Characterization of rimegepant drug-drug interactions using the cytochrome P450 probe drugs, itraconazole, rifampin, fluconazole, and midazolam.

OBJECTIVE: Reported here are the results of four rimegepant phase I studies, in healthy participants, aimed at determining the in vivo potential of rimegepant (75 mg) for cytochrome P450 (CYP) 3A4-related drug-drug interactions (DDIs). BACKGROUND: Rimegepant orally disintegrating tablet (Pfizer Inc., New York, NY, USA) is a calcitonin gene-related peptide receptor antagonist approved for acute treatment of migraine and preventive treatment of episodic migraine. People with migraine commonly use multiple drug treatments, with the potential for DDIs. METHODS: Each study was an open-label, single-arm, single-sequence, crossover study. Rimegepant was tested as a victim drug by separate co-administration of itraconazole (a strong CYP3A4 inhibitor and P-glycoprotein inhibitor) in Study 1, rifampin (a strong CYP3A4 inducer and moderate CYP2C9 inducer) in Study 2, and fluconazole (a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor) in Study 3, and as a perpetrator drug by co-administration with midazolam (a CYP3A4 substrate) in Study 4. RESULTS: Mean values of single-dose rimegepant maximum concentration (Cmax) and area under the curve from time 0 to infinity (AUC0-inf) increased with itraconazole co-administration (n = 22) by 1.42-fold (90% confidence interval [CI] 1.25-1.61) and by 4.14-fold (90% CI 3.87-4.44), respectively, and decreased with rifampin co-administration (n = 21) to 36% (90% CI 31.2-41.4%) and to 19% (90% CI 16.3-21.4%), respectively. Co-administration with fluconazole (n = 23) increased rimegepant mean AUC0-inf by 1.80-fold (90% CI 1.68-1.93), with no impact on Cmax (1.04-fold; 90% CI 0.94-1.15). Co-administration of rimegepant single dose (300 mg; n = 14) or multiple doses (150 mg/day; n = 14) increased the mean Cmax of midazolam by 1.38-fold (90% CI 1.13-1.67) and 1.53-fold (90% CI 1.32-1.78), respectively, and the AUC0-inf of midazolam by 1.86-fold (90% CI 1.58-2.19) and 1.91-fold (90% CI 1.63-2.25), respectively. CONCLUSIONS: Based on the magnitude of DDIs, these studies indicate the following: co-administration of rimegepant with a strong CYP3A4 inhibitor should be avoided; during co-administration with a moderate CYP3A4 inhibitor, another dose of rimegepant within 48 h should be avoided; co-administration of rimegepant with a strong or moderate CYP3A4 inducer should be avoided; CYP2C9 does not play a meaningful role in rimegepant metabolism; and there is no clinically meaningful CYP3A4 inhibition by rimegepant.

A real-world adverse events study of rimegepant from the FAERS database.

BACKGROUND: The primary objective of this research is to conduct an exhaustive evaluation of rimegepant with the Food and Drug Administration Adverse Event Reporting System (FAERS) repository. RESEARCH DESIGN AND METHODS: This study downloaded the reporting files related to rimegepant from the second quarter of 2020 to the first quarter of 2024. Disproportionality analysis was utilized to explore the relationship between rimegepant and adverse drug events (ADEs). RESULTS: This study analyzed 6659 ADE reports associated with rimegepant as the primary suspected (PS) drug. In the disproportionate analysis of system organ classes (SOCs), the significant signal for rimegepant was general disorders and administration site conditions.On the preferred terms level, 35 ADEs were identified following the exclusion. The top 5 ADEs with high signal strengths were medication overuse headache, nasal edema, tension headache, performance status decreased, and motion sickness. The most frequent ADEs were nausea, feeling abnormal, abdominal pain upper, somnolence, and hypersensitivity. In addition, we need to pay attention to the ADEs not mentioned in the instruction and clinically significant: vertigo, hyperacusis, somnolence, Raynaud's phenomenon, motion sickness, panic attack, and fear. CONCLUSIONS: This study highlights previously unrecognized safety concerns associated with the use of rimegepant. These novel safety aspects suggest that while these treatments can be effective, additional risks may need further exploration.

Post-marketing safety concerns with rimegepant based on a pharmacovigilance study.

PURPOSE: This study aimed to comprehensively assess the safety of rimegepant administration in real-world clinical settings. METHODS: Data from the Food and Drug Administration Adverse Event Reporting System (FAERS) spanning the second quarter of 2020 through the first quarter of 2023 were retrospectively analyzed in this pharmacovigilance investigation. This study focuses on employing subgroup analysis to monitor rimegepant drug safety. Descriptive analysis was employed to examine clinical characteristics and concomitant medication of adverse event reports associated with rimegepant, including report season, reporter country, sex, age, weight, dose, and frequency, onset time, et al. Correlation analysis, including techniques such as violin plots, was utilized to explore relationships between clinical characteristics in greater detail. Additionally, four disproportionality analysis methods were applied to assess adverse event signals associated with rimegepant. RESULTS: A total of 5,416,969 adverse event reports extracted from the FAERS database, 10, 194 adverse events were identified as the "primary suspect" (PS) drug attributed to rimegepant. Rimegepant-associated adverse events involved 27 System Organ Classes (SOCs), and the significant SOC meeting all four detection criteria was "general disorders and administration site conditions" (SOC: 10018065). Additionally, new significant adverse events were discovered, including "vomiting projectile" (PT: 10047708), "eructation" (PT: 10015137), "motion sickness" (PT: 10027990), "feeling drunk" (PT: 10016330), "reaction to food additive" (PT: 10037977), etc. Descriptive analysis indicated that the majority of reporters were consumers (88.1%), with most reports involving female patients. Significant differences were observed between female and male patients across age categories, and the concomitant use of rimegepant with other medications was complex. CONCLUSION: This study has preliminarily identified potential new adverse events associated with rimegepant, such as those involving the gastrointestinal system, nervous system, and immune system, which warrant further research to determine their exact mechanisms and risk factors. Additionally, significant differences in rimegepant-related adverse events were observed across different age groups and sexes, and the complexity of concomitant medication use should be given special attention in clinical practice.

The influence of pharmacodynamics and pharmacokinetics on the antimigraine efficacy and safety of novel anti-CGRPergic pharmacotherapies: a narrative review.

INTRODUCTION: Migraine is a complex disorder, and its etiology is not yet fully understood. In the last 40 years, calcitonin gene-related peptide (CGRP) has been central to the understanding of migraine pathophysiology, leading to the development of new molecules targeting the CGRPergic system. These new molecules, such as gepants and monoclonal antibodies, are effective, well-tolerated, and safe, and are approved for clinical use. AREAS COVERED: By searching multiple electronic scientific databases, this narrative review examined: (i) the role of CGRP in migraine; and (ii) the current knowledge on the effects of CGRPergic antimigraine pharmacotherapies, including a brief analysis of their pharmacodynamic and pharmacokinetic characteristics. EXPERT OPINION: Current anti-CGRPergic medications, although effective, have limitations, such as side effects and lack of antimigraine efficacy in some patients. The existence of patients with medication-resistant migraine may be due to the: (i) complex migraine pathophysiology, in which several systems appear to be deregulated before, during, and after a migraine attack; and (ii) pharmacodynamic and pharmacokinetic properties of antimigraine medications. As envisioned here, although seminal studies support the notion that CGRP plays a key role in migraine headache, the dysfunction of CGRPergic transmission does not seem to be relevant in all cases.

Evaluation of rimegepant utilization patterns and patient characteristics among new users: a United States administrative claims-based study.

OBJECTIVE: To assess tablet utilization patterns and describe pre-treatment characteristics among new users of rimegepant. BACKGROUND: Rimegepant is the only oral calcitonin gene-related peptide antagonist approved in the United States for both the acute and preventive treatment of migraine. METHODS: We conducted a retrospective cohort study of people with migraine who initiated treatment with rimegepant using two US commercial claims databases (MarketScan and Optum). Patients (≥18 years old) with migraine who newly initiated rimegepant were included. Patients were stratified into two groups representing acute (quantity = 8) and prevention (quantity = 15 or 16) use cohorts. Baseline characteristics and medication use history were assessed on index and during the 365-day pre-index period. Rimegepant utilization periods were calculated based on days supplied and varying approaches to define use periods. Tablet quantity per 30 days was reported separately for both acute and prevention cohorts. RESULTS: In MarketScan, a total of 14,037 rimegepant users were identified; 11,195 (79.8%) in the acute group and 1,880 (13.4%) in the prevention group. Rimegepant utilization for acute use was 4.9 ± 2.1 tablets per 30 days and for preventive use was 13.1 ± 7.7 tablets per 30 days. There was high baseline prevalence of triptan contraindications, warnings, and high cardiovascular risk, with a combined 46.2% meeting one or more of these criteria. Acute medication overuse was also common (25.1%) prior to rimegepant initiation. Results were consistent in the Optum database. CONCLUSION: Our analysis provides the first real-world data available on tablet utilization and characteristics of new users of rimegepant.

There is little information available on the characteristics of people with migraine who start to use rimegepant, which is the only medicine approved for both the prevention of migraine attacks and the acute treatment of migraine attacks after they have started. Information on new users of rimegepant at least 18 years of age was obtained from two commercial databases of US healthcare claims (MarketScan and Optum). The researchers used this information to evaluate people's age, sex, pre-existing illnesses, and prior use of migraine medications at the time they started using rimegepant, and they also used several different methods to estimate how often people used rimegepant after treatment was started. The MarketScan database contained information on 14,037 people with migraine who started using rimegepant, with this group having an average age of 43 years and being comprised mostly of females (88%). Prior to starting rimegepant, almost half (46%) of the people were considered to have high cardiovascular risk and 25% considered at risk of overusing acute migraine medications. Most of the 14,037 people (80%) who started rimegepant used it to treat migraine attacks after they started and this group used approximately 5 tablets every month. The smaller number of people who used rimegepant to prevent migraine attacks used approximately 13 tablets every month. The information obtained from the Optum database was similar to that obtained from the MarketScan database. The researchers' analysis is the first to describe the characteristics of people with migraine who start to use rimegepant outside the setting of a controlled clinical trial. Their results show that new users of rimegepant represent a complex population with a significant profile of pre-existing illness and a diverse treatment history.

First real-world study on the effectiveness and tolerability of rimegepant for acute migraine therapy in Chinese patients.

BACKGROUND: Rimegepant, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is indicated for acute and preventive migraine treatment in the United States and other countries. However, there is a lack of prospective real-world evidence for the use of rimegepant in Chinese migraine patients. METHODS: This was a single-arm, prospective, real-world study. While taking rimegepant to treat migraine attacks as needed, eligible participants were asked to record their pain intensity, functional ability, and accompanying symptoms for a single attack at predose and 0.5, 1, 2, 24, and 48 h postdose via a digital platform. Adverse events (AEs) during the rimegepant treatment period were recorded and analysed. The percentages of participants who experienced moderate to severe pain at predose and 0.5, 1, 2, 24, and 48 h postdose were assessed. Additionally, the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose were analysed. In addition, the total cohort (full population, FP) was stratified into a prior nonresponder (PNR) group to observe the effectiveness and safety of rimegepant for relatively refractory migraine and a rimegepant and eptinezumab (RE) group to observe the effectiveness and safety of the combination of these drugs. RESULTS: By November 24th, 2023, 133 participants (FP, n = 133; PNR group, n = 40; RE group, n = 28) were enrolled, and 99 participants (FP, n = 99; PNR group, n = 30; RE group, n = 23) were included in the analysis. Rimegepant was effective in treating migraine in the FP and both subgroups, with a significant decreasing trend in the percentages of participants experiencing moderate to severe pain postdose (p < 0.05) and a marked increase in the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose compared with predose. AEs were reported by 6% of participants in the FP, and all AEs were mild. CONCLUSIONS: In the real world, rimegepant is effective in the acute treatment of migraine patients in China. The low incidence rate of AEs highlighted the favourable tolerability profile of rimegepant. TRIAL REGISTRATION: Clinicaltrials.gov NCT05709106. Retrospectively registered on 2023-02-01.

Cost-effectiveness analysis of rimegepant for on-demand acute treatment of migraine in China.

Purpose: This study assesses the cost-effectiveness of rimegepant for the on-demand acute treatment of migraine in the Chinese population, focusing on headache relief within a 2 h timeframe. Utilizing data from Phase III clinical trials on rimegepant involving Asian populations, this analysis aims to provide essential insights for healthcare decision-making in the context of migraine management in China. Patients and methods: Employing a decision tree model, this research evaluates the cost-effectiveness of rimegepant over a concise 2 h period, exclusively considering its direct market price of 219.00 CNY per dose for on-demand, single-use treatment upon approval in China. This model is based on pain relief outcomes from a clinical trial, categorizing health outcomes by the achievement of pain freedom and alleviation from the most bothersome symptom within two hours post-administration. Results: The study unveils that rimegepant adds 0.0018 quality-adjusted life days (QALD) with an incremental cost-effectiveness ratio (ICER) of 122,166.07 CNY/QALD. Against a daily cost-effectiveness threshold derived from the 2023 per capita GDP of China (734.45 CNY/day), rimegepant falls short of proving its cost-effectiveness. A significant price reduction to approximately 1.32 CNY per dose is required for rimegepant to be considered cost-effective within this framework. Furthermore, a series of sensitivity analyses were conducted to validate the robustness of these results. Conclusion: While rimegepant shows clinical efficacy in providing rapid relief from migraine symptoms, its current pricing exceeds the threshold for cost-effectiveness in the Chinese healthcare setting. This study underscores the need for price adjustments to enhance the accessibility and economic viability of new migraine treatments.

Rimegepant and atogepant: novel drugs providing innovative opportunities in the management of migraine.

INTRODUCTION: Rimegepant and atogepant, two innovative oral medications for the treatment of migraine, are gaining prominence in the treatment of migraine. However, outside of specialist headache centers, these novel medications remain subjectively underutilized. While multiple rationales exist describing their underutilization, a leading factor is the complexity and clinical flexibility attributed to the individual members of the gepant medication class. AREAS COVERED: This review provides a brief review of the current uses, common adverse events, and potential areas of future clinical innovation attributed to rimegepant and atogepant. A database search for the term 'Rimegepant OR Atogepant' was completed, yielding 240 individual results. Following multiple rounds of assessment that aimed to determine relevance of each individual result, 42 studies were included in the synthesis of this review. EXPERT OPINION: Rimegepant and atogepant are exciting medications that demonstrate significant clinical innovation within the field of migraine therapy. While current indications are clear, data is lacking regarding the future expanded roles of these medications. Current areas of potential therapeutic innovation for rimegepant and atogepant include the pediatric population, in pregnancy and breastfeeding, in cluster headache and post-traumatic headache, and in patients that previously discontinued calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) therapy.

Cost per treatment responder analysis of atogepant compared to rimegepant for the preventive treatment of episodic migraine.

OBJECTIVE: To estimate the number needed to treat and cost per additional responder for atogepant and rimegepant versus placebo for the preventive treatment of episodic migraine (EM) in the United States. BACKGROUND: Migraine has an enormous impact on a person's daily activities and quality of life, and results in significant clinical and economic burden to both individuals and society. It is important to understand the comparative efficacy and economic value of oral calcitonin gene-related peptide receptor antagonists (gepants) for preventive treatment of EM. Currently, atogepant and rimegepant are US Food and Drug Administration approved for preventive treatment of migraine (rimegepant for EM and atogepant for EM and for chronic migraine). In the absence of head-to-head trials, we utilized an indirect treatment comparison on efficacy data from clinical trials conducted for the preventive treatment of EM. We estimated number needed to treat, a valuable metric used in clinical practice to compare treatment efficacy, and cost per additional responder, which can be used to establish the cost effectiveness of a treatment. METHODS: An indirect treatment comparison was conducted to compare the efficacy of atogepant 60 mg once daily and rimegepant 75 mg once every other day as preventive treatments for EM using published data from the registrational trials of atogepant (ADVANCE) and rimegepant (BHV3000-305). The efficacy outcome of interest was ≥50% reduction from baseline in mean monthly migraine/headache days (≥50% responder rate), which was variably defined for a base case and two scenario analyses. Number needed to treat and cost per additional responder versus placebo were calculated and compared between both treatments (weeks 9-12 in the base case analysis; weeks 1-12 and 9-12 for atogepant and during weeks 9-12 for rimegepant in the scenario analyses). RESULTS: In the base case analysis, ≥50% responder rates were 64.9% (95% confidence interval [CI], 53.9-74.5) for atogepant and 51.8% (95% CI, 42.9-60.6) for rimegepant, compared to 44.1% (95% CI, 39.4-49.0) for placebo. The median number needed to treat versus placebo in the base case scenario was 4.8 (95% CI, 3.1-9.0) for atogepant compared to 13.0 (95% CI, 5.9-75.1) for rimegepant. The cost per additional responder versus placebo in the base case scenario was estimated to be $15,823 (95% CI, $11,079-$29,516) for atogepant compared to $73,029 (95% CI, $32,901-$422,104) for rimegepant. Results of the two scenario analyses were consistent with the base case analysis. CONCLUSIONS: Atogepant had substantially lower numbers needed to treat and costs per additional responder versus placebo than rimegepant for the preventive treatment of EM across all evaluated scenarios. These analyses suggest that atogepant may be more cost effective than rimegepant for the preventive treatment of EM. Limitations include differences in inclusion/exclusion criteria and in reporting of the ≥50% responder rates between trials.

Comparison of gepant effects at therapeutic plasma concentrations: connecting pharmacodynamics and pharmacokinetics.

BACKGROUND: Orally administered second-generation gepants are effective for the treatment of migraine. The intranasal administration of the third-generation gepant zavegepant might have additional benefits including a rapid onset of action, but it is not clear yet to which extent this has clinical relevance. METHODS: We examined the effect of zavegepant on the relaxations induced by calcitonin gene-related peptide (CGRP) in human isolated middle meningeal arteries. Furthermore, we connected the pharmacodynamics and pharmacokinetics of gepants by combining data from clinical and basic research. RESULTS: We showed that 10 nM zavegepant potently antagonized the functional response to CGRP. We also showed that all gepants are effective at inhibiting functional responses to CGRP at their therapeutic plasma concentrations. CONCLUSIONS: The relatively low predicted potency of zavegepant to inhibit CGRP-induced relaxation at therapeutic systemic plasma concentrations may point to the relevance of local delivery to the trigeminovascular system through intranasal administration. This approach may have additional benefits for various groups of patients, including overweight patients.

Situational prevention in migraine: are we doing the right thing?

This commentary addresses the use of rimegepant for situational prevention in migraine management. While the approach of using prophylactic treatments during high-risk periods is not new, its application with rimegepant described by Lipton et al. raises ethical and clinical concerns. These include the challenge of defining high-risk periods, the potential for overmedication, and the risk of medication overuse headache (MOH). The current evidence on MOH with gepants is inconclusive, and recommendations on dosing may be insufficient. Additionally, the long-term safety of calcitonin gene-related peptide (CGRP) antagonists remains uncertain, especially regarding cardiovascular and other systemic effects. The commentary emphasizes the need for caution and thorough investigation into the long-term risks and benefits of situational prevention with rimegepant before widespread adoption.

Safety of Rimegepant in Adults with Migraine and Cardiovascular Risk Factors: Analysis of a Multicenter, Long-Term, Open-Label Study.

INTRODUCTION: Cardiovascular (CV) risk factors can limit treatment options for migraine. Rimegepant is an orally administered small-molecule calcitonin gene-related peptide receptor antagonist that does not induce vasoconstriction. The aim of these post hoc subgroup analyses was to assess the safety of rimegepant according to CV risk. METHODS: In a multicenter, long-term, open-label, phase II/III safety study, participants with a history of 2-14 migraine attacks per month of moderate or severe pain intensity self-administered rimegepant 75 mg, orally, to treat migraine up to once daily for up to 52 weeks. Uncontrolled, unstable, or recently diagnosed CV disease was part of the exclusion criteria. Safety was assessed across subgroups according to number of CV risk factors (0, 1, or ≥ 2) and Framingham Risk Score (< 10% or ≥ 10%). RESULTS: Of 1800 treated participants, 28.8% had one CV risk factor and 12.1% had ≥ 2 CV risk factors; 7.0% had Framingham Risk Score ≥ 10%. Across the subgroups with 0, 1, and ≥ 2 CV risk factors and Framingham Risk Score < 10% and ≥ 10%, respectively, proportions of participants reporting adverse events (AEs; 59.6%, 61.4%, 62.2%, 59.9%, 67.5%) and serious AEs (2.7%, 2.5%, 2.3%, 2.6%, 2.4%) were consistent, and AEs leading to study drug discontinuation were low (1.9%, 3.1%, 5.5%, 2.5%, 4.8%). CONCLUSIONS: Rimegepant showed favorable safety and tolerability in adults with migraine and CV risk factors, including those with moderate to high CV risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT03266588.

Older patients with migraine often have cardiovascular (CV) disease ­ such as a prior heart attack ­ or risk factors for CV disease. Examples of CV risk factors are high blood pressure, diabetes, smoking, high cholesterol, and a family history of heart disease. The choice of treatments for migraine is limited by safety concerns for patients who have CV risk factors. Newer treatments for migraine ­ including rimegepant ­ work differently than older drugs, by targeting calcitonin gene-related peptide. The safety of rimegepant for patients with migraine and CV risk factors can be studied in a clinical trial. In a long-term trial, patients with migraine took rimegepant tablets to treat migraine attacks, up to once a day, for up to 52 weeks. Some of the patients in the study had CV risk factors. We analyzed the results of the study by grouping the patients based on how many CV risk factors they had. We found that the side effects of rimegepant were similar across the groups. This showed that rimegepant was safe and well tolerated in adults with migraine and CV risk factors.

Efficacy and Safety of Rimegepant 75 mg Oral Tablet, a CGRP Receptor Antagonist, for the Acute Treatment of Migraine: A Randomized, Double-Blind, Placebo-Controlled Trial.

Purpose: This study compared the efficacy, tolerability, and safety of rimegepant 75 mg oral tablet - a small molecule calcitonin-gene receptor peptide (CGRP) receptor antagonist - with placebo in the acute treatment of migraine. Methods: This double-blind, randomized, placebo-controlled trial enrolled adults aged ≥18 years with at least a 1-year history of migraine. Participants randomized to rimegepant 75 mg oral tablet or placebo treated a single migraine attack of moderate or severe pain intensity. The coprimary endpoints, pain freedom and freedom from the most bothersome symptom ([MBS] nausea, photophobia, or phonophobia) at 2 hours postdose, were evaluated using Mantel-Haenszel risk estimation. Results: Of the 1485 participants enrolled, 1162 (78.2%) were randomized to rimegepant (n = 582) or placebo (n = 580). Most participants (85.5%) were female; the population had a mean (SD) age of 41.6 (12.2) years and a history of 4.7 (1.8) migraine attacks per month. At 2 hours postdose, rimegepant-treated participants had higher pain freedom rates (19.2% [104/543] vs 14.2% [77/541]; risk difference 4.9; 95% confidence interval [CI] 0.5 to 9.3; P=0.0298) and MBS freedom rates (36.6% [199/543] vs 27.7% [150/541]; risk difference 8.9; 95% CI 3.4 to 14.4; P=0.0016) than placebo-treated participants. Rimegepant-treated participants also had higher rates of pain relief (56.0% [304/543] vs 45.7% [247/541]; risk difference 10.3; 95% CI 4.4 to 16.2, P=0.0006) at 2 hours postdose. The most common adverse events were nausea (0.9% [5/546] vs 1.1% [6/549]) and dizziness (0.7% [4/546] vs 0.4% [2/549]). No signal of drug-induced liver injury due to rimegepant was identified. Conclusion: Rimegepant 75 mg oral tablet was effective in the acute treatment of migraine. Tolerability and safety were similar to placebo, with no evidence of hepatotoxicity. Trial Registration: Clinicaltrials.gov Identifier: NCT03235479.

Researchers wanted to know if rimegepant 75 mg is effective and safe for the acute treatment of migraine. They gave half the participants rimegepant and half placebo and waited 2 hours. Then, they measured the percentages of participants whose headache and most bothersome migraine symptom besides pain (nausea, sensitivity to light or sound) were gone. They also measured side effects to make sure rimegepant is safe. The study included 1084 adults with migraine, 927 (86%) of whom were women. Two hours after taking the medicine: pain freedom was 19% with rimegepant and 14% with placebo. Freedom from the most bothersome symptom was 37% with rimegepant and 28% with placebo. Pain relief rates, defined as the transition from moderate or severe pain to pain that was mild or absent, occurred in 56% with rimegepant and 46% with placebo. The most common side effects were nausea and dizziness, which affected fewer than 1% of rimegepant patients. Rimegepant 75 mg was more effective than placebo for migraine, with similar tolerability and safety.

Safety and Efficacy of Calcitonin Gene-related Peptide Receptor Antagonists and Selective Serotonin Receptor Agonist in the Management of Migraine: A Systematic Review and Meta-analysis.

BACKGROUND: Recently, US Food and Drug Administration (FDA) has approved calcitonin gene-related peptide receptor antagonists (rimegepant, and ubrogepant), and selective serotonin receptor agonists (lasmiditan) in the management of migraine. However, the exact safety and efficacy profile of these drugs is unclear so far. METHODS: The study's primary objective was to determine the exact safety and efficacy profile. The overall estimate was calculated in terms of risk ratios using a suitable model. The subgroup analysis was also performed to check the effect of individual drugs on the outcome, whereas sensitivity analysis was performed to check the effects of outliers on the outcome. All the analyses were performed using Rev Man 5. The drugs have shown significant improvement in efficacy parameters (pain freedom, most bothersome symptoms, phonophobia, nausea, and photophobia). RESULTS: The subgroup analysis results have shown significant improvement in all efficacy parameters in the rimegepant and ubrogepant groups. The effect of ubrogepant on safety parameters was found to be non-significant, indicating a better safety profile of ubrogepant than lasmiditan. CONCLUSION: The sensitivity analysis results have shown no effect of outliers on the efficacy parameters. Based on the available evidence, recently approved drugs are effective in the treatment of migraine, however, associated with few adverse drug reactions.

Long-Term Use of Rimegepant 75 mg for the Acute Treatment of Migraine is Associated with a Reduction in the Utilization of Select Analgesics and Antiemetics.

Purpose: To examine use of concomitant analgesics and antiemetics during treatment with rimegepant in adults with migraine. Patients and Methods: This was a post hoc analysis of a long-term, open-label, safety study in adults with a history of 2-14 moderate or severe migraine attacks per month. Participants self-administered rimegepant 75 mg (1) up to once daily as needed (PRN) for 52 weeks or (2) every other day plus PRN (EOD+PRN) for 12 weeks. The PRN cohort was further divided based on baseline attack frequency, with PRN (2-8) and PRN (9-14) cohorts having a history of 2-8 or 9-14 attacks per month, respectively. Use of select analgesics and antiemetics was analyzed during a 30-day pre-treatment observation period (OP) and during rimegepant treatment. Results: Overall, 1800 rimegepant-treated participants (PRN n = 1514, EOD+PRN n = 286) were included in the analysis. Select analgesics or antiemetics were used by 80.1% of participants during the OP. Among 1441 participants using analgesics or antiemetics during the OP, the proportion who did not use any analgesics or antiemetics following initiation of rimegepant treatment increased during weeks 1-4 (36.9%), 5-8 (52.6%), and 9-12 (56.5%). The mean number of days per month using analgesics or antiemetics was also significantly reduced over time in all cohorts beginning at weeks 1-4 (P < 0.001 vs OP). This pattern of reduced analgesic or antiemetic use was consistent for all rimegepant cohorts, but was most pronounced in the EOD+PRN cohort in which 74.8% of participants reported ≥50% reduction in analgesic/antiemetic days at weeks 9-12. Reduction in use was maintained over time, with 61.3% of participants not using any analgesics or antiemetics during weeks 49-52 of PRN treatment. Conclusion: Long-term treatment with oral rimegepant was associated with reduced analgesic and antiemetic use. Clinicaltrials.gov: NCT03266588.

Safety of Rimegepant in Patients Using Preventive Migraine Medications: A Subgroup Analysis of a Long-Term, Open-Label Study Conducted in the United States.

Purpose: To evaluate the safety and tolerability of rimegepant 75 mg for the acute treatment of migraine in participants concurrently using a preventive migraine medication. Patients and Methods: This long-term, open-label safety study (NCT03266588) enrolled adults with a history of 2-14 moderate or severe migraine attacks per month. Participants self-administered rimegepant 75 mg (1) up to once daily as needed for 52 weeks to treat attacks of any pain intensity or (2) every other day plus as needed for 12 weeks. Preventive migraine medications were allowed if dosing was stable for ≥2 months prior to the baseline visit. Results: Of 1800 rimegepant-treated participants, 243 (13.5%) took a concomitant preventive medication. The most common preventive medication was topiramate (26.3%). Rimegepant exposure was comparable in both groups (mean [SD] number of doses per 4 weeks was 7.8 [4.5] in those taking preventives and 7.7 [4.7] in those not taking preventives). The proportion of participants experiencing ≥1 on-treatment adverse event (AE) was 68.7% among those using preventive medication and 59.2% among those not using preventives. Serious AEs occurred in 4.5% of those using preventive medication and 2.3% of those who were not using preventives. AEs leading to study drug discontinuation occurred in 4.5% of those taking preventive medication and 2.4% of those not taking preventives. AEs occurring in ≥5% of participants in either cohort (with preventives vs without preventives) were upper respiratory tract infection (7.4% vs 9.0%), nasopharyngitis (7.8% vs 6.6%), sinusitis (7.0% vs 4.8%), urinary tract infection (5.3% vs 3.6%), and back pain (5.3% vs 2.8%). Conclusion: Acute treatment of migraine with rimegepant 75 mg for up to 52 weeks was well tolerated and had a favorable safety profile in adults who were concomitantly using preventive migraine medication.

Cost-effectiveness of rimegepant oral lyophilisate compared to best supportive care for the acute treatment of migraine in the UK.

AIMS: Migraine is the most common disabling headache disorder and is characterized by recurrent throbbing head pain and symptoms of photophobia, phonophobia, nausea, and vomiting. Rimegepant 75 mg, an oral lyophilisate calcitonin gene-related peptide antagonist, is the first treatment approved for both the acute and preventative treatment of migraine, and the first acute therapy approved in over 20-years. The objective was to assess the cost-utility of rimegepant compared with best supportive care (BSC) in the UK, for the acute treatment of migraine in the adults with inadequate symptom relief after taking at least 2 triptans, or for whom triptans are contraindicated or not tolerated. MATERIALS AND METHODS: A de novo model was developed to estimate incremental costs and quality-adjusted life years (QALYs), structured as a decision tree followed by Markov model. Patients received rimegepant or BSC for a migraine attack and were assessed for response (pain relief at 2-h). Responders and non-responders followed different pain trajectories over 48-h cycles. Non-responders discontinued treatment while responders continued treatment for subsequent attacks, with a proportion discontinuing over time. Data sources included a post-hoc pooled analysis of the phase 3 acute rimegepant trials (NCT03235479, NCT03237845, NCT03461757), and a long-term safety study (NCT03266588). The analysis was conducted from the perspective of the UK National Health Service and Personal Social Services over a 20-year time horizon. RESULTS: Rimegepant resulted in an incremental cost-utility ratio (ICUR) of £10,309 per QALY gained vs BSC, which is cost-effectiveness at a willingness to pay threshold of £30,000/QALY. Rimegepant generated +0.44 incremental QALYs and higher incremental lifetime costs (£4,492). Improved QALYs for rimegepant were a result of less time spent with severe and moderate headache pain. CONCLUSION: This study highlights the economic value of rimegepant which was found to be cost-effective for the acute treatment of migraine in adults unsuitable for triptans.

Rimegepant orally disintegrating tablet 75 mg for acute treatment of migraine in adults from China: a subgroup analysis of a double-blind, randomized, placebo-controlled, phase 3 clinical trial.

BACKGROUND: Rimegepant orally disintegrating tablet (ODT), an oral small-molecule calcitonin gene-related peptide receptor antagonist, is indicated for acute and preventive treatment of migraine in the United States and other countries. Previously, a large clinical trial assessed the efficacy and safety of rimegepant ODT 75 mg for the acute treatment of migraine in adults living in China or South Korea. A post hoc subgroup analysis of this trial was performed to evaluate the efficacy and safety of rimegepant for acute treatment of migraine in adults living in China. METHODS: Eligible participants were ≥ 18 years of age and had a ≥ 1-year history of migraine, with 2 to 8 attacks of moderate or severe pain intensity per month and < 15 headache days per month during the 3 months before screening. Participants self-administered rimegepant ODT 75 mg or matching placebo to treat a single migraine attack of moderate or severe pain intensity. The co-primary endpoints were pain freedom and freedom from the most bothersome symptom (MBS) at 2 h post-dose. Key secondary endpoints included pain relief at 2 h post-dose, ability to function normally at 2 h post-dose, use of rescue medication within 24 h post-dose, and sustained pain freedom from 2 to 24 h and 2 to 48 h post-dose. All p values were nominal. Safety was assessed via treatment-emergent adverse events (TEAEs), electrocardiograms, vital signs, and routine laboratory tests. RESULTS: Overall, 1075 participants (rimegepant, n = 538; placebo, n = 537) were included in the subgroup analysis. Rimegepant was more effective than placebo for the co-primary endpoints of pain freedom (18.2% vs. 10.6%, p = 0.0004) and freedom from the MBS (48.0% vs. 31.8%, p <  0.0001), as well as all key secondary endpoints. The incidence of TEAEs was comparable between the rimegepant (15.2%) and placebo (16.4%) groups. No signal of drug-induced liver injury was observed, and no study drug-related serious TEAEs were reported in the rimegepant group. CONCLUSIONS: A single dose of rimegepant 75 mg rimegepant was effective for the acute treatment of migraine in adults living in China, with safety and tolerability similar to placebo. TRIAL REGISTRATION: Clinicaltrials.gov NCT04574362 Date registered: 2020-10-05.

CGRP receptor antagonists (gepants).

Small molecule calcitonin gene-related peptide (CGRP) receptor antagonists are commonly referred to as gepants. The first generation of gepants provided the first line of evidence of CGRP-mediated antimigraine medication in 2004-2011. However, further development was halted due to either lack of oral availability or concerns of hepatotoxicity. More than 15 years later, the first second generation of gepants, ubrogepant and rimegepant, are now approved for the acute treatment of migraine with or without aura. Furthermore, a novel and promising third-generation gepant, zavegepant, has recently been approved as well. In this chapter, we review the evidence supporting the effectiveness, safety, and tolerability of gepants for the acute treatment of migraine. Furthermore, we discuss the potential limitations and future directions of this class of migraine-specific medication.