Nurtec ODT (Rimegepant)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Acute treatment of migraine with or without aura | Adults (≥18 years) | Acute / as-needed (PRN) | FDA Approved |
| Preventive treatment of episodic migraine | Adults (≥18 years) | Preventive (every other day dosing) | FDA Approved |
Rimegepant is the first and only medication with FDA approval for both the acute treatment and preventive treatment of migraine, offering a unified therapeutic approach with a single molecule. It was first approved for acute migraine treatment in February 2020, and received the preventive treatment indication in May 2021. Unlike anti-CGRP monoclonal antibodies, rimegepant is a small molecule that blocks the CGRP receptor (rather than the CGRP ligand), is taken orally, has CYP-mediated metabolism, and has a much shorter half-life (~11 hours vs 27–31 days for mAbs). The 2024 American Headache Society position statement recommends CGRP-targeting therapies, including oral gepants, as first-line options for migraine prevention alongside traditional oral preventives.
Chronic migraine prevention: The pivotal prevention trial enrolled patients with episodic migraine (4–18 migraine days per month). Data in chronic migraine (≥15 headache days/month) are limited. Evidence quality: Low.
Medication overuse headache: Gepants lack the risk of medication overuse headache associated with triptans and analgesics, making them a theoretical option for this population. Prospective trial data are limited. Evidence quality: Very low.
Dosing
Acute Treatment of Migraine
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Acute migraine attack — moderate to severe | 75 mg orally, as needed | 75 mg PRN (one dose per attack) | 75 mg per 24-hour period | No loading dose; treat at onset of moderate-severe headache pain Safety of >18 doses in 30 days not established (FDA PI) |
| Acute migraine — triptan-intolerant or contraindicated | 75 mg orally, as needed | 75 mg PRN | 75 mg per 24-hour period | No vasoconstrictive activity; suitable for patients with cardiovascular risk factors where triptans are contraindicated Does not carry triptan-associated coronary vasoconstriction risk |
| Acute migraine — with strong CYP3A4 inhibitor | Avoid concomitant use | N/A | N/A | Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) increase rimegepant AUC ~4-fold See Drug Interactions section for full list |
Preventive Treatment of Episodic Migraine
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Episodic migraine prevention — standard regimen | 75 mg orally every other day | 75 mg every other day | 75 mg per 24-hour period | No loading dose; no titration needed; efficacy demonstrated by first month with significance at weeks 9–12 Can also treat breakthrough attacks on non-dosing days (max 75 mg/24h) |
| Dual-purpose use — prevention + acute treatment | 75 mg every other day (scheduled) | 75 mg every other day + 75 mg PRN on off-days | 75 mg per 24-hour period | On scheduled dosing days, the scheduled dose also provides acute relief. On non-dosing days, 75 mg may be taken PRN for breakthrough migraine Unified approach eliminates the need for separate acute and preventive medications |
Rimegepant is unique among current migraine therapies in offering both acute and preventive treatment with a single agent. Patients taking the preventive regimen (75 mg every other day) can also take an additional dose on non-dosing days if a breakthrough migraine occurs, without exceeding the 75 mg/24-hour limit. This simplifies treatment regimens and may improve adherence. Unlike triptans and analgesics, gepants do not carry a risk of medication overuse headache with frequent use, which is a significant clinical advantage. The ODT dissolves on or under the tongue without water, making it convenient during migraine attacks with nausea.
Pharmacology
Mechanism of Action
Rimegepant is an orally administered small molecule that antagonizes the calcitonin gene-related peptide (CGRP) receptor, blocking the binding of CGRP to its receptor complex. This distinguishes it mechanistically from anti-CGRP monoclonal antibodies (galcanezumab, fremanezumab), which bind to the CGRP ligand itself, and from erenumab, which is a monoclonal antibody targeting the CGRP receptor. As a small molecule, rimegepant crosses the blood-brain barrier to a limited extent and blocks both peripheral and potentially some central CGRP signaling involved in migraine pathogenesis. The CGRP receptor is a heterodimer consisting of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). Rimegepant competes with CGRP for binding at this receptor, inhibiting the downstream vasodilatory and pro-inflammatory signaling cascades that propagate migraine attacks. Its relatively short half-life (~11 hours) allows intermittent receptor blockade with every-other-day dosing for prevention, while providing rapid acute relief within 1–2 hours of a single dose.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax ~1.5 h; absolute oral bioavailability ~64%; high-fat meal reduces Cmax 42–53% and AUC 32–38% | Rapid absorption enables use as acute treatment; food effect on efficacy is unknown (clinical trials dosed without regard to food) |
| Distribution | Vd ~120 L (steady state); protein binding ~96% | Large Vd indicates extensive tissue distribution; high protein binding means unlikely to be removed by dialysis |
| Metabolism | Primary: CYP3A4; minor: CYP2C9; parent compound is ~77% of circulating drug; no major metabolites (>10%) | CYP3A4 dependence creates clinically significant drug interactions with strong inhibitors (4-fold AUC increase) and inducers (80% AUC decrease) |
| Elimination | t½ ~11 h; 78% fecal, 24% urinary; unchanged drug: 42% of fecal, 51% of urinary excretion | Short half-life supports both PRN acute dosing and every-other-day preventive scheduling; dual fecal/urinary elimination |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea (acute treatment) | 2.0% (vs 0.4% placebo) | Most common adverse effect in the acute treatment trial (Study 1); generally mild and transient |
| Nausea (preventive treatment) | 2.7% (vs 0.8% placebo) | Reported in the preventive treatment trial (Study 2) with every-other-day dosing |
| Abdominal pain / Dyspepsia (preventive) | 2.4% (vs 0.8% placebo) | Reported with every-other-day dosing in Study 2; typically mild gastrointestinal discomfort |
| Nasopharyngitis (preventive) | 3.5% (vs 2.4% placebo) | Rates similar to placebo; not clearly drug-related |
| Urinary tract infection (preventive) | 2.4% (vs 2.2% placebo) | Similar frequency to placebo across pooled analyses; unlikely drug-related |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Serious hypersensitivity (dyspnea, severe rash, anaphylaxis) | <1% (clinical trials); rare (postmarketing) | Hours to days after administration; delayed serious hypersensitivity has occurred | Permanent discontinuation; initiate appropriate therapy; report to manufacturer |
| Hypertension (new-onset or worsening) | Rare (postmarketing) | Most commonly within 7 days of dose | Monitor BP; initiate antihypertensive if needed; consider discontinuation |
| Raynaud’s phenomenon (new-onset or worsening) | Rare (postmarketing) | Median 1.5 days after dosing (small molecule CGRP antagonist class data) | Discontinue rimegepant; refer for evaluation; most cases resolve after discontinuation |
| Hepatotransaminase elevation (>3× ULN) | ~1.1% (preventive trial) | During treatment period | Check baseline LFTs; monitor if symptoms arise; discontinue if clinically significant hepatotoxicity |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Adverse events (preventive trial) | 2% (7/370) (vs 1% placebo) | Low rate; no single adverse event driving discontinuation |
| Serious adverse events (pooled acute trials) | 0.2% (vs 0.2% placebo) | Rate identical to placebo; no pattern of specific serious events |
Rimegepant has a notably clean tolerability profile compared to many migraine treatments. In pooled acute treatment trials (n=3,553), the overall incidence of adverse events was 14.2% with rimegepant versus 11.7% with placebo. No hepatotoxicity signals were seen with rimegepant ODT, unlike the first-generation gepants (telcagepant, MK-3207), which were discontinued due to liver safety concerns. Long-term safety data from over 1,700 patients treated for up to one year support sustained tolerability.
Drug Interactions
Unlike anti-CGRP monoclonal antibodies, rimegepant is a small molecule metabolized primarily by CYP3A4 and is a substrate of P-glycoprotein (P-gp) and BCRP efflux transporters. This creates clinically significant interactions with strong CYP3A4 inhibitors and inducers. Rimegepant itself is a weak inhibitor of CYP3A4 with time-dependent inhibition but does not significantly affect CYP1A2, 2B6, 2C9, 2C19, or 2D6 at therapeutic concentrations.
Monitoring
-
Blood Pressure
Baseline, then periodically
Routine Postmarketing reports of new-onset and worsening hypertension with CGRP antagonists, most commonly within 7 days of dosing. Particularly important in patients with pre-existing hypertension. -
Migraine Diary
Continuous; review at 3 months
Routine Track monthly migraine days, acute medication use, and headache severity. For preventive treatment, assess response at weeks 9–12 per the pivotal trial primary endpoint timeline. -
Hepatic Function
Baseline; as clinically indicated
Trigger-based Transaminase elevations >3× ULN occurred in ~1.1% of patients in the preventive trial. Avoid use in severe hepatic impairment (Child-Pugh C) where rimegepant exposure is ~2-fold higher. No adjustment needed for mild/moderate impairment. -
Hypersensitivity
After each dose; can be delayed
Trigger-based Reactions can occur days after administration and may be prolonged. Delayed serious hypersensitivity has occurred. Educate patients to watch for rash, dyspnea, or facial swelling appearing days after dosing. -
Drug Interaction Review
At initiation; with any medication change
Routine Review for concurrent strong CYP3A4 inhibitors or inducers, and potent P-gp inhibitors before prescribing. Unlike monoclonal antibody CGRP therapies, rimegepant has clinically important CYP-mediated interactions. -
Raynaud’s Symptoms
Ongoing patient reporting
Trigger-based Median onset ~1.5 days after dosing for small molecule CGRP antagonists (shorter than the ~71-day median for mAbs). Discontinue if new symptoms of cold-induced color changes or pain in extremities develop.
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to rimegepant or any component of Nurtec ODT. Delayed serious hypersensitivity, including anaphylaxis, has been reported.
Relative Contraindications (Specialist Input Recommended)
- Severe hepatic impairment (Child-Pugh C): Rimegepant exposure approximately doubles. Avoid use per FDA labeling.
- End-stage renal disease (CrCl <15 mL/min): Not studied in this population. Avoid use per FDA labeling.
- Concurrent use of strong CYP3A4 inhibitors: Results in approximately 4-fold increase in rimegepant exposure. Contraindicated by clinical practice guidelines.
Use with Caution
- Pre-existing hypertension: Postmarketing reports of new-onset and worsening hypertension. Monitor BP and consider discontinuation if inadequately controlled.
- History of Raynaud’s phenomenon: New-onset or worsening symptoms reported; median onset 1.5 days for small molecule CGRP antagonists.
- Pregnancy: No adequate human data. Animal studies showed decreased fetal body weight and skeletal variations at doses with maternal toxicity. Pregnancy exposure registry available (1-877-366-0324 or nurtecpregnancyregistry.com).
- Concurrent moderate CYP3A4 inhibitors or potent P-gp inhibitors: Avoid another dose within 48 hours. Includes common medications such as diltiazem, verapamil, erythromycin, and cyclosporine.
The FDA updated labeling for all CGRP antagonists, including rimegepant, to include warnings for hypertension and Raynaud’s phenomenon based on postmarketing reports. For small molecule CGRP antagonists specifically, Raynaud’s symptom onset occurred a median of 1.5 days following dosing (compared with a median of 71 days for monoclonal antibody CGRP antagonists). Many cases involved serious outcomes including hospitalization and disability. In most cases, discontinuation of the CGRP antagonist led to symptom resolution.
Patient Counselling
Purpose of Therapy
Rimegepant can serve two roles: as an acute treatment taken at the onset of a migraine attack to relieve pain, and as a preventive treatment taken every other day to reduce the frequency of future migraine attacks. It does not cure migraine but can significantly reduce both the severity and frequency of attacks. Unlike triptans, rimegepant does not carry a risk of medication overuse headache with frequent use. Patients using rimegepant for prevention can also take an additional dose on non-scheduled days if a breakthrough migraine occurs, as long as they do not exceed 75 mg in any 24-hour period.
How to Take
Nurtec ODT is an orally disintegrating tablet. Do not remove the blister from the outer aluminum pouch until ready to use. Using dry hands, peel back the foil covering and gently remove the tablet (do not push it through the foil). Place the tablet on or under the tongue; it will dissolve in saliva and can be swallowed without water. Take the tablet immediately after opening the blister; do not store outside the blister. The medication can be taken with or without food. Store at room temperature (20–25°C / 68–77°F).
Sources
- Pfizer Inc. NURTEC ODT (rimegepant) orally disintegrating tablets, for sublingual or oral use: US Prescribing Information. Revised March 2025. FDA Label Primary source for dosing, pharmacokinetics, adverse reactions, drug interactions, contraindications, and March 2025 labeling updates.
- European Medicines Agency. Vydura (rimegepant) EPAR — Summary of Product Characteristics. EMA EPAR EU regulatory assessment (marketed as Vydura in Europe) providing SmPC data for acute migraine treatment.
- Croop R, Goadsby PJ, Stock DA, et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial (Study 303). Lancet. 2019;394(10200):737–745. doi:10.1016/S0140-6736(19)31606-X Pivotal phase 3 trial of the ODT formulation (Study 1 in PI) establishing acute efficacy for pain freedom and MBS freedom at 2 hours.
- Lipton RB, Croop R, Stock EG, et al. Rimegepant, an oral calcitonin gene-related peptide receptor antagonist, for migraine (Study 301). N Engl J Med. 2019;381(2):142–149. doi:10.1056/NEJMoa1811090 Phase 3 trial of the conventional tablet formulation confirming acute migraine efficacy with favorable tolerability (N=1,186).
- Croop R, Lipton RB, Kudrow D, et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial (Study 305). Lancet. 2021;397(10268):51–60. doi:10.1016/S0140-6736(20)32544-7 Pivotal trial (Study 2 in PI) demonstrating every-other-day rimegepant efficacy for migraine prevention (N=747).
- American Headache Society. The American Headache Society Consensus Statement: update on integrating new migraine treatments into clinical practice. Headache. 2021;61(7):1021–1039. doi:10.1111/head.14153 AHS position statement on sequencing of CGRP-targeting therapies including gepants within the migraine treatment algorithm.
- Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies — successful translation from bench to clinic. Nat Rev Neurol. 2018;14(6):338–350. doi:10.1038/s41582-018-0003-1 Comprehensive review of CGRP pathway pharmacology including the development of small molecule receptor antagonists (gepants).
- Edvinsson L. Oral rimegepant for migraine prevention. Lancet. 2021;397(10268):4–5. doi:10.1016/S0140-6736(20)32624-6 Expert commentary on the significance of rimegepant as the first dual acute-preventive CGRP therapy.
- Berman G, Croop R, Kudrow D, et al. Safety of rimegepant, an oral CGRP receptor antagonist, plus CGRP monoclonal antibodies for migraine. Headache. 2020;60(8):1734–1742. doi:10.1111/head.13930 Safety analysis of concomitant rimegepant and anti-CGRP monoclonal antibody use from long-term extension data.
- Bhardwaj R, Morris B, Matschke KT, Bertz R, Croop R, Liu J. Characterization of rimegepant drug-drug interactions using the cytochrome P450 probe drugs, itraconazole, rifampin, fluconazole, and midazolam. Headache. 2025;65(2):291–302. doi:10.1111/head.14836 Original phase 1 DDI data characterizing the CYP3A4 interaction magnitude with itraconazole (4.14-fold AUC), rifampin (80% AUC decrease), and fluconazole (1.80-fold AUC).
- Scott LJ. Rimegepant: a review in the acute treatment and preventive treatment of migraine. Drugs. 2022;82(15):1539–1555. doi:10.1007/s40265-022-01789-3 Comprehensive clinical review covering efficacy, safety, pharmacology, and place in therapy for both acute and preventive migraine indications.
- Ailani J, Lipton RB, Goadsby PJ, et al. Atogepant for the preventive treatment of migraine. N Engl J Med. 2021;385(8):695–706. doi:10.1056/NEJMoa2035908 Comparator gepant trial (atogepant ADVANCE study) providing class context for the preventive gepant mechanism.