Expert consensus on gepants for acute and preventive treatment of migraine in Thailand

Abstract

Introduction

Gepants, a calcitonin gene-related peptide (CGRP) receptor antagonist, is a class of migraine therapeutic options with extensive evidence supporting a favorable efficacy and safety profile. However, as a novel class of medication in Thailand, specific guidelines or recommendations regarding rational drug use are currently unavailable. This could hinder physicians from utilizing the medications for eligible patients and prevent pharmacists from providing information to physicians and patients.

Main body

In order to develop consensus-based statement recommendations, a modified Delphi approach was employed, which included two rounds of surveys, discussions, and voting. General recommendations were made, as well as specific recommendations of gepants in both acute and preventive treatment roles. Additionally, clinical settings where gepants could be suitable options were identified, along with the recommendations for their use in special populations and relevant precautions.

Conclusion

Gepants can serve as both acute and preventive therapy for migraines. They provide an alternative to first-line therapies for patients with limitations to conventional agents, including contraindications or intolerance. Gepants can be utilized as monotherapy or in combination with other treatment approaches. Optimal prescribing practices for eligible patients could ensure that patients receive maximum benefit with minimal risk.

Introduction

Gepants, small molecule drugs, represent a new class of anti-migraine medications that specifically target the calcitonin gene-related peptide (CGRP) signaling pathway. These drugs function as CGRP receptor antagonists, exerting their effects primarily in peripheral areas outside the blood-brain barrier, such as the trigeminal ganglion and meninges. By blocking CGRP activity, gepants prevent the vasodilation and inflammation associated with migraine attacks caused by this neuropeptide [1]. Currently, there are four United States Food and Drug Administration (USFDA)-approved gepants available in various formulations: ubrogepant, rimegepant, atogepant, and zavegepant. These medications have revolutionized migraine pharmacotherapy by demonstrating proven efficacy in achieving pain freedom and reducing the frequency and severity of migraines. They serve both as acute treatments and preventive therapies while exhibiting favorable safety profiles with a low rate of non-serious side effects [2]. Table 1 shows a summary of approved indications, dosage regimen, and key considerations among four gepants in adults [3].

Table 1.

Approved indications, dosage regimen, and key considerations of gepants in adult patients

Medications	Year of USFDA approval	Approved indication	Dosage regimen	Populations requiring dose adjustments or avoidance
Ubrogepant	2019	• Acute treatment of migraine with or without aura in adults	• 50 mg or 100 mg taken orally. • If needed, the second dose may be taken at least two hours after the initial dose. • Total daily intake should not exceed 200 mg. • The safety of using more than eight doses in a 30-day period has not been established.	• Renal impairment (CrCl < 30 mL/min) • Hepatic impairment (Child-Pugh ≥ C)
Rimegepant	2020	• Acute treatment of migraines with or without aura in adults • Preventive treatment of episodic migraine in adults	• For acute treatment of migraine: 75 mg taken orally as needed. • Total daily intake should not exceed 75 mg. • For preventive treatment of episodic migraine: 75 mg taken orally every other day. • The safety of using more than 18 doses in a 30-day period has not been established.	• Renal impairment (CrCl < 15 mL/min) • Hepatic impairment (Child-Pugh > C)
Atogepant	2021	• Preventive treatment of migraine in adults	• For preventive treatment of episodic migraine: 10 mg, 30 mg, or 60 mg taken once daily. • For preventive treatment of chronic migraine: 60 mg taken once daily.	• Renal impairment (CrCl < 30 mL/min) • Hepatic impairment (Child-Pugh ≥ C)
Zavegepant	2023	• Acute treatment of migraine with or without aura in adults	• 10 mg given as a single spray in one nostril, as needed. • Total daily dose should not exceed 10 mg. • The safety of using more than eight doses in a 30-day period has not been established.	• Renal impairment (CrCl < 30 mL/min) • Hepatic impairment (Child-Pugh ≥ C)

CrCl creatinine clearance, USFDA United States Food and Drug Administration

Regarding the role in acute migraine therapy, the International Headache Society lists rimegepant, ubrogepant and zavegepant as drugs recommended for the acute treatment in patients whom triptan monotherapy or combination therapy are ineffective, only partially effective or not tolerated, or in individuals with contraindications to triptans [4]. In terms of prevention, the American Headache Society has updated its position statement that include gepants as first-line preventive options, particularly rimegepant for episodic migraine and atogepant for both episodic and chronic migraine [5]. Gepants are also recommended by the International Headache Society as alternative option for patients whose initial preventive drugs are ineffective or not well-tolerated [6].

In Thailand, the Thai Headache Society under the Neurological Society of Thailand, in collaboration with related medical professional societies, published clinical practice guidelines for the treatment of migraine in 2022 [7]. However, there was no specific recommendation on the use of gepants in clinical settings since the drugs were not locally available during that period. Given that gepants represent a novel class of medication in Thailand, first launched in 2024, and there are currently no guidelines that exclusively focus on the application of gepants, general practitioners may face challenges in effectively utilizing these new drugs. To address this gap, the authors have established a consensus with the objectives of gathering and synthesizing expert opinions and consensus-based recommendations regarding the use of gepants for both acute and preventive treatment of migraines in Thailand. Rimegepant was highlighted because it was the only gepant available in the country. This initiative seeks to enhance the understanding and management of migraines within the healthcare community, including physicians and health care personnel in Thailand.

Methods

A group of 15 experts from academic, public, and private settings were gathered to provide consensus-based recommendations. Expert panelists must meet at least one of the following selection criteria:

• They must be a neurologist and a member of the Thai Headache Society committee.

• They must be certified as a headache specialist or board-certified in headache specialties.

• They must have experience working in headache clinics or centers for at least five years.

A modified Delphi approach was employed to achieve consensus among panelists on a set of statements [8]. The process included two rounds of surveys, discussions, and voting. In the first round, a total of 30 statements were developed and distributed to panelists for initial feedback. All panelists were asked to rate their opinions on three aspects: content validity on a four-point scale ranging from “not clear”, “somewhat clear”, “quite clear” to “very clear”; level of agreement on a five-point scale ranging from “strongly disagree”, “disagree”, “neither agree nor disagree”, “agree” to “strongly agree”; and proposed action whether to retain, remove or modify the statement, along with any additional comments. The survey feedback was gathered from 15 panelists. Descriptive statistics were used to summarize the data. The agreement percentage was determined by dividing the sum of experts who responded “Agree” and “Strongly Agree” by the total number of experts. Statements achieving ≥ 75% agreement from panelists were retained as part of the final consensus with or without discussion depending on additional comments. Statements with < 75% agreement were identified for further discussion and modification. A hybrid meeting was held on 13^th November 2024, with eight experts attending in person and another seven participating online. During the meeting, panelists discussed the statements with < 75% agreement, and modifications were made based on panelist input to enhance clarity and relevance. For the second round, the modified statements were summarized and redistributed to the panelists on 14^th November 2024 for review. Discussion and voting took place on 15^th November 2024, in a hybrid meeting attended by nine experts in person and six others via online participation. The final expert consensus statements were compiled based on the outcomes of the voting process. Results for which the experts voted “Agree” were summed up and divided by the total number of experts in order to determine the agreement percentage. The consensus criteria were as follows: statements that received ≥ 75% agreement from the panelists (with a minimum of 12 panelists voting “Agree”) were deemed to have reached a final consensus, while statements with < 75% agreement were removed. The consensus development process is summarized in Fig. 1. The classification and terminology of migraine were compliant with the definitions from the third edition of the International Classification of Headache Disorders (ICHD-3) [9].

Fig. 1.

Summary of the method of consensus development

Results

There were initially 30 statements launched for the first survey. The statements were categorized into four domains: general considerations, acute treatment, preventive treatment and special populations and considerations. Following the first round of discussion, nine statements achieved final consensus. One statement mentioning that “Gepants should be considered as a first-line treatment for acute migraine attack.” was remove due to redundancy with other statements. Furthermore, one additional statement (Statement 14) was introduced under the “Acute Treatment” category. The remaining 21 statements underwent a second survey and discussion and reached a final consensus through a process of discussion and voting. Each step of statement development is shown in Fig. 2. The final expert consensus comprises 30 statements that achieved over 75% agreement among the panelists (Table 2). Additionally, the panelists suggested that all approved indications for each gepant should be included in the introduction (Table 1). They also recommended adding a footnote to indicate gepants with specific indications in all relevant statements. The rationale supporting each statement recommendation is described in the discussion section.

Fig. 2.

Outcomes of the statement development process on each round of survey and meeting

Table 2.

Expert consensus recommendations on gepants for the treatment of migraine in Thailand

Consensus statement	%Agreement
General considerations
Statement 1: There is a need for the established local consensus guidelines to ensure the appropriate and effective use of gepants for both acute and preventive treatment in individuals with episodic and chronic migraine in Thailand.	93.33
Statement 2: Rimegepant can be used for both acute and preventive treatment of migraine.	93.33
Statement 3: Gepants should not be used in concomitance with strong inhibitors of CYP3A4 (for example: clarithromycin, itraconazole, ketoconazole, posaconazole, ritonavir, etc.) and strong or moderate inducers of CYP3A4 (for example: carbamazepine, phenobarbital, phenytoin, rifampin, etc.).	93.33
Acute treatment
Statement 4: Adults diagnosed with migraine, with or without aura, or chronic migraine could be offered gepantsa as another option for acute pharmacological treatment.	100.00
Statement 5: Gepantsa could be considered for the acute treatment of migraine attacks in adults diagnosed with migraines with or without aura, or chronic migraines, who are contraindicated to triptans or other acute migraine medications.	93.33
Statement 6: Gepantsa could be considered for acute treatment of migraine attacks in adults diagnosed with migraines with or without aura, or chronic migraines, who have poor tolerance to triptans or other acute migraine medications.	100.00
Statement 7: Gepantsa could be considered for acute treatment of migraine attacks in adults diagnosed with migraines with or without aura, or chronic migraines, who have an inadequate response to triptans or other acute migraine medications.	100.00
Statement 8: There is no well-established evidence in humans regarding the use of gepants in patients with a history of cardiovascular disease. The risk and benefits should be assessed with a physician before considering the use of gepants.	86.67
Statement 9: Gepants can be used in patients with cardiovascular risk factors, such as hypertension, diabetes, dyslipidemia, obesity and a family history of heart disease.	93.33
Statement 10: Consider co-administration of antiemetics with gepants in patients who experience nausea or vomiting.	86.67
Statement 11: For migraine patients who can identify premonitory symptoms, gepantsa should be administered during the premonitory phase. However, for those who cannot identify these symptoms, it is suggested to take gepantsa as soon as the headache starts.	100.00
Statement 12: In migraine patients with atypical aura, such as hemiplegic migraine, migraine with brainstem aura and retinal migraine, risk and benefits should be assessed before considering the use of gepants.a	100.00
Statement 13: Gepantsa could be used for abortive treatment in conjunction with CGRP monoclonal antibodies.	86.67
Statement 14: Gepantsa can be used in conjunction with other acute migraine medications as a combined treatment approach.	86.67
Preventive treatment
Statement 15: For individuals with migraine who require preventive treatment, gepantsb should be considered as a treatment option for migraine prevention.	86.67
Statement 16: For patients with episodic migraine who cannot use other preventive treatments because of comorbidities, adverse events, or poor tolerability, gepantsb could be considered.	100.00
Statement 17: For patients with chronic migraine who cannot use other preventive treatments because of comorbidities, adverse events, or poor tolerability, gepantsb might be considered	86.67
Statement 18: In the preventive treatment of migraine, gepantsb should, if possible, be continued for at least 6 months, depending on the patient’s clinical features and the physician’s assessment.	93.33
Special populations and considerations
Statement 19: The data on the safety of combining gepantsb as prophylactic treatment with CGRP monoclonal antibodies and other migraine prophylactic medications are limited; however, this combination is likely safe and may be considered.	80.00
Statement 20: The use of gepants in combination with non-pharmacological therapies is recommended to enhance patient outcomes.	80.00
Statement 21: In patients who are planning a pregnancy, discontinuation/continuation of gepants should be discussed between patient and the physician prior to pregnancy.	86.67
Statement 22: Gepants are not recommended for migraine treatment in pregnant women.	93.33
Statement 23: Gepants are not recommended for migraine treatment in breastfeeding women.	80.00
Statement 24: Due to limited data, gepants might be used in patients under 18 years of age only if other treatment options have been exhausted and it is deemed necessary by the treating physician.	100.00
Statement 25: Avoid the use of gepants in patients with severe hepatic impairment (Child-Pugh C).	100.00
Statement 26: Avoid the use of gepants in patients with end-stage renal disease (CrCl < 15 ml/min).	100.00
Statement 27: Gepants does not cause medication overuse headache.	93.33
Statement 28: Gepants could be considered for management of medication-overuse headache.	80.00
Statement 29: Gepants could be considered for migraine treatment in patients with frequent attacks or at-risk of medication overuse headache.	93.33
Statement 30: Gepantsb could be considered for the “short-term prevention” of menstrual migraine in individuals with a regular menstrual cycle.	100.00

^aGepants with approved indication as acute treatment are ubrogepant, rimegepant and zavegepant

^bGepants with approved indication as preventive treatment are rimegepant and atogepant

Discussion

Although gepants are medications supported by robust evidence to use as both acute and preventive therapy for migraine, local physicians in Thailand remain unfamiliar with their application due to the novelty of these medications in the region. This knowledge gap could lead to the underutilization of specific migraine treatments, including gepants, and partly contribute to “medication underuse headache”. This term is gaining recognition and highlights the necessity for appropriate prescriptions of migraine-specific medications, such as CGRP targeted therapy. Patients should be encouraged to initiate the treatments as early as possible, especially when headache frequency is low, to prevent migraine progression and chronification [10, 11]. This concept aligns with the 2025 International Headache Society position statement that advocates setting higher standards for migraine prevention [12]. As a result, the development of local consensus guidelines could provide valuable guidance for physicians to identify suitable candidates for gepant prescriptions, ensuring both efficacy and safety for patients (statement 1).

Unmet needs in migraine treatment (statement 5, 6, 7, 16, 17)

Triptans and non-steroidal anti-inflammatory drugs (NSAIDs) remain primary treatments for acute migraine attacks. However, triptans pose challenges in patients with established cardiovascular or cerebrovascular diseases, as these drugs are contraindicated due to their vasoactive properties. Caution is also warranted in patients with cardiovascular risk factors [13]. For NSAIDs, these drugs have various organ toxicities that limit their use in individuals with underlying conditions such as peptic ulcer disease, renal disease and cardiovascular disease. Additionally, elevated blood pressure, increased bleeding risk, risk of drug allergy, and idiosyncratic reactions, such as hypersensitivity and hepatotoxicity, should also be considered [14]. Ergots are another class of medications used for acute treatment. Ergotamine, in particular, has a more pronounced systemic vasoconstrictive effect, which can increase the risk of serious vasoconstriction complications, such as ergotism. Therefore, it is advisable to avoid using this drug in patients with cardiovascular diseases. Additionally, ergotamine is mainly metabolized by cytochrome P450 (CYP) 3A4 in the liver. It is recommended to avoid its use in patients taking strong CYP3A4 inhibitors, such as reverse transcriptase inhibitors, macrolide antibiotics, and azole antifungals, due to the higher risk of toxicity [15]. Moreover, ergots are contraindicated in pregnancy, and NSAIDs should be avoided, especially during the first and third trimesters [16]. Aside from safety concerns, it is well-known that a substantial number of patients respond suboptimally to triptans, failing to relieve headaches within two hours for at least 24 hours when using one or more triptans. These patients are classified as triptan non-responders, triptan-resistant, or triptan-refractory [17]. A network meta-analysis has demonstrated the efficacy of rimegepant and ubrogepant for acute treatment of migraine in triptan-insufficient responders, defined as those with a history of triptan discontinuation for any reason [18]. Moreover, using triptans and NSAIDs repeatedly, either alone or in combination, can result in medication overuse headaches and increase the progression from episodic to chronic migraine [13]. As a result, the panelists have proposed gepants as an acute treatment option for patients who are ineligible, unable to tolerate, or have insufficient efficacy with triptans or other migraine medications.

In terms of migraine prevention, numerous unmet needs persist regarding traditional preventive medications. The use of these medications is restricted by their contraindications, especially in patients with multiple comorbidities. Moreover, traditional preventive agents are associated with a range of adverse effects, including drowsiness and constipation from tricyclic antidepressants, weight gain and erectile dysfunction from beta blockers, and weight loss and depression from topiramate. These side effects could lead to poor tolerability and reduced long-term adherence. Consequently, the panelists suggest considering gepants as alternative options for patients who face limitations with traditional preventive treatments [19].

Gepants for acute treatment (statement 4, 11, 12, 13, 14)

All panelists agreed that gepants are suitable options for acute pharmacological treatment, aligning with the recommendations from the American Headache Society and the International Headache Society [4, 20]. Robust evidence supports the efficacy of three gepants: ubrogepant, rimegepant and zavegepant. These drugs have demonstrated efficacy over placebo in randomized clinical trials, showing higher rate of headache pain freedom and absence of the most bothersome symptoms (photophobia, phonophobia, or nausea) at two hours after dosing [21–25]. Furthermore, gepants can be used in conjunction with other classes of drugs such as CGRP monoclonal antibodies, triptans or NSAIDs. Real-world study indicates that combining CGRP monoclonal antibodies with gepants (rimegepant, ubrogepant) is both safe and well-tolerated [26]. The synergistic effect has been proposed from the dual blockage of the CGRP pathway [27]. Moreover, deep insight into the distinctive mechanisms between these two drug classes in the dura has been proposed. Atogepant could attenuate the early activation of C-fibres and the delayed activation of the Aδ-fibres whereas fremanezumab, a CGRP monoclonal antibody, only inhibits the delayed activation and sensitization of Aδ-fibres and high threshold neurons, without affecting the early activation and sensitization of C-fibres and wide dynamic range neurons [28]. Additionally, there is evidence supporting the use of two gepants. Results from the TANDEM study show that the combination of ubrogepant as an acute pharmacological treatment and atogepant as a preventive medication demonstrates similar safety profiles compared to using one gepant alone, with no new adverse events observed [29].

In concordance with a strategy of “medication underuse”, gepants could be administered during the premonitory phase. This phase is characterized by premonitory symptoms that serve as warnings of an impending migraine attack, occurring 2–48 hours before the aura in migraines with aura and prior to pain onset in migraines without aura. This stage is crucial in the migraine process, as it precedes the onset of pain and represents the optimal moment for administering gepants to prevent trigeminal activation [9, 30]. The PRODROME study supports this concept by demonstrating that administering ubrogepant during the prodrome resulted in a significantly higher rate of absence of moderate or severe headache within 24 hours, occurring in 46% of qualifying prodrome events compared to 29% of events treated with placebo [31]. While there is currently no evidence supporting the efficacy of other gepants, a class effect is considered plausible. It is important to provide patients with comprehensive education and training to help them identify premonitory symptoms for timely initiations of gepants therapy. These symptoms include fatigue, neck stiffness, mood changes, concentration difficulties, nausea, and photophobia [32]. However, for patients who cannot identify these symptoms, it is suggested to take gepants as soon as the headache begins. Patients should initiate the medication when they sense their headache is progressing to a migraine attack [10].

For migraine patients with atypical aura, such as hemiplegic migraine, migraine with brainstem aura and retinal migraine, the use of triptans is contraindicated due to potential safety concerns associated with their vasoconstrictive effects [4]. Although all experts acknowledged a lack of concrete evidence supporting the use of gepants as acute therapy in certain patients, their use should not be restricted. Instead, gepants should be considered with a careful evaluation of the balance between risks and benefits. Furthermore, the panel noted that this concept could potentially be applied to the use of gepants for migraine prophylaxis.

Gepants for preventive treatment (statement 15, 16, 17, 18, 19, 20)

Apart from acute treatment, the panelists consider gepants as viable options for preventive therapy. Rimegepant has shown efficacy in a randomized placebo-controlled trial in patients experiencing 4–18 moderate to severe migraine attacks per month over the last 3 months, significantly reducing the mean number of migraine days per month [33]. Similarly, atogepant demonstrated positive efficacy results in a randomized placebo-controlled trial involving patients with 4–14 migraine days per month, improving both the number of migraine days and headache days, as well as the Activity Impairment in Migraine Diary (AIM-D) scores [34]. Furthermore, the PROGRESS study assessed atogepant’s efficacy in preventing chronic migraines among patients with at least a one-year history of chronic migraines, revealing strong efficacy in reducing the number of migraine days [35]. As a result, the panel advocates the use of gepants as preventive therapy for episodic migraine. For chronic migraine, although the evidence is limited due to the small number of participants in the trial, rimegepant might still be considered as a treatment option.

Regarding the duration of prevention, the American Headache Society made no specific recommendation on how long patients should take gepants but stated that treatment regimens should be informed by clinical trial protocols and tailored to individual patient needs. Up to one year of rimegepant was used in clinical trials, demonstrating an acceptable tolerability profile without signs of hepatotoxicity [20]. Furthermore, the long-term administration of gepants has been associated with the absence of rebound headaches, suggesting a potential anti-rebound effect [36]. While gepants are likely to provide long-term benefits for patients, the International Headache Society recommends to continuing oral preventive treatment for at least six months [6]. After considering these perspectives, the duration of prevention proposed by the panelists is at least six months, as recommended for other oral preventive medications. It is important to acknowledge that this recommendation may vary based on individual patient clinical features and physician considerations.

There is limited data regarding combination therapy of gepants with other agents such as CGRP monoclonal antibodies. One study reported the use of rimegepant for acute therapy in combination with CGRP monoclonal antibodies as preventive therapy among 13 patients. With a mean treatment period of 9.6 weeks, favorable tolerability was observed, and no serious safety issues were identified [37]. Given the potential benefits, the panelists suggested that these combinations may be considered, though further study is warranted. Furthermore, they advocate the integration of gepants with non-pharmacological therapies to improve migraine control.

Gepants use in specific conditions

Medication overuse headache (statement 2, 27, 28, 29)

One advantage that distinguishes gepants from other medications with long-term use is the current lack of concern about inducing medication overuse headache [38]. A preclinical study using a rodent model of medication overuse headache have demonstrated that repeated administration of ubrogepant does not induce cutaneous allodynia or latent sensitization, suggesting a negligible risk of medication overuse headache [39]. Additionally, clinical data on chronic gepant use has not demonstrated the induction of this condition. Although the relationship between medication overuse headache and the CGRP signaling pathway remains unclear, and clinical data on the use of gepants at doses exceeding the recommended monthly limits are lacking, the panelists recognized the potential benefits of gepants in this clinical context. They proposed gepants as an option for managing patients with medication overuse headaches. Furthermore, this drug may also offer benefits for high-risk patients with frequent migraine attacks and warrant consideration. Given their unique ability to serve both as preventive measures and as acute treatments, gepants allow for a reduction in reliance on traditional analgesics, which are often associated with adverse effects such as medication overuse headaches. Rimegepant, notably, has been approved for both acute and preventive treatment modalities.

Menstrual migraine (statement 30)

Situational prevention represents a novel strategy in migraine management, where patients who can identify the high-risk periods for migraine attacks are advised to preemptively administer medication to prevent migraine episodes. Rimegepant has been utilized for this approach in two cases of migraine triggered by stress from examinations and life events, as well as in one case with a predictable weekly migraine pattern [40]. Among the scenarios suitable for this approach, menstrual migraine is proposed as the most promising area for situational prevention [40]. There is very limited data on menstrual migraine treatment using gepants available on the market. Only ubrogepant was shown in a post hoc analysis to demonstrate similar efficacy between perimenstrual migraine and non-perimenstrual migraine [41]. Consequently, the panelists suggested using gepants solely for short-term prevention in patients with a regular menstrual cycle.

Safety concerns (statement 3, 8, 9, 10)

Real-world data has demonstrated a generally favorable safety profile for rimegepant, atogepant, and ubrogepant. However, data regarding zavegepant remain limited due to its recent introduction to the market. The most frequently reported adverse events are related to gastrointestinal disorders, particularly nausea [42]. According to the International Headache Society guidelines, antiemetics are suggested to be added to analgesics if not contraindicated [4]. The panelist therefore allows the addition of antiemetics to gepants concurrently in patients who develop the symptoms of nausea and vomiting, irrespective of whether these symptoms are medication side effects or are manifestations of the migraine itself.

In patients with prior cardiovascular events, the panelists voice concerns regarding the lack of solid data demonstrating the safety of gepants use because clinical trials have typically excluded patients with a history of cardiovascular or cerebrovascular events. Although existing research indicates that gepants might be safer than triptans and ergots, the sample sizes are too small and insufficient to draw definitive conclusions. Despite the absence of label contraindications from regulatory agencies, real-world data indicate potential signal for cardiac adverse events, such as atrial flutter, associated with atogepant [42, 43]. Raynaud’s phenomenon is another adverse event of concern, as associations between this condition and the use of gepants have been identified in pharmacovigilance databases [44, 45]. Consequently, while there are no significant red flags concerning the use of gepants in this population, there remains a lack of safety data to provide reassurance for their use among patients with cardiovascular conditions. The risks and benefits should be thoroughly discussed with patients, and it is ideal to involve cardiologists to facilitate a comprehensive assessment. Conversely, for patients with cardiovascular risk factors without established events, the use of gepants is not prohibited. Post-hoc analyses of clinical trials indicate a favorable safety profile for ubrogepant, rimegepant, and atogepant in this population [46–48].

Concomitant use of gepants with other medications necessitates careful consideration. Given that gepants are primarily metabolized in the liver by CYP enzymes, especially CYP3A4, coadministration with strong CYP3A4 inducers or inhibitors may significantly result in a subtherapeutic response or increased risk of side effects, respectively [49]. As a result, the panel advised against the concurrent administration of the medications and emphasized the importance of medication reconciliation. Moreover, the concomitant use of these medications may require dosage adjustments to ensure efficacy and safety, highlighting the need for effective communication among healthcare professionals and patient education [50].

Special populations

Pregnancy and breastfeeding (statement 21, 22, 23)

Due to the current paucity of safety data, the panel advised against the use of gepants in pregnant women. This is in accordance with the recommendation from the American College of Obstetricians and Gynecologists against rimegepant and ubrogepant for the treatment of primary headache in pregnancy, which is based on the absence of published human pregnancy data [51]. For patients planning a pregnancy, the expert advice a thorough discussion with healthcare providers regarding the continuation or discontinuation of gepants. The rationale for recommending gepants as a more suitable option for patients planning a pregnancy, compared to monoclonal antibodies, is based on the differing safety profiles and cessation timelines associated with these treatments. The shorter half-lives of several hours for gepants facilitate a shorter discontinuation period prior to pregnancy, when compared to CGRP monoclonal antibodies that have longer half-lives, lasting several weeks to months. While experts discussed the potential benefits of providing specific recommendations regarding when to discontinue these medications, they acknowledged the challenges of implementing such recommendations in real-world clinical practice. The variability in individual patient circumstances complicates the standardized cessation timelines.

Concerning the management of breastfeeding patients, although the International Headache Society indicates that gepants may be utilized with caution by withholding breastfeeding for a duration of 8 to 12 hours [4], the panel did not recommend them as treatment options due to the requirement for more long-term safety data.

Pediatric population (statement 24)

Favorable efficacy and safety data of gepants, specifically rimegepant and ubrogepant, when used as acute treatments in pediatric populations were observed in patients under 18 years old [52]. While high-quality evidence regarding the use of gepants in pediatric patients remains limited, preliminary studies suggest a favorable safety and efficacy profile, warranting consideration in this population for cases of refractory migraine. Suitable candidates may include pediatric patients who have experienced treatment failure with other medications and present with high disease severity. Gepants should be started with the lowest possible dose and with careful monitoring for adverse effects and therapeutic response [53].

Hepatic and renal impairment (statement 25, 26)

Patients with mild or moderate liver impairment (Child-Pugh A or B) may receive standard doses of gepants. However, due to limited data regarding the use in severe liver disease, it is advisable to avoid gepants given their potential hepatotoxicity [54]. Generally, gepants require no dosage adjustment in patients with a creatinine clearance of more than 30 ml/min. Nevertheless, dose reductions are indicated for both ubrogepant and atogepant in individuals with severe renal impairment. In cases of end-stage renal disease, the use of gepants should typically be avoided [54].

Conclusion

Gepants represent essential therapeutic options in migraine therapy, providing valuable alternatives as monotherapy or in combination with other drugs. For acute treatment, gepants are suitable for patients with contraindications or intolerance to conventional therapies and should be initiated as early as possible, ideally during the premonitory phase. In terms of prevention, gepants can be used in individuals with limitation due to the long-term adverse effects of standard drugs, with a recommended duration of prevention continuing for at least six months. Long-term use has not been associated with medication overuse headache, suggesting that gepants might be utilized in patients with established or at high risk of this condition. While a favorable safety profile has been observed, careful monitoring for potential drug interactions is advised when used in patients with polypharmacy. Additionally, due to limited evidence, patients with migraine with atypical aura, patients with prior cardiovascular events, and pediatric populations should undergo a risk-benefit evaluation before prescribing gepants. The long-term safety profile during post-marketing surveillance among gepants and potential newer indications or combinations with other drugs warrants vigilant monitoring.

Abbreviations

AIM-D

Activity Impairment in Migraine Diary

CGRP

Calcitonin gene-related peptide

CYP

Cytochrome P450

ICHD

International Classification of Headache Disorders

NSAIDs

Non-steroidal anti-inflammatory drugs

USFDA

United States Food and Drug Administration

Authors’ contributions

All authors participated in both the surveys and meetings to create and refine the statements until consensus was reached. The expert meetings were led by ST (Surat Tanprawate) and moderated by PA and WR. PA and WR conceptualized the manuscript and reviewed the draft manuscript. All authors read, revised and approved the final manuscript for the intellectual content.

Funding

This research was funded by Pfizer (Thailand) Ltd., which facilitated expert consensus meetings and supported the publication process without influencing the statements and manuscript development.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

PA has received speaker and advisory board honoraria from BL HUA, DKSH, Lundbeck, Pfizer, and ZP therapeutics. WR declares receiving speaker and advisory board honoraria from BL HUA, DKSH, Lundbeck, Pfizer, Viatris and ZP therapeutics. KV discloses participation in speaker’s bureaus for Abbott, AbbVie, Daiichi Sankyo, DKSH, Eli Lilly, GSK, Lundbeck, Merck, Novartis, Pfizer, Servier, Teva Pharma, Viatris, ZP therapeutics and Zuellig Pharma, as well as being a consultant for Daiichi Sankyo, Lundbeck, Novartis, Pfizer, Teva Pharma, and Zuellig Pharma. TP (Thanakit Pongpitakmetha) has received speaker honoraria from BL HUA, Daiichi Sankyo, Eisai, Lundbeck, Pfizer, Servier and ZP therapeutics. ST (Sekh Thanprasertsuk) reports speaker and advisory board honoraria from BL HUA, DKSH, Lundbeck, Pfizer, Viatris and ZP therapeutics. TP (Thaninjitra Poonpedpun) declares receiving speaker and advisory board honoraria from DKSH, Lundbeck, Pfizer and ZP therapeutics. PS has received speaker honoraria from BL HUA, DKSH, Pfizer and ZP therapeutics. KS discloses potential interests in receiving speaker honoraria from DKSH, Pfizer and ZP therapeutics. KK has received speaker and advisory board honoraria from BL HUA, DKSH, Lundbeck, Pfizer, Viatris and ZP therapeutics. SK declares receiving honoraria as a speaker for BL HUA, DKSH, Lundbeck, Pfizer, Viatris and ZP therapeutics, as well as participation in advisory board meeting of Lundbeck. Both PD and CT report receiving an advisory board honorarium from Pfizer. NS has received speaker and advisory board honoraria from Abbott, A.Menarini, Bayer, BL HUA, Daiichi Sankyo, DKSH, Lundbeck, Novartis, Orion, Pfizer, Viatris and ZP therapeutics. NY received speaker and advisory board honoraria from BL HUA, Pfizer and ZP therapeutics. ST (Surat Tanprawate) discloses receiving speaker and advisory board honoraria from BL HUA, DKSH, Lundbeck, Pfizer, Viatris and ZP therapeutics.