Abstract
Rimegepant [Nurtec® ODT (USA); Vydura® (EU)] is a calcitonin gene-related peptide (CGRP) receptor antagonist approved for the acute treatment of migraine with or without aura in adults, and for the preventive treatment of episodic migraine in adults. Rimegepant is available as an orally disintegrating tablet (ODT), which offers convenience and a potentially faster response time than the conventional tablet formulation. In pivotal phase III trials, rimegepant was more effective than placebo at relieving pain and the most bothersome symptom when taken as needed for the acute treatment of migraine. Rimegepant was also more effective than placebo at reducing the number of monthly migraine days when taken every other day for the preventive treatment of migraine. The beneficial effects of rimegepant in reducing migraine frequency and improving quality of life were maintained over the longer term (up to 52 weeks). Rimegepant was generally well tolerated, with no evidence of hepatotoxicity or cardiovascular toxicity in clinical trials. As the first dual agent approved for both treatment and prevention of migraine, rimegepant represents a useful option for the management of migraine in adults.
Plain Language Summary
Migraine is a type of headache that causes severe throbbing pain, usually on one side of the head. Bothersome symptoms that may occur during a migraine include nausea, vomiting and sensitivity to light and sound. Medications for migraine are aimed at stop** symptoms (acute treatment) and/or reducing the frequency of future attacks (preventive treatment). Calcitonin gene-related peptide (CGRP) is a protein that is released during migraine attacks, causing inflammation and activation of other pathophysiological processes responsible for pain. Rimegepant [Nurtec® ODT (USA); Vydura® (EU)] is an oral medication that works by blocking the CGRP receptors. A convenient quick-dissolve tablet formulation is available that can be placed on or under the tongue and swallowed without water. Rimegepant relieves pain and bothersome symptoms when taken as needed for a single migraine attack, and reduces the number of migraine days per month when taken every other day to prevent migraine. Rimegepant is generally well tolerated. As the first medication approved to both treat acute migraine attacks and help prevent future attacks, rimegepant represents a useful treatment option for patients with migraine.
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Digital Features for this Adis Drug Evaluation can be found at https://doi.org/10.6084/m9.figshare.21938357 |
Small molecule CGRP receptor antagonist |
Available as an orally disintegrating tablet formulation |
Relieves pain and the most bothersome symptom when taken as needed for the acute treatment of migraine |
Reduces migraine frequency when taken every other day for the preventive treatment of migraine |
Generally well tolerated |
1 Introduction
Migraine is a prevalent and highly debilitating neurological disorder [1,2,3]. It is typically characterized by recurrent attacks of unilateral and pulsatile headache lasting 4–72 h, often accompanied by symptoms such as photophobia, phonophobia, nausea, vomiting and cutaneous allodynia [1, 2, 4]. Approximately one-third of patients also experience aura, a range of transient focal neurological disturbances that precede the attack [1,2,3].
The pharmacological management of migraine includes acute treatment, which aims to relieve pain and disability, and preventive treatment, which aims to reduce the overall frequency and severity of attacks [1, 4]. Medications commonly used for the acute treatment of migraine include nonsteroidal anti-inflammatory drugs (NSAIDs) and other analgesics, which were not specifically developed to treat migraine [2,3,4]. Triptans are migraine-specific medications and have long been the gold standard in migraine treatment [1,2,3,4]. However, approximately one-third of patients do not respond adequately to triptans [1, 5] and ≥ 20% of patients have a cardiovascular disease contraindication to triptans [6]. Medications commonly used for the preventive treatment of migraine include antihypertensives, anticonvulsants and antidepressants [1, 3]. Some of these agents may have contraindications, interactions, limited to moderate efficacy or moderate to high rates of adverse events (AEs) that limit their use [1, 7].
Calcitonin gene-related peptide (CGRP) has been shown to play a pivotal role in the pathophysiology of migraine [2] and therefore offers a novel targeted approach for both the acute and preventive treatment of migraine [2]. First-generation small molecule CGRP receptor antagonists (also known as gepants) demonstrated promising efficacy, but further development was discontinued for various reasons, including hepatotoxicity concerns [2, 8, 9]. Second-generation gepants that do not cause hepatotoxicity have now been developed [2, 9].
Rimegepant [Nurtec® ODT (USA); Vydura® (EU)] is an orally administered, second-generation gepant. It is approved in several countries, including the USA [10] and those of the EU [11], for the acute treatment of migraine with or without aura in adults, and for the preventive treatment of episodic migraine in adults. Rimegepant is the only gepant available in an orally disintegrating tablet (ODT) formulation, which was developed to improve patient convenience and response time [12]. This review focuses on therapeutic efficacy and tolerability data relevant to rimegepant in these patient populations and summarizes its pharmacological properties.
2 Pharmacodynamic Properties of Rimegepant
The small molecule CGRP receptor antagonist rimegepant binds with high affinity to the human CGRP receptor, thereby blocking CGRP activity [11]. The relationship between the pharmacodynamic activity of rimegepant and the exact mechanism(s) by which it produces its therapeutic effects is unknown [10, 11].
In vitro, rimegepant effectively antagonized CGRP activity at both the CGRP receptor and the structurally related amylin 1 (AMY1) receptor, but was ≈ 30-fold more effective at blocking the CGRP receptor [13, 14]. Rimegepant inhibited CGRP-induced currents with inhibition potencies (pIC50 values) of 11.30 for the CGRP receptor and 9.91 for the AMY1 receptor [14]. In non-clinical assays, rimegepant antagonized CGRP-mediated increases in facial blood flow (a surrogate marker for intracranial artery dilation), with 75% inhibition at ≈ 700 nmol/L [15, 16]. The inhibitory constant (Ki) of rimegepant against the CGRP receptor was 0.027 nmol/L (6.9% fraction unbound) [15].
Rimegepant, at concentrations up to 10 μmol/L, exhibited no active vasoconstrictive properties in ex vivo human coronary or cerebral arteries [17]. Conversely, sumatriptan exhibited progressive, concentration-dependent constriction of arteries, a known limitation of the triptan class. The absence of rimegepant-induced vasoconstriction was not due to arteriolar defect, as each vessel exhibited vasoconstriction in the presence of 10 μmol/L serotonin [17]. In primates, exposure to high concentrations of rimegepant (i.e. 10 x greater than those observed in humans at the recommended dose of 75 mg) had no effect on haemodynamic or electrocardiographic parameters [18]. There were also no changes in cardiovascular parameters after 9 months of daily administration of rimegepant 50 mg/kg (i.e. ≈ 20 × the human therapeutic dose) [18].
In healthy volunteers, a single therapeutic (75 mg) or supratherapeutic (300 mg) dose of rimegepant did not prolong the QT interval to any clinically relevant extent [19]. There were no clinically relevant differences in resting blood pressure when rimegepant was coadministered with sumatriptan (two 6 mg tablets taken 1 h apart) relative to sumatriptan alone [20].
3 Pharmacokinetic Properties of Rimegepant
The ODT formulation of rimegepant administered sublingually was bioequivalent to the conventional oral tablet formulation of rimegepant in a randomized, open-label, phase I trial in healthy volunteers (n = 35) [21]. The 90% CIs of geometric mean ratios for area under the concentration-time curve (AUC) over the dosing interval (AUC0–τ), AUC from zero to infinity (AUC0–∞) and maximum plasma concentration (Cmax) were within the predefined range for bioequivalence (80–125%). The least squares mean time to Cmax (tmax) was 1.48 h with the ODT formulation versus 1.92 h with the conventional tablet formulation (p = 0.0021), a difference of 26 min [21].
Rimegepant exhibits greater than dose-proportional linear pharmacokinetics following a single oral dose [11]. The absolute oral bioavailability of rimegepant is ≈ 64% [10, 11]. When rimegepant was administered with a high-fat meal, tmax was prolonged by ≈ 1–1.5 h, Cmax was reduced by 42–53% and AUC was reduced by 32–38%. The clinical impact of reduced rimegepant exposure due to food is unknown. However, in clinical trials, rimegepant was administered without regard to food. Rimegepant has a steady-state volume of distribution of 120 L and is highly (≈ 96%) bound to plasma proteins [10, 11].
Rimegepant is metabolized primarily by CYP3A4 and, to a lesser extent, by CYP2C9, with no major metabolites detected in plasma [10, 11]. It is eliminated mostly (≈ 77% of the dose) as unchanged drug, with 78% of the dose recovered in the faeces (42% as unchanged drug) and 24% in the urine (51% as unchanged drug). Rimegepant has an elimination half-life of ≈ 11 h [10, 11].
The pharmacokinetics of rimegepant were not affected by sex, age (i.e. non-elderly 18–45 years vs elderly ≥ 65 years [22]), race/ethnicity (including Chinese vs non-Chinese ethnicity [23]), body weight, migraine status, CYP2C9 genotype, impaired kidney function (mild, moderate or severe), or mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment [10, 11]. Rimegepant has not been studied in patients with end-stage renal disease (ESRD; creatinine clearance < 15 mL/min) or patients on dialysis; its use in patients with ESRD should be avoided [10, 11]. Rimegepant exposure was ≈ 2-fold higher in subjects with severe hepatic impairment (Child-Pugh Class C) than in matched controls with normal hepatic function [24]; the use of rimegepant should be avoided in patients with severe hepatic impairment [10, 11].
3.1 Drug Interactions
Rimegepant is a substrate of CYP3A4, CYP2C9, P-gp and BCRP, and a weak inhibitor of CYP3A4 [10, 11]. Coadministration of rimegepant with strong CYP3A4 inhibitors and strong or moderate CYP3A4 inducers is not recommended. Another dose of rimegepant within 48 h should be avoided when the drug is coadministered with moderate CYP3A4 inhibitors or strong P-gp inhibitors. Rimegepant is an inhibitor of OATP1B3, OCT2 and MATE1, and a weak inhibitor of OATP1B1 and OAT3. No clinical drug interactions are expected for rimegepant with OAT1PB3 or OCT2 at clinically relevant concentrations. There were no significant pharmacokinetic interactions when rimegepant was coadministered with oral contraceptives (norelgestromin, ethinyl estradiol), midazolam (a sensitive CYP3A4 substrate), metformin (a MATE1 substrate) or sumatriptan [10, 11].
4 Therapeutic Efficacy of Rimegepant
4.1 Acute Treatment of Migraine
The efficacy of rimegepant for the acute treatment of migraine was evaluated in four randomized, double-blind, multicentre, placebo-controlled, phase III trials [25,26,27,28]. One trial (study 303) investigated the efficacy of the ODT formulation of rimegepant (Sect. 4.1.1) [25], while the other three trials (studies 301, 302 and 310) investigated the efficacy of the conventional tablet formulation of rimegepant (Sect. 4.1.2) [26,27,28]. These data are supported by a phase II dose-ranging study [29], which is not discussed further.
The trials enrolled patients aged ≥ 18 years [25,26,27] or 18–65 years [28] with ≥ 1-year history of migraine with or without aura [25,26,27,28]. Patients were also required to have a history of 2–8 migraine attacks of moderate or severe intensity per month, < 15 monthly headache days (migraine or non-migraine) during the previous 3 months [25,26,27,28] and migraine onset before the age of 50 years [25,26,27]. Patients receiving preventive migraine medication had to be on a stable dose for ≥ 3 months before study entry [25,26,27,28]. Across all trials, the mean age of patients was 38–42 years and most (81–89%) patients were female. The mean number of moderate to severe attacks per month was 3.6–4.7 and the mean duration of untreated attacks was 20.0–32.5 h [25,26,27,28].
Following a 3- to 28-day screening period, patients were randomized to rimegepant 75 mg or placebo and instructed to treat a single migraine attack of moderate to severe pain intensity within 45 days [25,26,27,28]. Patients were provided with an electronic diary and asked to provide information about the treated attack from pre-dose to 48 h post-dose. The co-primary endpoints were freedom from pain at 2 h post-dose and freedom from the most bothersome symptom (MBS; e.g. phonophobia, photophobia, nausea) at 2 h post-dose. Secondary endpoints were tested hierarchically [25,26,27,28].
4.1.1 ODT Formulation
A single 75 mg dose of rimegepant ODT provided superior efficacy to placebo for the acute treatment of migraine [25]. At 2 h post-dose, a significantly higher proportion of patients in the rimegepant ODT than placebo group were free from pain and free from the MBS (Table 1). With the exception of freedom from nausea and pain relapse, all secondary endpoints significantly favoured rimegepant ODT over placebo (based on 95% CIs), including the proportions of patients with pain relief at 2 h post-dose (59.3 vs 43.3%; risk difference 16.1; 95% CI 10.8–21.3; p < 0.001), ability to function normally at 2 h post-dose (38.1 vs 25.8%; risk difference 12.3; 95% CI 7.4–17.2), no use of rescue medication within 24 h post-dose (85.8 vs 70.8%; risk difference 15.0; 95% CI 10.7–19.3) and sustained pain relief from 2 to 24 h post-dose (47.8 vs 27.7%; risk difference 20.1; 95% CI 15.1–25.2) and 2–48 h post-dose (42.2 vs 25.2%; risk difference 16.9; 95% CI 12.0–21.9) [25].
4.1.2 Conventional Tablet Formulation
Single doses of rimegepant 75 mg were more effective than placebo for the acute treatment of migraine [26,27,28]. At 2 h post-dose, significantly more rimegepant than placebo recipients achieved freedom from pain and freedom from the MBS (Table 1) [26,27,28].
In studies 301 and 302, the first three hierarchically tested secondary endpoints (i.e. the proportions of patients with freedom from photophobia, freedom from phonophobia, and pain relief, all at 2 h post-dose) significantly favoured rimegepant over placebo (all p < 0.03) [26, 27]. There were no significant between-group differences for the subsequent hierarchical secondary endpoint of the proportion of patients with freedom from nausea at 2 h post-dose; therefore, no statistical inferences could be made for any of the remaining secondary endpoints [26, 27].
In study 310, which was conducted in adults from China and the Republic of Korea, rimegepant was significantly more effective than placebo for all key secondary endpoints, including the proportions of patients with 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 freedom from pain at 2–24 h and 2–48 h post-dose (all p < 0.0001) [28].
4.1.3 Pooled Analyses of ODT and Tablet Formulations
Results of pooled (post hoc [30, 31]) analyses of studies 301, 302 and 303 were consistent with those from the individual trials [32, 33]. Rimegepant (ODT or tablet) provided superior efficacy to placebo for the acute treatment of migraine, as evidenced by early (≤ 2 h) and sustained (2–48 h) pain relief and return to normal function [34], freedom from nausea at 2 h post-dose [31] and reduced use of rescue medication at 2–24 h post-dose [35]. Rimegepant was also significantly more effective than placebo irrespective of migraine attack frequency (≤ 4 or > 4 attacks per month) [32], history of triptan treatment failure (failed 1 or ≥ 2 triptans) [30] and whether or not patients were taking concurrent preventive migraine medications [33].
4.1.4 Real-World Setting
In a real-world analysis of data from a large US-based commercial claims database, there was a correlation between acute treatment of migraine with rimegepant and reduced opioid use [36]. The study population comprised migraine patients with ≥ 2 rimegepant prescription fills and ≥ 18 months of claims history before and after initiation of rimegepant (n = 16,639). They also had ≥ 1 opioid prescription fill in the 9 months prior to initiation of rimegepant. After treatment with rimegepant, the mean monthly morphine milligram equivalent dispensed decreased by 3.17% and mean monthly opioid prescription fills decreased by 16.11% (both p < 0.000001). In addition, 40.1% of patients stopped using opioids after initiation of rimegepant. Similar results were seen regardless of triptan use during the study [36].
4.2 Preventive Treatment of Migraine
The efficacy of rimegepant for the preventive treatment of migraine was evaluated in a randomized, double-blind, multicentre, placebo-controlled, phase II/III trial (study 305) [37]. The trial consisted of a screening phase (including a 4-week observation period) and a 12-week double-blind treatment phase, followed by a 52-week open-label extension (OLE) phase (Sect. 4.3). Eligible patients were aged ≥ 18 years with ≥ 1-year history of migraine with or without aura or chronic migraine, with an initial presentation before 50 years of age. They also had 4–18 migraine attacks of moderate or severe intensity per month during the 3 months prior to screening and ≥ 6 migraine days during the 4-week observation period. Patients receiving preventive migraine medication during the 12-week double-blind treatment phase had to be on a stable dose for ≥ 3 months before the 4-week observation period. The mean age of patients at baseline was 41 years and most (83%) patients were female. Patients had migraine with (40%) or without (60%) aura, and 23% had a history of chronic migraine. The mean number of moderate to severe attacks per month was 7.8 and the median duration of untreated attacks was 24 h [37].
At the end of the 4-week observation period, patients were randomized to oral rimegepant 75 mg or placebo every other day for 12 weeks [37]. Patients used an electronic diary to document the occurrence and severity of migraine attacks. The primary endpoint was the change from the 4-week observation period in the mean number of monthly migraine days (MMDs) in the last 4 weeks of the double-blind treatment phase (weeks 9–12). Secondary endpoints were tested hierarchically [37].
Rimegepant, taken every other day, was more effective than placebo for the preventive treatment of migraine [37]. Rimegepant was superior to placebo for the primary endpoint (Table 2). The first two hierarchically tested secondary endpoints (i.e. the proportion of patients with ≥ 50% reduction in the mean number of moderate or severe MMDs during weeks 9–12 and the change from baseline in the mean number of total MMDs during weeks 1–12) also significantly favoured rimegepant over placebo (Table 2). There were no significant between-group differences for the subsequent hierarchical secondary endpoint of rescue medication use; therefore, no further statistical testing was done and p-values for the remaining secondary endpoints are nominal (Table 2) [37].
An exploratory post hoc analysis demonstrated that rimegepant was more effective than placebo in terms of the proportion of patients with ≥ 50% reduction in the mean number of moderate or severe MMDs during weeks 9–12, regardless of whether or not patients had a history of chronic migraine [37]. In another post hoc analysis, the superior efficacy of rimegepant versus placebo for the least squares mean reduction in weekly migraine days was observed as early as week 1, with this benefit sustained over the first 4 weeks of double-blind treatment [38].
4.3 Long-Term Acute and Preventive Treatment of Migraine
The long-term efficacy of rimegepant for both the acute and preventive treatment of migraine was evaluated in an open-label, multicentre, safety study (study 201; Sect. 5.1) and in the 52-week OLE phase of study 305 (Sect. 4.2).
Study 201 enrolled adults aged ≥ 18 years with ≥ 1-year history of migraine with or without aura, migraine onset before the age of 50 years and 2–14 moderate or severe MMDs during the previous 3 months [39, 40]. In this study, patients with 2–8 (n = 1033) and 9–14 (n = 481) MMDs received oral rimegepant 75 mg as needed (up to once per day) for the acute treatment of migraine for 52 weeks, while patients with 4–14 MMDs (n = 286) received rimegepant 75 mg every other day for the preventive treatment of migraine plus rimegepant 75 mg as needed on non-scheduled dosing days for the acute treatment of migraine for 12 weeks [39, 40]. The OLE phase of study 305 enrolled patients who completed the 12-week double-blind treatment phase (n = 603) [41]. During the OLE phase, they continued to receive rimegepant 75 mg every other day for the preventive treatment of migraine for 52 weeks, and could also take rimegepant 75 mg as needed (up to once per day) on non-scheduled dosing days for the acute treatment of migraine [41].
Rimegepant was effective over the longer term when taken every other day for the preventive treatment of migraine and/or as needed for the acute treatment of migraine [41, 42]. In a post hoc subgroup analysis of patients in study 201 with ≥ 6 MMDs at baseline (n = 1044), as-needed rimegepant reduced the mean number of MMDs from 10.9 at baseline to 8.9 at week 52 [42]. In the OLE phase of study 305, long-term preventive and acute treatment with rimegepant consistently reduced migraine frequency through 52 weeks [41]. The proportion of patients with ≥ 50% reduction in the mean number of moderate or severe MMDs ranged from 63.6% in weeks 1–4 to 80.9% in weeks 49–52. Similar results were seen for ≥ 75% reductions (from 44.1% in weeks 1–4 to 65.8% in weeks 49–52) and 100% reductions (from 25.6% in weeks 1–4 to 49.3% in weeks 49–52) [41].
Through 52 weeks, preventive and/or acute treatment of migraine with rimegepant also improved quality of life (QOL), as measured by scores on the role restrictive, role preventive and emotional function domains of the Migraine-Specific QOL Questionnaire [40, 43] and EuroQol-5 Dimensions-3 Level utility values [40], and reduced migraine-related disability, as measured by total scores on the Migraine Disability Assessment Scale, as well as individual scores for absenteeism and presenteeism [39, 44, 45].
The majority of patients receiving long-term rimegepant for the preventive and/or acute treatment of migraine preferred rimegepant to their previous migraine medications [46, 47], eliminated the use of common analgesic and antiemetic medications [48], were satisfied with treatment [46] and experienced improvement on the Clinical Global Impression of Change scale [46, 47].
5 Tolerability of Rimegepant
The tolerability profile of rimegepant (ODT or tablet) was similar to that of placebo when administered as needed for the acute treatment of migraine [25,26,27,28, 37]. In a pooled analysis of studies 301, 302 and 303 (n = 3553), the overall incidence of AEs was 14.2% with rimegepant and 11.7% with placebo [49]. The majority of AEs were mild or moderate in severity and resolved without treatment. The most common AEs were nausea (1.5% with rimegepant vs 0.8% with placebo) and urinary tract infection (UTI; 1.1 vs 0.6%). Treatment-related AEs (TRAEs) occurred in 6.4% of rimegepant recipients and 4.8% of placebo recipients and the incidence of serious AEs was low (0.2 vs 0.2%). Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than the upper limit of normal (ULN) were seen in 2.7% of rimegepant recipients and 2.9% of placebo recipients [49]. The pooled analysis also demonstrated no meaningful differences in rimegepant tolerability by age (< 40, ≥ 40, < 65, ≥ 65 years), sex or race [50]. The favourable tolerability profile of rimegepant for the acute treatment of migraine was confirmed in an open-label expanded access study (n = 77) [51].
The tolerability profile of rimegepant was also similar to that of placebo when administered every other day for the preventive treatment of migraine [37]. In study 305, the overall incidence of AEs was 36% in both treatment groups. Most AEs were of mild or moderate severity. The most common (incidence ≥ 2%) AEs were nasopharyngitis (4% with rimegepant vs 2% with placebo), nausea (3 vs 1%), UTI (2 vs 2%) and upper respiratory tract infection (2 vs 3%). TRAEs occurred in 11% of rimegepant and 9% of placebo recipients, and serious AEs occurred in 1% of patients in both treatment groups. Relatively few patients discontinued treatment due to AEs (2% with rimegepant vs 1% with placebo). ALT or AST levels > 3 × ULN were seen in 1% of patients in both treatment groups [37].
There have been reports of hypersensitivity reactions (including dyspnoea and rash) in patients receiving rimegepant [10, 11]. Reactions can occur days after administration, and delayed serious hypersensitivity has been reported. In clinical trials, hypersensitivity reactions were seen in < 1% of rimegepant recipients. Rimegepant is contraindicated in patients with a history of hypersensitivity to rimegepant or any of its components. If hypersensitivity reactions occur, rimegepant should be discontinued and appropriate therapy should be initiated [10, 11].
5.1 Long-Term Safety and Tolerability
Rimegepant, taken every other day for the preventive treatment of migraine and/or as needed for the acute treatment of migraine, was generally well tolerated in study 201 [52] and in the OLE phase of study 305 (Sect. 4.2) [53]. Over the longer term, the safety profile of rimegepant was consistent with that seen in previous clinical trials, and no hepatotoxicity signals were identified [52, 53].
Subgroup analyses of study 201 demonstrated that rimegepant was safe and well tolerated for the long-term preventive and/or acute treatment of migraine in patients with a history of treatment failure with one triptan (n = 546) or ≥ 2 triptans (n = 246) [54], frequent migraines (≥ 15 days per month; n = 246) [55], concomitant use of preventive migraine medications (n = 243) [56], a history of depression (n = 426) or anxiety (n = 417) [57], concomitant use of selective serotonin reuptake inhibitors (n = 181) or other antidepressants (n = 195) [58] and cardiovascular risk factors (n = 735) [59].
6 Dosage and Administration of Rimegepant
In the USA [10] and the EU [11], rimegepant is indicated for the acute treatment of migraine with or without aura in adults, and for the preventive treatment of episodic migraine in adults (who have ≥ 4 migraine attacks per month [11]) [10, 11]. Rimegepant is not indicated for the treatment of chronic migraine. The recommended dose of rimegepant for the acute treatment of migraine is 75 mg, as needed [10, 11]. The recommended dose of rimegepant for the preventive treatment of migraine is 75 mg every other day. The maximum dose of rimegepant in a 24-h period is 75 mg, and the safety of using > 18 doses in a 30-day period has not been established. Rimegepant is available as an ODT which dissolves in saliva when placed on or under the tongue and can be swallowed without additional liquid. The efficacy and safety of rimegepant in paediatric patients have not been established [10, 11]. Consult local prescribing information for further details, including contraindications, warnings and precautions, drug interactions and use in special populations.
7 Place of Rimegepant in the Acute Treatment and Preventive Treatment of Migraine
For the acute treatment of migraine, the primary goals are to relieve pain and bothersome symptoms, restore the ability to function and reduce the need for repeat doses and/or rescue medication [1]. Effective treatment of an acute migraine attack has been defined as the attainment (within 2 h of drug intake) and maintenance (for ≥ 24 h) of a well-being status comprising improvement of headache from severe/moderate to mild/none, minimal/no disturbances due to migraine-related non-pain symptoms, and no meaningful drug-related AEs [5]. A stepped care approach to the acute treatment of migraine involves the use of NSAIDs as first-line therapy, with migraine-specific medications recommended as second-line (e.g. triptans) or third-line (e.g. gepants, ditans) therapy [3]. The main aims of the preventive treatment of migraine are to reduce the frequency, duration and severity of attacks, improve functioning and reduce disability [1]. The preventive treatment of migraine involves the use of evidence-based medications [3]. The choice of treatment is individualized, and is based on the patient’s history, comorbidities, concomitant medications and treatment preferences [3]. Dual-use medications with efficacy in both acute and preventive treatment may represent a new approach to the management of migraine [60]. Such an integrated approach may assist in achieving goals common to both treatment and prevention [37]. The CGRP receptor antagonist rimegepant is the first dual therapy indicated for both the acute and preventive treatment of migraine [9]. As the most recent guidelines for the management of migraine were published prior to the approval of rimegepant, updates are awaited with interest.
In pivotal phase III trials, rimegepant relieved pain and bothersome symptoms when taken as needed for the acute treatment of migraine (Sect. 4.1). The ODT formulation of rimegepant, which has demonstrated bioequivalence to the conventional oral tablet formulation (Sect. 3), was significantly more effective than placebo in relieving pain and the MBS at 2 h post-dose in study 303 (Sect. 4.1.1). Rimegepant ODT offers improved absorption and a shorter tmax (Sect. 3), which may contribute to the early onset of action (Sect 4.1.1) [25]. The relatively long half-life of rimegepant (Sect. 3) may contribute to its sustained effects through to 48 h post-dose (Sect 4.1.1) [25]. Additionally, the convenience of a quick dissolving tablet that can be taken without water (Sect. 6) is particularly beneficial for patients who experience nausea and vomiting with migraines [61]. In studies 301, 302 and 310, the conventional tablet formulation of rimegepant was also significantly more effective than placebo in relieving pain and the MBS at 2 h post-dose (Sect. 4.1.2). It should be noted that the single-attack design of all four trials prevented evaluation of the within-patient consistency of treatment response from attack to attack over time [25, 27].
Rimegepant also reduced migraine frequency when taken every other day for the preventive treatment of migraine (Sect. 4.2). Relative to placebo, rimegepant significantly reduced MMDs during weeks 9–12. Improvements favouring rimegepant were also seen during the first 4 weeks of treatment (Sect. 4.2), indicating the early onset of preventive action [37]. Study 305 used assessment methods recommended by the International Headache Society and the European Medicines Agency [37], including responder rate analysis, which is purported to be a better indicator of clinical usefulness than mean MMDs [62]. Indeed, approximately half of all rimegepant recipients achieved ≥ 50% reduction in MMDs (Sect. 4.2), which is broadly within the range of 50% responder rates observed with CGRP monoclonal antibodies [62].
The beneficial effects of rimegepant were maintained over the longer term, including in an OLE of study 305 (Sect. 4.3). Through 52 weeks, rimegepant was effective when taken every other day for the preventive treatment of migraine and/or as needed for the acute treatment of migraine. Rimegepant was also associated with improvements in QOL compared with placebo. Most patients who used long-term rimegepant for the preventive and/or acute treatment of migraine preferred it to their previous migraine medications and were satisfied with treatment (Sect. 4.3).
Rimegepant was generally well tolerated when administered as needed for the acute treatment of migraine or every other day for the preventive treatment of migraine (Sect. 5). The majority of AEs were of mild to moderate severity, with relatively few patients discontinuing treatment because of AEs. The most common AEs were nausea, UTI and upper respiratory tract infection. There was no evidence of hepatotoxicity (Sect. 5), a significant issue associated with first-generation gepants [2]. Rimegepant was also generally well tolerated over the longer term, with a safety profile consistent with that seen in previous clinical trials (Sect. 5.1).
To date, no studies have directly compared the efficacy and tolerability of rimegepant with other migraine treatments. Indeed, the lack of an active comparator was considered a limitation of study 303 [25], study 302 [27] and study 305 [37]. Some systematic reviews and/or network meta-analyses have demonstrated few differences in efficacy and/or tolerability between rimegepant and other migraine medications, including ubrogepant and lasmiditan for the acute treatment of migraine [63,64,65,66], and atogepant and CGRP monoclonal antibodies (eptinezumab, erenumab, fremanezumab and galcanezumab) for the preventive treatment of migraine [67]. In other analyses, rimegepant was generally less effective than triptans, with a more favourable tolerability profile [66, 68,69,70]. However, results of such indirect comparisons should be treated with caution. Future head-to-head comparative studies are warranted to clearly define the role of rimegepant relative to other migraine treatments [61]. Given the high costs associated with new classes of migraine drugs [7], robust cost effectiveness analyses of rimegepant would also be of interest. According to the Institute for Clinical and Economic Review, rimegepant and ubrogepant are more cost effective than lasmiditan in situations where triptans are contraindicated or cannot be used due to intolerance and/or lack of efficacy [71].
In conclusion, rimegepant is effective and generally well tolerated for the acute treatment and preventive treatment of migraine. An ODT formulation is available, offering convenience and a potentially faster response time. As the first dual agent approved for both treatment and prevention of migraine, rimegepant represents a useful option for the management of migraine in adults.
Data Selection Rimegepant: 232 records identified
Duplicates removed | 1 |
Excluded during initial screening (e.g. press releases; news reports; not relevant drug/indication; preclinical study; reviews; case reports; not randomized trial) | 89 |
Excluded during writing (e.g. reviews; duplicate data; small patient number; nonrandomized/phase I/II trials) | 71 |
Cited efficacy/tolerability articles | 36 |
Cited articles not efficacy/tolerability | 35 |
Search Strategy: EMBASE, MEDLINE and PubMed from 1946 to present. Clinical trial registries/databases and websites were also searched for relevant data. Key words were rimegepant, NURTEC, VYDURA, migraine, episodic migraine in adults. Records were limited to those in English language. Searches last updated 9 January 2023 | |
Change history
04 July 2023
A Correction to this paper has been published: https://doi.org/10.1007/s40263-023-01019-2
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During the peer review process, the manufacturer of rimegepant was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.
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The manuscript was reviewed by: P. Martelletti, Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy; A. Singh, All India Institute of Medical Sciences, Raipur, India; A. Zandi, Shahid Beheshti University of Medical Sciences School of Medicine, Tehran, Iran.
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Blair, H.A. Rimegepant: A Review in the Acute Treatment and Preventive Treatment of Migraine. CNS Drugs 37, 255–265 (2023). https://doi.org/10.1007/s40263-023-00988-8
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DOI: https://doi.org/10.1007/s40263-023-00988-8