Rimegepant: A Comprehensive Pharmacological and Clinical Review of an Oral CGRP Receptor Antagonist for Migraine Treatment and Prevention

Abstract

Rimegepant, an orally administered small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, represents a significant advancement in migraine pharmacotherapy. Developed initially by Biohaven Pharmaceuticals and now part of Pfizer's portfolio, rimegepant has achieved the novel distinction of being the first oral agent approved by both the U.S. Food and Drug Administration (FDA) and the European Commission (EC) for the dual indications of acute treatment of migraine with or without aura and the preventive treatment of episodic migraine in adults. Its mechanism of action involves selectively blocking CGRP receptors, thereby inhibiting the effects of CGRP, a key neuropeptide implicated in migraine pathophysiology. Pharmacokinetically, rimegepant exhibits good oral bioavailability, an 11-hour half-life suitable for its dual dosing regimens, and metabolism primarily via CYP3A4. Pivotal Phase 3 clinical trials have demonstrated its efficacy in providing pain freedom and relief from most bothersome symptoms in acute migraine attacks, as well as reducing monthly migraine days in episodic migraine prevention. Notably, rimegepant possesses a favorable safety and tolerability profile, characterized by a lack of vasoconstrictive effects—a crucial advantage over triptans, particularly for patients with cardiovascular contraindications—and no evidence of hepatotoxicity. This comprehensive review details the chemical properties, regulatory journey, pharmacological profile, clinical efficacy, safety, and therapeutic positioning of rimegepant in the evolving landscape of migraine management.

1. Introduction: The Evolving Landscape of Migraine Therapy and the Advent of Rimegepant

1.1. Migraine: A Disabling Neurological Disorder and Unmet Therapeutic Needs

Migraine is a prevalent and often debilitating neurological disorder, characterized by recurrent episodes of moderate to severe headache, frequently accompanied by symptoms such as nausea, vomiting, photophobia, and phonophobia. This condition imposes a substantial burden on individuals, affecting their quality of life, daily functioning, and productivity.1 For many years, therapeutic options for migraine have included non-specific analgesics (e.g., non-steroidal anti-inflammatory drugs, paracetamol) and migraine-specific agents, primarily triptans (serotonin 5-HT1B/1D receptor agonists). While triptans can be effective for acute migraine attacks, their utility is limited by inconsistent efficacy, poor tolerability in some patients, and, significantly, contraindications in individuals with or at high risk of cardiovascular and cerebrovascular disease due to their vasoconstrictive properties.3 These limitations have underscored a persistent unmet medical need for novel migraine therapies with improved efficacy, better tolerability, and broader applicability across diverse patient populations.

1.2. The Role of Calcitonin Gene-Related Peptide (CGRP) in Migraine Pathophysiology

Research over the past few decades has firmly established the pivotal role of calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine. CGRP is a 37-amino acid neuropeptide abundantly expressed in the trigeminal nervous system, which plays a crucial role in cranial nociception.7 During a migraine attack, activation of the trigeminal ganglion leads to the release of CGRP from perivascular nerve endings.9 This release contributes to a cascade of events including dilation of cerebral and dural blood vessels, release of inflammatory mediators from dural mast cells, and transmission of nociceptive signals from intracranial structures to the central nervous system, ultimately leading to the perception of migraine pain.8 Several lines of evidence support CGRP's involvement: serum CGRP levels are elevated during migraine attacks and normalize after successful treatment with triptans 7, and intravenous infusion of CGRP can trigger migraine-like headaches in susceptible individuals.7

1.3. Rimegepant: A Novel Oral CGRP Receptor Antagonist

The elucidation of CGRP's role in migraine paved the way for the development of a new class of targeted therapies: CGRP antagonists. Rimegepant (DrugBank ID: DB12457) is an orally administered, small molecule CGRP receptor antagonist, belonging to the "gepant" class of drugs.7 It was developed by Biohaven Pharmaceuticals. What distinguishes rimegepant and marks a significant advancement in migraine management is its approval as the first oral CGRP antagonist for both the acute treatment of migraine attacks and the preventive treatment of episodic migraine in adults.1 This dual indication offers a novel therapeutic approach, particularly for patients who have contraindications to, or have experienced inadequate response or tolerability with, existing therapies such as triptans.

The development of rimegepant addresses a critical gap left by triptans, particularly for patients with cardiovascular risk factors. By offering a targeted mechanism devoid of vasoconstrictive effects, it provides a mechanistically distinct and potentially safer alternative for a substantial patient population. Unlike triptans, which exert their effects through serotonin 5-HT1B/1D receptors and can cause vasoconstriction, rimegepant directly modulates the CGRP pathway without such cardiovascular liabilities.[4]

2. Chemical, Regulatory, and Commercial Profile of Rimegepant

2.1. Chemical and Physical Properties

Rimegepant is a small molecule drug.10 Its generic name is rimegepant, and it is marketed under the brand names Nurtec ODT in the United States and Vydura in the European Union and Switzerland.10 The DrugBank Accession Number for rimegepant is DB12457.10 The Chemical Abstracts Service (CAS) Number for the free base form of rimegepant is 1289023-67-1.18 A common salt form is rimegepant sulfate sesquihydrate, with CAS number 1374024-48-2 (for 0.5 sulfate 1.5 hydrate).20

The International Union of Pure and Applied Chemistry (IUPAC) name for rimegepant is (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate.[15] The molecular formula for the free base is C28​H28​F2​N6​O3​.[10] The molecular weight of rimegepant free base is 534.56 g/mol, while rimegepant sulfate sesquihydrate (C28​H28​F2​N6​O3​⋅0.5H2​SO4​⋅1.5H2​O) has a molecular weight of 610.63 g/mol.[10] Rimegepant sulfate is described as a white to off-white, crystalline solid that is slightly soluble in water.[21]

Rimegepant is formulated as an orally disintegrating tablet (ODT), with each tablet containing 75 mg of rimegepant (equivalent to 85.7 mg of rimegepant sulfate).[12] The ODT formulation includes inactive ingredients such as benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, menthyl acetate, sucralose, and vanillin.[22] The ODT formulation offers convenience, as it can be taken without water and dissolves rapidly on or under the tongue, which may lead to a faster onset of action and improved patient adherence, particularly during a migraine attack when nausea or vomiting might make swallowing conventional tablets difficult.[12]

2.2. Development and Global Regulatory Approvals

Rimegepant was originally developed by Biohaven Pharmaceuticals 10, under the developmental codes BMS-927711 and BHV-3000.15

Key regulatory approvals include:

• United States (FDA):
• Approved for the acute treatment of migraine with or without aura in adults on February 27, 2020.[10]
• Approval extended for the preventive treatment of episodic migraine in adults on May 27, 2021.[11]
• European Union (European Commission/EMA):
• Granted marketing authorization for Vydura for both acute treatment of migraine with or without aura and prophylaxis of episodic migraine in adults who have at least four migraine attacks per month on April 27, 2022.[1] This followed a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in February 2022.[1] The approval is valid in all 27 EU member states, as well as Iceland, Liechtenstein, and Norway.[1]
• Other Notable Approvals:
• Switzerland (Swissmedic): Vydura approved on October 18, 2023.[17]
• United Arab Emirates and Israel: Approved in March 2021.[11]
• Canada: Approved in December 2023.[11]
• United Kingdom (NICE): Approved for both prophylaxis and acute treatment of migraine in adults.[11]
• China (NMPA): Approved in 2024.[15]

The rapid succession of approvals across major regulatory bodies for these dual indications underscores the strength of the clinical data supporting Rimegepant's efficacy and safety, as well as the recognized unmet medical need it addresses in migraine management. Such comprehensive regulatory acceptance is indicative of a robust clinical development program and a compelling benefit-risk profile.

2.3. Commercialization and Marketing

Initially marketed by Biohaven Pharmaceuticals, rimegepant became part of Pfizer Inc.'s portfolio following Pfizer's acquisition of Biohaven, which was completed on October 3, 2022. The acquisition included Biohaven's CGRP franchise, notably rimegepant and zavegepant.11 Prior to the full acquisition, Pfizer and Biohaven had entered into a strategic partnership in November 2021 for the commercialization of rimegepant outside the United States.2 Pfizer reported revenues of US$928 million for Nurtec ODT/Vydura in 2023.11 The acquisition by a major pharmaceutical entity like Pfizer, for a significant sum (approximately $11.6 billion for Biohaven, largely driven by its CGRP assets), highlights the perceived therapeutic and market potential of rimegepant.28 Pfizer's extensive global infrastructure is anticipated to maximize the drug's market penetration and accessibility to patients worldwide.25

Table 1: Rimegepant - Key Drug Information

Feature	Details
Generic Name	Rimegepant
Brand Names	Nurtec ODT (USA), Vydura (EU, Switzerland)
DrugBank ID	DB12457
CAS Number (Free Base)	1289023-67-1
CAS Number (Sulfate Sesquihydrate)	1374024-48-2 (for 0.5 sulfate 1.5 hydrate)
Synonyms (Developmental)	BHV-3000, BMS-927711
Chemical Formula (Free Base)	C28​H28​F2​N6​O3​
Molecular Weight (Free Base)	534.56 g/mol
Molecular Weight (Sulfate Sesquihydrate)	610.63 g/mol
Drug Type	Small Molecule
Developer	Biohaven Pharmaceuticals (acquired by Pfizer Inc.)
Key Regulatory Approvals	FDA (USA): Acute (Feb 2020), Preventive (May 2021) <br> EC (EU): Acute & Preventive (Apr 2022) <br> Swissmedic: Oct 2023

Sources: User Query,.[1]

3. Pharmacological Profile: Mechanism, Pharmacokinetics, and Pharmacodynamics

3.1. Mechanism of Action

Rimegepant functions as a highly potent and selective, orally bioavailable small molecule antagonist of the human calcitonin gene-related peptide (CGRP) receptor, specifically targeting the calcitonin gene-related peptide type 1 receptor.7 It exerts its therapeutic effect by competitively binding to CGRP receptors, thereby preventing the binding and subsequent actions of the endogenous CGRP neuropeptide.2

CGRP is a well-established key player in migraine pathophysiology. This 37-amino acid neuropeptide is abundantly present in trigeminal ganglia and is released from trigeminal nerve endings during migraine attacks.[7] The release of CGRP initiates a cascade of events including vasodilation of cerebral and dural blood vessels, degranulation of dural mast cells leading to the release of inflammatory mediators, and transmission of nociceptive (pain) signals from intracranial structures to the central nervous system.[8] These processes collectively contribute to the severe headache and associated symptoms characteristic of migraine. Rimegepant's antagonism of CGRP receptors effectively interrupts this pathological cascade, leading to the termination of migraine pain and associated symptoms when used acutely, and reducing the frequency of attacks when used preventively.[10] A crucial aspect of rimegepant's mechanism, distinguishing it from triptans, is its lack of direct vasoconstrictive activity.[10] Rimegepant exhibits high affinity for the human CGRP receptor, with a reported Ki​ of 0.027 nM and an IC50​ of 0.14 nM.[19] This targeted mechanism represents a more specific pharmacological intervention for migraine compared to older, broader-acting medications, which likely contributes to its generally favorable side effect profile.

3.2. Pharmacokinetics

The pharmacokinetic profile of rimegepant has been characterized in healthy subjects and specific patient populations.10

• Absorption: Rimegepant demonstrates good oral absorption, with an absolute oral bioavailability of approximately 64%. Following administration of the 75 mg orally disintegrating tablet (ODT), maximum plasma concentrations (Cmax​) are achieved at a median Tmax​ of 1.5 hours. The presence of food can affect absorption; a high-fat meal delays Tmax​ by approximately 1 to 1.5 hours, reduces Cmax​ by 42-53%, and decreases the area under the plasma concentration-time curve (AUC) by 32-38%. However, the clinical impact of this food effect is considered unknown, as rimegepant was administered without regard to food in pivotal clinical trials.[10]
• Distribution: Rimegepant is extensively distributed into tissues, with a steady-state volume of distribution (Vd​) of approximately 120 L. Plasma protein binding is high, at approximately 96%, although the specific binding proteins have not been fully elucidated.[10]
• Metabolism: Rimegepant is primarily metabolized by the cytochrome P450 (CYP) enzyme CYP3A4, with a lesser contribution from CYP2C9. Despite undergoing metabolism, unchanged rimegepant is the principal circulating moiety, accounting for approximately 77% of the drug in plasma. No major active metabolites (defined as >10% of parent drug exposure) have been detected.[10]
• Elimination: The elimination half-life (t1/2​) of rimegepant in healthy subjects is approximately 11 hours.[31] Rimegepant is eliminated from the body primarily as unchanged drug. Following administration of a radiolabeled dose, approximately 78% of the total radioactivity was recovered in feces and 24% in urine. Unchanged rimegepant accounted for 42% of the administered dose in feces and 51% in urine.[10] The substantial proportion of the drug excreted unchanged suggests that metabolism is a minor pathway of elimination overall.[10]
• Pharmacokinetics in Special Populations:
• Renal Impairment: No dosage adjustments are necessary for patients with mild, moderate, or severe renal impairment (Creatinine Clearance [CrCl] ≥15 mL/min). However, use in patients with end-stage renal disease (CrCl <15 mL/min) should be avoided as it has not been studied in this population.[10]
• Hepatic Impairment: No dosage adjustments are required for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. In patients with severe hepatic impairment (Child-Pugh C), rimegepant exposure (Cmax and AUC) is approximately doubled, and therefore, its use should be avoided in this group.[10]
• Elderly (age ≥65 years): Limited clinical experience exists in this population, but pharmacokinetic studies suggest that age does not significantly affect rimegepant's disposition, and thus no dose adjustment is required based on age alone.[26]

The pharmacokinetic characteristics of rimegepant, particularly its oral bioavailability, an 11-hour half-life, and significant excretion as unchanged drug, are well-suited for its dual role in both as-needed acute migraine treatment and every-other-day preventive dosing. The primary reliance on CYP3A4 for the metabolized fraction, however, underscores the potential for clinically significant drug-drug interactions, necessitating careful consideration by prescribers.

Table 2: Rimegepant - Pharmacokinetic Profile

Parameter	Value	References
Absolute Oral Bioavailability	~64%	10
Tmax​ (ODT)	1.5 hours	10
Effect of High-Fat Meal	Tmax​ delayed by 1-1.5h; Cmax​ ↓ 42-53%; AUC ↓ 32-38%	10
Volume of Distribution (Vd​)	~120 L	10
Plasma Protein Binding	~96%	10
Primary Metabolism Enzymes	CYP3A4 (major), CYP2C9 (minor)	10
Major Metabolites (% unchanged in plasma)	~77% (no major metabolites detected)	10
Elimination Half-life (t1/2​)	~11 hours (healthy subjects)	31
Primary Route of Excretion	Feces (42% unchanged), Urine (51% unchanged)	10
Total Radioactivity Recovery	78% in feces, 24% in urine	10

4. Clinical Development and Efficacy in Migraine

Rimegepant has undergone extensive clinical development, leading to its approval for both acute and preventive treatment of migraine.

4.1. Acute Treatment of Migraine

Rimegepant is indicated for the acute treatment of migraine with or without aura in adults.10 The efficacy of a single 75 mg dose of rimegepant was established in multiple randomized, double-blind, placebo-controlled Phase 3 trials.

Key pivotal trials include:

• Study 1 (NCT03461757 - ODT formulation): This trial demonstrated the superiority of rimegepant 75 mg ODT over placebo. The co-primary endpoints were pain freedom at 2 hours post-dose (21% for rimegepant vs. 11% for placebo; p<0.0001) and freedom from the Most Bothersome Symptom (MBS, selected from nausea, photophobia, or phonophobia) at 2 hours post-dose (35% for rimegepant vs. 27% for placebo; p=0.0009).[35]
• Study 303 (NCT03235479 - oral tablet formulation): This study also met its co-primary endpoints, with rimegepant 75 mg showing significantly higher rates of pain freedom at 2 hours (19.2% vs. 14.2% for placebo) and MBS freedom at 2 hours (36.6% vs. 27.7% for placebo).[16]
• Other Supporting Trials (e.g., Study 302 - tablet, Study 310 - ODT): These trials provided further evidence of rimegepant's efficacy, with consistent results favoring rimegepant over placebo for the co-primary endpoints of 2-hour pain freedom and 2-hour MBS freedom.[16] For instance, in Study 302, pain freedom at 2 hours was 19.6% for rimegepant versus 12.0% for placebo, and MBS freedom was 37.6% versus 25.2%. In Study 310 (ODT), pain freedom was 19.8% versus 10.7%, and MBS freedom was 50.5% versus 35.8%.[16]

Pooled analyses and other data indicate that rimegepant provides rapid relief, with many patients experiencing pain relief (defined as a reduction from moderate/severe pain to mild or no pain) at 2 hours (e.g., 59.3% with Nurtec ODT vs. 43.3% with placebo).[35] For some patients, this pain relief can be sustained for up to 48 hours.[10] Real-world evidence from a multicenter pilot study further supports these findings, with 32.1% of intakes resulting in pain freedom at 2 hours, significant reductions in headache intensity, and high rates of freedom from MBS (photophobia 43%, phonophobia 53%, nausea 57%). A notable 59% of instances allowed a full return to daily activities at 2 hours post-dose.[6]

Table 3: Rimegepant - Pivotal Clinical Trial Efficacy for Acute Migraine (Key Endpoints at 2 hours post-dose)

Trial ID (Formulation)	Endpoint	Rimegepant 75 mg (%)	Placebo (%)	Risk Difference / Absolute Difference (95% CI)	p-value	References
Study 1 (NCT03461757) (ODT)	Pain Freedom	21.2	10.9	10.4 (6.5–14.2)	<0.0001	16
	MBS Freedom	35.1	26.8	8.3 (3.4–13.2)	0.0009	16
Study 303 (NCT03235479) (Tablet)	Pain Freedom	19.2	14.2	5.0 (0.7–9.3)	0.0298	16
	MBS Freedom	36.6	27.7	8.9 (3.4–14.3)	0.0016	16
Study 302 (Tablet)	Pain Freedom	19.6	12.0	7.6 (3.3–11.9)	<0.001	16
	MBS Freedom	37.6	25.2	12.4 (6.9–17.9)	<0.001	16
Study 310 (ODT)	Pain Freedom	19.8	10.7	9.2	<0.0001	16
	MBS Freedom	50.5	35.8	14.8	<0.0001	16

MBS = Most Bothersome Symptom.

4.2. Preventive Treatment of Episodic Migraine

Rimegepant is also approved for the preventive treatment of episodic migraine in adults, typically defined as patients experiencing fewer than 15 headache days per month or at least 4 migraine attacks per month.11

The pivotal Phase 3 trial (Study 2 / NCT03732638) evaluated rimegepant 75 mg taken every other day (EOD) against placebo for 12 weeks.[14]

• Primary Endpoint: The primary efficacy measure was the change from baseline in the mean number of monthly migraine days (MMDs) during weeks 9-12 of the double-blind treatment phase. Patients receiving rimegepant experienced a mean reduction of 4.3 MMDs, compared to a reduction of 3.5 MMDs for those on placebo. The least squares mean (LSM) difference between groups was -0.8 days (95% CI: -1.5 to -0.2), demonstrating statistical superiority for rimegepant.[14]
• Key Secondary Endpoint: A key secondary endpoint was the proportion of patients achieving a ≥50% reduction in the mean number of moderate-to-severe MMDs during weeks 9-12. This was achieved by 49% of patients in the rimegepant group versus 41% in the placebo group.[14]
• Early Onset of Effect: Notably, the preventive effects of rimegepant were observed as early as the first week of therapy.[14]

Long-term open-label extension studies have confirmed that the beneficial effects of rimegepant in reducing migraine frequency and improving quality of life are maintained for up to 52 weeks of treatment.[2]

Table 4: Rimegepant - Pivotal Clinical Trial Efficacy for Preventive Migraine (Key Endpoints from Study 2 / NCT03732638)

Endpoint	Rimegepant 75 mg EOD (n=348)	Placebo (n=347)	LSM Between-Group Difference (95% CI)	References
Change from Baseline in Mean MMDs (Weeks 9-12)	-4.3 days	-3.5 days	-0.8 days (-1.5 to -0.2)	16
≥50% Reduction in Moderate/Severe MMDs (Weeks 9-12)	49%	41%	8% (0 to 15)	16

MMDs = Monthly Migraine Days; EOD = Every Other Day; LSM = Least Squares Mean.

The consistent efficacy demonstrated across multiple large Phase 3 trials for both co-primary endpoints in acute treatment (pain freedom and MBS freedom) and for the primary endpoint in prevention (reduction in MMDs) firmly established rimegepant as an effective therapy for migraine. The ODT formulation provides a practical advantage for acute use, potentially enhancing compliance and speed of relief for patients experiencing nausea.

5. Safety, Tolerability, and Drug Interactions

5.1. Overall Safety Profile

Rimegepant has been generally well tolerated in extensive clinical trial programs for both its acute and preventive indications.6 In acute treatment trials, its safety profile was comparable to that of placebo.37

A significant advantage of rimegepant is its cardiovascular safety profile. Unlike triptans, rimegepant does not possess vasoconstrictive properties, making it a suitable option for patients with cardiovascular disease or risk factors where triptans may be contraindicated.[4] This lack of vasoconstrictive activity is a direct consequence of its targeted CGRP receptor antagonism mechanism, which does not involve serotonin pathways implicated in triptan-mediated vasoconstriction.

Furthermore, clinical trials have shown no evidence of hepatotoxicity with rimegepant.[7] This is a critical distinction from some earlier investigational gepants, such as telcagepant, which was discontinued due to concerns about liver toxicity.[7] The absence of hepatotoxicity with rimegepant enhances its safety profile and broadens its patient applicability.

Another important safety aspect is that rimegepant has not been associated with addiction potential or medication overuse headache (MOH) in clinical trials.[2] MOH is a common and challenging complication associated with the frequent use of triptans and other acute analgesics, and the lack of this risk with rimegepant is a considerable clinical benefit.

5.2. Adverse Reactions from Clinical Trials

The most commonly reported adverse reactions in clinical trials were generally mild to moderate.

• Acute Treatment (Study 1 - NURTEC ODT 75 mg vs. Placebo):
• Nausea was the most common adverse reaction, reported in 2% of patients receiving Nurtec ODT compared to 0.4% of patients receiving placebo.[35] Some sources report slightly different figures (e.g., 0.9% vs 1.1%) which may reflect different study populations or analyses.[38]
• Preventive Treatment (Study 2 - Rimegepant 75 mg EOD vs. Placebo):
• Nausea: 2.7% in the rimegepant group vs. 0.8% in the placebo group.[14]
• Abdominal pain/dyspepsia: 2.4% in the rimegepant group vs. 0.8% in the placebo group.[14]
• Hypersensitivity Reactions: These occurred in less than 1% of patients in clinical studies and can include symptoms such as dyspnea and rash. Importantly, hypersensitivity reactions can be delayed, occurring days after administration.[23]
• Other less common adverse events (generally <5%) reported include dizziness, somnolence, and dry mouth.[7]

5.3. Postmarketing Experience

Postmarketing surveillance has identified additional potential adverse reactions:

• Hypertension: Reports of new-onset hypertension or worsening of pre-existing hypertension have emerged. Some cases required pharmacological treatment or hospitalization, and hypertension was often reported within 7 days of therapy initiation.[41]
• Raynaud's Phenomenon: New-onset or worsening of pre-existing Raynaud's phenomenon has also been reported.[41] The emergence of these adverse events in the postmarketing phase, while not prominent in the initial controlled trials, underscores the importance of ongoing pharmacovigilance for new drug classes. Broader use in more diverse patient populations can reveal rarer or specific population-related adverse effects that might not be apparent in the more selected populations of clinical trials.

5.4. Warnings and Precautions (Per FDA Label)

The FDA label for Nurtec ODT includes the following warnings and precautions 23:

• Hypersensitivity Reactions: Patients should be advised to discontinue NURTEC ODT and seek appropriate therapy if a serious hypersensitivity reaction (e.g., dyspnea, rash) occurs.
• Hypertension: Patients should be monitored for new-onset hypertension or worsening of pre-existing hypertension. Discontinuation of NURTEC ODT should be considered if blood pressure is inadequately controlled or if an alternative etiology cannot be established.
• Raynaud's Phenomenon: Patients with a history of Raynaud's phenomenon should be monitored for worsening symptoms. NURTEC ODT should be discontinued if new signs or symptoms of Raynaud's phenomenon develop.

5.5. Contraindications

Rimegepant is contraindicated in 13:

• Patients with a history of hypersensitivity reaction to rimegepant or any of its components.
• Patients with severe hepatic impairment (Child-Pugh C).
• Patients with end-stage renal disease (CrCl <15 mL/min) (though some sources state no dose adjustment for severe renal impairment, ESRD is listed as an avoidance [10]).

5.6. Drug Interactions

Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9; it is also a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) transporters.32 These metabolic pathways make it susceptible to drug interactions.

• CYP3A4 Inhibitors:
• Strong inhibitors (e.g., itraconazole): Concomitant use should be avoided as they can increase rimegepant AUC by approximately 4-fold and Cmax​ by ~1.5-fold.[32]
• Moderate inhibitors (e.g., fluconazole): If co-administered, another dose of rimegepant should be avoided within 48 hours. These may increase rimegepant AUC by less than 2-fold.[32]
• Weak inhibitors: Not expected to cause clinically significant interactions.[32]
• CYP3A4 Inducers:
• Strong or moderate inducers (e.g., rifampin): Concomitant use should be avoided as they can significantly reduce rimegepant exposure (rifampin decreased AUC by 80% and Cmax​ by 64%), potentially leading to loss of efficacy.[32]
• Weak inducers: Clinically significant interactions are not expected.[32]
• P-glycoprotein (P-gp) Inhibitors:
• Potent P-gp inhibitors (e.g., cyclosporine, quinidine): If co-administered, another dose of rimegepant should be avoided within 48 hours. These may increase rimegepant exposure by more than 50% but less than 2-fold.[33]
• Rimegepant as a Perpetrator: Rimegepant itself is a weak, time-dependent inhibitor of CYP3A4.[32]
• Concomitant use with sumatriptan: Well tolerated and does not result in clinically significant hemodynamic changes.[13]

The primary metabolism of rimegepant via CYP3A4 dictates its susceptibility to significant interactions with strong modulators of this enzyme. This pharmacokinetic characteristic directly informs the dosing recommendations and contraindications listed in the prescribing information, which are critical for ensuring the safe use of the medication.

Table 5: Rimegepant - Common Adverse Events and Key Drug Interactions

Category	Details	Frequency/Recommendation	References
Common Adverse Events (Acute Treatment)	Nausea	Rimegepant: ~2% vs. Placebo: ~0.4%	35
Common Adverse Events (Preventive Treatment)	Nausea	Rimegepant: 2.7% vs. Placebo: 0.8%	35
	Abdominal Pain/Dyspepsia	Rimegepant: 2.4% vs. Placebo: 0.8%	35
Drug Interactions: CYP3A4 Inhibitors	Strong (e.g., itraconazole)	Avoid concomitant use	32
	Moderate (e.g., fluconazole)	Avoid another rimegepant dose within 48 hours	32
Drug Interactions: CYP3A4 Inducers	Strong or Moderate (e.g., rifampin)	Avoid concomitant use	32
Drug Interactions: P-gp Inhibitors	Potent (e.g., cyclosporine)	Avoid another rimegepant dose within 48 hours	33

6. Therapeutic Role and Comparative Landscape in Migraine Management

6.1. Positioning in Migraine Treatment

Rimegepant has established a distinct and important position in the therapeutic armamentarium for migraine. Its approval for both acute and preventive treatment of episodic migraine in adults offers a unique versatility.1 This dual utility allows for a simplified treatment approach for some patients, potentially reducing polypharmacy and improving adherence, especially for those who experience frequent episodic migraines that also necessitate acute intervention.

Rimegepant is particularly valuable for patients who have contraindications to triptans, such as those with established cardiovascular or cerebrovascular disease, or significant risk factors for these conditions. Its mechanism of CGRP receptor antagonism does not involve the vasoconstrictive effects associated with triptans, making it a safer alternative in these populations.[4] It is also a suitable option for patients who have experienced an inadequate response to, or intolerable side effects from, triptans.[4] Furthermore, rimegepant is not associated with medication overuse headache (MOH), a common and problematic consequence of frequent triptan or analgesic use, which further enhances its utility for patients requiring regular acute treatment.[2]

6.2. Comparative Considerations

• Versus Triptans:
• Mechanism and Cardiovascular Safety: The most significant difference lies in their mechanisms and resulting cardiovascular safety profiles. Rimegepant targets the CGRP pathway without inducing vasoconstriction, whereas triptans act on serotonin 5-HT1B/1D receptors, leading to vasoconstriction and potential cardiovascular risks.[4] This makes rimegepant a preferred option for patients with cardiovascular concerns.
• Efficacy (Acute Treatment): While both are effective, some network meta-analyses suggest that certain triptans (e.g., eletriptan, sumatriptan) may achieve higher rates of pain freedom at 2 hours compared to rimegepant.[3] The number needed to treat (NNT) for pain freedom at 2 hours for rimegepant (NNT=9) is comparable to some NSAIDs, while some triptans exhibit lower (more favorable) NNTs.[4] However, real-world data indicate higher persistence rates with rimegepant compared to oral triptans, possibly reflecting a better overall balance of efficacy and tolerability or greater patient satisfaction in routine clinical practice.[5]
• Tolerability: Rimegepant is generally associated with fewer side effects than triptans. Nausea is the most common side effect with rimegepant, whereas triptans are often associated with chest symptoms (tightness, pressure), dizziness, and fatigue.[3]
• Medication Overuse Headache: Rimegepant does not carry the risk of MOH, unlike triptans.[2]
• Versus Injectable CGRP Monoclonal Antibodies (mAbs) for Prevention:
• Route of Administration: Rimegepant is an oral ODT, offering patient preference for non-injectable options compared to the monthly or quarterly subcutaneous/intravenous injections required for CGRP mAbs.[47]
• Half-life and Dosing Frequency: Rimegepant has a relatively short half-life (~11 hours), necessitating every-other-day dosing for prevention. In contrast, mAbs have very long half-lives, allowing for much less frequent administration.[47]
• Indications: Rimegepant is approved for episodic migraine prevention, while mAbs are approved for both episodic and chronic migraine prevention.[47]
• Efficacy (Prevention): Direct head-to-head comparative trials are limited. Some indirect comparisons and network meta-analyses have suggested that injectable mAbs (e.g., erenumab) might lead to greater reductions in MMDs compared to rimegepant.[40] However, one study noted similar efficacy for episodic migraine prevention between Emgality (galcanezumab) and Nurtec.[47] The choice often depends on patient preference, tolerability, and specific clinical circumstances.
• Side Effect Profiles: Generally different; mAbs are often associated with injection site reactions, whereas rimegepant's main side effect is nausea.[47]
• Versus Other Gepants:
• Rimegepant holds the distinction of being the first gepant approved for both acute and preventive treatment of migraine.[12] Other gepants include ubrogepant and zavegepant (nasal spray) for acute treatment, and atogepant for preventive treatment.[13] The availability of multiple gepants provides clinicians and patients with more options within this targeted therapeutic class.

The unique dual approval of rimegepant for both acute and preventive migraine management is a significant development. It allows for a potentially simplified and unified therapeutic strategy for patients who experience frequent episodic migraines and also require acute relief. This could enhance patient adherence and streamline treatment, particularly for individuals in whom triptans are contraindicated or poorly tolerated.

Table 6: Rimegepant vs. Triptans - Comparative Profile for Migraine Treatment

Feature	Rimegepant	Triptans (e.g., Sumatriptan)	References
Mechanism of Action	CGRP Receptor Antagonist	Serotonin (5-HT1B/1D) Receptor Agonist	10
Vasoconstrictive Effects	No	Yes	User Query, 4
Common Cardiovascular Contraindications	None specific due to mechanism (but caution with severe hepatic/renal impairment)	Ischemic heart disease, uncontrolled hypertension, history of stroke/TIA, peripheral vascular disease	13
Suitability for Patients with Cardiovascular Disease/Risk	Generally Considered Safer	Contraindicated or Caution Advised	User Query, 4
Risk of Medication Overuse Headache (MOH)	Not established/Low	Yes, with frequent use	2
Common Adverse Events	Nausea, abdominal pain/dyspepsia (mild)	Paresthesias, dizziness, somnolence, chest tightness/pressure, flushing	35
Route of Administration	Oral (Orally Disintegrating Tablet)	Oral, Subcutaneous, Nasal	22
Dual Indication (Acute/Preventive)	Yes (for episodic migraine prevention)	No (primarily acute treatment)	11

7. Conclusion: Rimegepant's Transformative Role in Migraine Management

Rimegepant has emerged as a transformative agent in the pharmacotherapy of migraine. As an orally administered, potent, and selective CGRP receptor antagonist, it directly targets a key neuropeptide central to migraine pathophysiology. Its most notable distinction is its dual approval by major regulatory agencies, including the FDA and EMA, for both the acute treatment of migraine attacks (with or without aura) and the preventive treatment of episodic migraine in adults. This dual utility offers unprecedented flexibility and simplification in migraine management for appropriate patients.

The clinical development program for rimegepant has robustly demonstrated its efficacy in providing rapid pain freedom and relief from the most bothersome symptoms during acute attacks, as well as significantly reducing the frequency of monthly migraine days when used preventively. Its orally disintegrating tablet formulation enhances convenience, particularly for patients experiencing nausea during an attack.

Crucially, rimegepant possesses a favorable safety and tolerability profile. Its lack of vasoconstrictive effects renders it a vital alternative for the significant population of migraine sufferers who have cardiovascular contraindications to triptans or cannot tolerate them. Furthermore, the absence of signals for hepatotoxicity and medication overuse headache addresses other important limitations of older migraine therapies. While generally well-tolerated, postmarketing surveillance has identified potential risks of hypertension and Raynaud's phenomenon, underscoring the need for continued vigilance. Clinically significant drug interactions, primarily with strong or moderate CYP3A4 modulators and potent P-gp inhibitors, require careful management.

In the evolving landscape of migraine treatment, rimegepant offers a unique combination of targeted mechanism, oral administration, dual indications, and a favorable cardiovascular safety profile. It represents a significant step towards more personalized and effective migraine care, improving the quality of life for many individuals burdened by this debilitating neurological condition. Continued real-world evidence and further comparative studies will continue to refine its precise place in therapy alongside other CGRP-targeted agents and traditional migraine treatments.

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