and%20their
  4. www.tandfonline.com/doi/full/10.1080/17425255.2023.2280221
  5. journals.sagepub.com/doi/full/10.1177/03331024231160519#:~:text=Our%20results%20support%20the%20proposal,options%20were%20limited%20or%20absent.
  6. www.tandfonline.com/doi/full/10.1080/14740338.2022.2130890
  7. www.ncbi.nlm.nih.gov/pmc/articles/PMC7496574/
  8. www.ncbi.nlm.nih.gov/pmc/articles/PMC7526667/
  9. www.ncbi.nlm.nih.gov/pmc/articles/PMC8252052/
  10. headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.14433
  11. headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.14153
  12. www.liebertpub.com/doi/10.1089/bfm.2021.0250
  13. headachejournal.onlinelibrary.wiley.com/doi/full/10.1111/head.14244
  14. thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-024-01721-6#xd_co_f=MzQxZGI0NDAtOGQ2OS00MGM2LTk2MGMtNmFiNGQ0M2FmNzg0~

Kylie Petrarca is a Registered Nurse and has experience in both medical-surgical nursing and critical care. Her passion for patient care led her to a new role in 2021 as the Education Program Director for the Association of Migraine Disorders. Kylie also lives with chronic migraine and is a student in the Master of Headache Disorders program at the University of Copenhagen.

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