AHFS Class:

• Calcitonin Gene-related Peptide (CGRP) Antagonists 28:32.12

Generic Name(s):

• Rimegepant Sulfate

Rimegepant sulfate, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is an antimigraine agent.1,4,6,12

Acute Treatment of Migraine

Rimegepant sulfate is used for the acute treatment of migraine with or without aura in adults.1,2,4,6 In clinical studies, acute treatment with rimegepant was more effective than placebo in relieving migraine pain and the patient's most bothersome symptoms (e.g., nausea, phonophobia, photophobia) at 2 hours post-dose.1,2,3,4,5,13

Clinical Experience

Efficacy of rimegepant for the acute treatment of migraine was established in 3 randomized, double-blind, placebo-controlled studies in adults with a history of migraine, with or without aura, according to the International Classification of Headache Disorders, third edition, beta version (ICHD-3 beta) diagnostic criteria, who were experiencing at least 2 migraine attacks of moderate or severe intensity per month.1,2,3,4,5,13 Two of the studies used rimegepant (immediate-release) tablets (not currently available in the US) and one of the studies used rimegepant orally disintegrating tablets.5,13 In these studies, patients were randomized to receive a single 75-mg dose of rimegepant or placebo for self-administration to treat a migraine of moderate to severe headache pain intensity.1,2,3,13 Aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), acetaminophen, antiemetics and/or baclofen were permitted after 2 hours if needed for rescue treatment; other forms of rescue treatment such as selective serotonin type 1 (5-HT₁) receptor agonists (triptans) were not allowed within 48 hours of initial treatment.1,3,13 In the study using rimegepant orally disintegrating tablets, approximately 14% of patients were receiving preventive migraine treatment (excluding therapies that act on the CGRP pathway) at baseline.1 The primary measures of efficacy in the study were freedom from pain (defined as a reduction in migraine pain from moderate or severe to none) and freedom from the most bothersome symptom (defined as the absence of the patient's self-identified most bothersome symptom) at 2 hours postdose.1,13

In all 3 studies, the primary efficacy endpoints were achieved in a statistically significantly greater proportion of patients who received rimegepant than in those who received placebo.1,2,3,4,13 In the study using rimegepant orally disintegrating tablets, 21.2% of patients achieved freedom from pain at 2 hours compared with 10.9% of placebo recipients, and freedom from the most bothersome symptom was achieved in 35.1% of patients receiving rimegepant orally disintegrating tablets compared with 26.8% of placebo recipients.1 The most common bothersome symptoms reported by patients in this study were photophobia (54%), nausea (28%), and phonophobia (15%).1

When rimegepant is used as an oral acute treatment of migraine in patients receiving preventive therapy with an anti-CGRP monoclonal antibody (e.g., erenumab, fremanezumab, galcanezumab), the drug has been well tolerated with no safety issues.19,20 In addition, rimegepant (administered at a dose of 75 mg) effectively treated breakthrough migraines in some of these patients.19,20 However, these findings are based on a limited number of patients in small studies and case reports only; therefore, further study is needed.19,20

Clinical Perspective

The American Headache Society (AHS) guidelines include the oral calcitonin gene-related peptide (CGRP) receptor antagonists (gepants) as one of several drugs with established efficacy in the acute treatment of migraine.12,21 Unlike 5-HT₁ receptor agonists (triptans) and ergot alkaloids, CGRP receptor antagonists do not cause constriction of blood vessels, and therefore may have a role in patients with cardiovascular contraindications to triptans.12 Because of the relatively high cost of CGRP receptor antagonists compared with oral triptans in the acute treatment of migraine, AHS recommends that oral CGRP receptor antagonists be considered for use only in patients who have contraindications to the use of triptans and/or who have an inadequate response or intolerance to at least 2 oral triptans.12,21

Preventive Treatment of Episodic Migraine

Rimegepant sulfate is also used for the preventive treatment of episodic migraine in adults.1,22

Clinical Experience

Efficacy and safety of rimegepant for preventive treatment of migraine have been established in a randomized, double-blind, placebo-controlled study with a different oral dosage form of rimegepant than the one that is commercially available.1,22 The study enrolled adults with at least a 1-year history of migraine, with or without aura.1 Patients in this study experienced an average of 10.9 headache days during the 28-day observational period, which included an average of 10.2 migraine days, prior to randomization.1 Patients were randomized to receive rimegepant 75 mg or placebo every other day for 12 weeks and were permitted to use acute headache treatments, including 5-HT₁ receptor agonists (triptans), NSAIAs, acetaminophen, antiemetics, muscle relaxants, and aspirin, as needed during the study.1 Approximately 10% of the patients were receiving one preventive treatment for migraine at baseline; however, concomitant use of drugs acting on the CGRP pathway was not permitted for either acute or preventive migraine treatment.1 The study excluded patients with myocardial infarction (MI), acute coronary syndrome (ACS), percutaneous coronary intervention (PCI), cardiac surgery, stroke, or transient ischemic attack (TIA) within 6 months of screening.1 The primary measure of efficacy was the change from baseline in mean monthly migraine days during weeks 9 through 12 of the double-blind treatment phase.1 The percentage of patients achieving at least a 50% reduction in moderate to severe migraine days per month during weeks 9-12 was also evaluated.1 Rimegepant demonstrated statistically significant improvements in these efficacy endpoints compared with placebo.1,22 The change from baseline in mean monthly migraine days from weeks 9-12 was -4.3 with rimegepant compared with -3.5 with placebo.1 The percentage of patients achieving at least a 50% reduction in moderate to severe mean migraine days per month during the study period was 49.1% in patients receiving rimegepant and 41.5% in those receiving placebo.1

Clinical Perspective

AHS has published expert consensus statements on integrating new migraine treatments into clinical practice over the last years.12,21 AHS states that rimegepant and other anti-CGRP small molecules offer a number of advantages over some oral migraine preventive therapies, including no need for dosage escalation, rapid onset of therapeutic activity (within days to weeks), demonstrated efficacy after failure of prior preventive treatments or in combination with oral preventive treatments, minimal risk of adverse drug interactions, and favorable overall tolerability profiles.12,21 In 2024, AHS stated that CGRP-targeting therapies should be considered as a first-line approach for migraine prevention along with previous first-line treatments, without a requirement for prior failure of other migraine preventive drug classes.23 AHS noted that the cumulative evidence for the efficacy, safety, and tolerability of CGRP-targeting therapies is significantly greater than that for any established migraine preventive therapy.23

Administration

Rimegepant is administered orally without regard to food.1,13

Rimegepant is commercially available as orally disintegrating tablets supplied in blister packs.1 Patients should be instructed to use dry hands to peel back the foil covering of one blister and gently remove the tablet.1 Do not push the tablet through the foil.1 Immediately place the tablet on or under the tongue where it will disintegrate in saliva and can be swallowed without additional liquid.1 Once the blister is opened, administer the tablet immediately and do not store outside the blister packaging for future use.1

Dosage

Dosage of rimegepant sulfate is expressed in terms of rimegepant.1

Acute Treatment of Migraine

For the acute treatment of migraine in adults, the recommended dosage of rimegepant is 75 mg taken orally, as needed.1 The manufacturer states that the maximum dose in a 24-hour period is 75 mg.1 The safety of using more than 18 doses in a 30-day period has not been established.1

Preventive Treatment of Episodic Migraine

For the preventive treatment of migraine in adults, the recommended dosage of rimegepant is 75 mg taken orally once every other day.1

Dosage Modification for Drug Interactions

Avoid taking another dose of rimegepant within 48 hours if the drug is used concomitantly with a moderate cytochrome P-450 (CYP) 3A4 inhibitor or potent P-glycoprotein (P-gp) inhibitor.1

Avoid concomitant use of potent CYP3A4 inhibitors or moderate or potent CYP3A inducers.1

Special Populations

Hepatic Impairment

Dosage adjustment is not necessary in patients with mild or moderate (Child-Pugh class A or B) hepatic impairment.1 Use of rimegepant in patients with severe hepatic impairment should be avoided.1

Renal Impairment

Dosage adjustment is not necessary in patients with mild, moderate, or severe renal impairment.1 Use of rimegepant in patients with end-stage renal disease or those requiring dialysis should be avoided.1

Contraindications

• History of hypersensitivity reaction to rimegepant or any ingredient in the formulation.1 Delayed serious hypersensitivity has occurred.1

Warnings/Precautions

Hypersensitivity

Hypersensitivity reactions, including dyspnea and rash, have occurred in patients receiving rimegepant in clinical studies.1 Delayed serious hypersensitivity reactions (e.g., days after administration) also have occurred.1

If a hypersensitivity reaction occurs, discontinue rimegepant and initiate appropriate therapy.1

Specific Populations

Pregnancy

There are no adequate data to date on the developmental risk associated with the use of rimegepant in pregnant women.1 In animal studies, adverse developmental effects (decreased fetal body weight and increased incidence of fetal variations) were observed in rats when rimegepant was administered at dosages resulting in systemic exposures well exceeding the exposure from the maximum recommended human dosage (75 mg daily) and that were associated with maternal toxicity.1 No adverse effects on embryofetal development were observed in pregnant rabbits administered rimegepant at dosages resulting in systemic exposures of up to approximately 10 times the exposure in humans at the maximum recommended dosage.1

The estimated rates of major birth defects and miscarriage among deliveries to women with migraine (2.2-2.9 and 17%, respectively) are similar to rates reported in women without migraine.1 Clinicians should be aware that published data suggest that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy.1

A pregnancy exposure registry exists that monitors outcomes in pregnant women exposed to rimegepant.1 Patients or clinicians can receive more information on the registry by calling 1-877-366-0324 or visiting [Web].1

Lactation

Clinical data support that the transfer of rimegepant into human milk is low.1 The effects of rimegepant on nursing infants or on milk production are not known.1 Consider the developmental and health benefits of breast-feeding along with the importance of rimegepant to the woman and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of rimegepant have not been established in pediatric patients.1

Geriatric Use

Clinical studies of rimegepant did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger patients.1 No clinically important pharmacokinetic differences have been observed between geriatric and younger adults.1

Hepatic Impairment

In a hepatic impairment study, rimegepant exposure was approximately twofold higher in individuals with severe (Child-Pugh class C) hepatic impairment compared with individuals with normal hepatic function.1 No clinically important differences in rimegepant exposure were observed in individuals with mild or moderate (Child-Pugh class A or B) hepatic impairment compared with individuals with normal hepatic function.1

Dosage adjustment of rimegepant is not necessary in patients with mild or moderate hepatic impairment.1

Avoid use of rimegepant in patients with severe hepatic impairment.1

Renal Impairment

In a renal impairment study, rimegepant exposure was approximately 40% higher in individuals with moderate renal impairment (creatinine clearance of 30-59 mL/minute); however, no obvious correlation between renal function and systemic exposure was observed.1 No clinically important difference in rimegepant exposure also was observed in individuals with severe renal impairment (creatinine clearance of 15-29 mL/minute).1,14

Dosage adjustment of rimegepant is not necessary in patients with mild, moderate, or severe renal impairment.1

Rimegepant has not been studied in patients with end-stage renal disease (creatinine clearance of <15 mL/minute) or those requiring dialysis.1 The drug is not expected to be substantially removed by dialysis because it is highly protein bound.1 Avoid use of rimegepant in patients with end-stage renal disease or those requiring dialysis.1

Pharmacogenomic Considerations

Contribution of cytochrome P-450 (CYP) isoenzyme 2C9 to rimegepant metabolism is considered minor; genetic polymorphism of CYP2C9 therefore is not expected to have clinically important effects on rimegepant exposure.1

The pharmacokinetics of rimegepant were similar in individuals with CYP2C9 *1/*2, *2/*2, and *1/*3 genotypes (i.e., intermediate metabolizers) and in individuals with CYP2C9 *1/*1 genotype (i.e., normal metabolizers).1

There are no adequate data to date on the pharmacokinetics of rimegepant in individuals with CYP2C9 *2/*3 genotype (i.e., poor metabolizers).1

Common Adverse Effects

Acute treatment of migraine: The most common adverse effect (≥1%) of rimegepant in clinical studies was nausea.1

Preventive treatment of episodic migraine: The most common adverse effects of rimegepant (≥2%) in clinical studies were nausea and abdominal pain/dyspepsia.1

Rimegepant is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP2C9.1 In vitro studies indicate that rimegepant is a weak inhibitor of CYP3A4 with time-dependent inhibition.1 Rimegepant does not inhibit CYP1A2, 2B6, 2C9, 2C19, or 2D6, or induce CYP1A2, 2B6, or 3A4 at clinically relevant concentrations.1 Rimegepant is also not an inhibitor of uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1.1

Rimegepant is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1 The drug is not a substrate of organic anion transporting polypeptide (OATP) 1B1 or OATP1B3 and is not expected to be a substrate of organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, multidrug and toxic compound extrusion protein (MATE) 1, or MATE2-K.1 The drug is an inhibitor of OATP1B3, OCT2, and MATE1, and a weak inhibitor of OATP1B1 and OAT3 but does not inhibit P-gp, BCRP, OAT1, or MATE2-K at clinically relevant concentrations.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 Inhibitors

Concomitant use of rimegepant and potent CYP3A4 inhibitors results in substantially increased rimegepant exposure.1 Concurrent administration of rimegepant (single 75-mg dose) and the potent CYP3A4 inhibitor itraconazole at steady state resulted in an approximately 1.5-fold increase in peak plasma concentration and fourfold increase in the AUC of rimegepant.1 Concurrent administration of rimegepant (single 75-mg dose) and fluconazole (400 mg daily), a combined moderate CYP3A4 and CYP2C9 inhibitor, resulted in a 1.8-fold increase in the AUC of rimegepant with no clinically important effect on peak plasma concentration.1 Concurrent administration of rimegepant and other moderate inhibitors of CYP3A4 is expected to increase rimegepant AUC by less than twofold.1

Concomitant use of rimegepant and potent CYP3A4 inhibitors should be avoided.1

In patients receiving a moderate CYP3A4 inhibitor, rimegepant doses should not be administered within 48 hours of each other.1,14

Weak CYP3A4 inhibitors are not expected to have clinically important effects on rimegepant exposure.1 Dosage adjustment of rimegepant is not necessary in patients concurrently receiving weak CYP3A4 inhibitors.14

CYP2C9 Inhibitors

CYP2C9 is considered a minor contributor to rimegepant metabolism and CYP2C9 inhibition alone is not expected to have clinically important effects on rimegepant exposure.1 Concurrent administration of rimegepant (single 75-mg dose) and fluconazole, a combined moderate CYP3A4 and CYP2C9 inhibitor, resulted in a 1.8-fold increase in the AUC of rimegepant with no clinically important effect on peak plasma concentration.1

Dosage adjustment of rimegepant is not necessary in patients receiving CYP2C9 inhibitors.14

CYP3A Inducers

Concomitant use of rimegepant and potent CYP3A inducers may result in substantially decreased rimegepant exposure and decreased efficacy of the drug.1 Concurrent administration of rimegepant (single 75-mg dose) and the potent CYP3A4 inducer rifampin at steady state decreased peak plasma concentration and AUC of rimegepant by 64 and 80%, respectively.1 Moderate CYP3A inducers also are expected to result in substantially decreased rimegepant exposure and decreased efficacy of rimegepant.1 Weak CYP3A inducers are not expected to have clinically important effects on rimegepant exposure.1

Concomitant use of rimegepant and moderate or potent CYP3A inducers should be avoided.1

P-gp and BCRP Inhibitors

Concomitant use of rimegepant with cyclosporine (a potent P-gp and BCRP inhibitor) and with quinidine (a potent P-gp inhibitor) resulted in an increase of similar magnitude in rimegepant exposure.1 Therefore, concurrent use of rimegepant with BCRP inhibitors is not expected to have a clinically significant impact on rimegepant exposure.1

In patients receiving a potent P-gp inhibitor, rimegepant doses should not be administered within 48 hours of each other.1

Metformin

No clinically important pharmacokinetic interactions were observed with concomitant use of rimegepant and metformin (a MATE1 substrate).1

Midazolam

No clinically important pharmacokinetic interactions were observed with concomitant use of rimegepant and midazolam (a sensitive CYP3A4 substrate).1

Oral Contraceptives

No clinically important pharmacokinetic interactions were observed with concomitant use of rimegepant and an oral contraceptive containing norelgestromin and ethinyl estradiol.1

Sumatriptan

No clinically important pharmacokinetic interactions were observed with concomitant use of rimegepant and sumatriptan.1 In addition, no clinically important effects on resting blood pressure were observed with concomitant use of rimegepant and sumatriptan compared with use of sumatriptan alone.1,14

Description

Rimegepant is a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist (gepant).1,4,6 CGRP is a potent vasodilator and pain-signaling neuropeptide that has been associated with migraine pathophysiology.6,7,9,10,18 CGRP and its receptors are located at sites that are relevant to migraine development such as the trigeminal neurons and are also widely distributed throughout the central and peripheral nervous systems as well as in nonneuronal tissues throughout the body.7,9,10,18 Serum CGRP concentrations are increased during acute migraine attacks and return to normal after resolution of the migraine.6 Furthermore, IV infusion of CGRP has been shown to induce migraines in patients with a history of migraines.6,9,10,18

Rimegepant and other small molecule CGRP receptor antagonists bind to CGRP receptors with high affinity, blocking the binding of CGRP to the receptor and preventing subsequent receptor activation.1,6,7,12 Unlike 5-HT₁ receptor agonists (triptans) and ergot alkaloids that are also used in the treatment of migraine, rimegepant does not appear to cause vasoconstriction.6,12 Rimegepant also does not appear to prolong the QT interval when administered at a dose 4 times higher than the recommended dose.1

Following administration of rimegepant sulfate as an orally disintegrating tablet, peak plasma concentrations of the drug occur at 1.5 hours.1 The absolute oral bioavailability of rimegepant is approximately 64%.1 Administration with a high-fat meal delays time to peak plasma concentration by 1 hour and decreases peak plasma concentration and AUC by 42-53 and 32-38%, respectively; the clinical importance of these changes is not known.1 Rimegepant was administered without regard to food in clinical studies.1 The drug is approximately 96% bound to plasma proteins.1 Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9; no major metabolites have been detected in plasma.1 Following administration of radiolabeled rimegepant, approximately 78 and 24% of the dose was recovered in feces and urine, respectively.1 Approximately 77% of the dose is eliminated as unchanged drug.1 The elimination half-life is approximately 11 hours.1

The pharmacokinetics of rimegepant are not substantially affected by age, sex, race/ethnicity, body weight, or CYP2C9 genotype.1

Advice to Patients

• Advise patients to read the manufacturer's patient information.1
• Instruct patients not to remove the tablet from the blister package until just before administering a dose, and to use dry hands when handling the tablet and to gently remove the tablet from the blister pack.1
• Risk of hypersensitivity reactions, which may occur days after rimegepant administration.1 Advise patients to seek immediate medical attention if they experience any symptoms of hypersensitivity reactions.1
• Inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
• Advise women to inform clinicians if they are or plan to become pregnant or are breast-feeding or plan to breast-feed.1 Advise patients that a pregnancy registry exists to monitor outcomes in women exposed to rimegepant during pregnancy.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Biohaven Pharmaceuticals, Inc. Nurtec ODT^® (rimegepant sulfate) tablets prescribing information. New Haven, CT; 2023 Apr.

2. 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. [abstract]. Lancet . 2019; 394:737-745. [PubMed 31311674]

3. U.S. National Library of Medicine. ClinicalTrials.gov. Trial in Adult Subjects With Acute Migraines. Accessed 2024 May 29. Available from [Web][Web]

4. Lipton RB, Croop R, Stock EG et al. Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine. N Engl J Med . 2019; 381:142-149. [PubMed 31291516]

5. Gao B, Yang Y, Wang Z et al. Efficacy and Safety of Rimegepant for the Acute Treatment of Migraine: Evidence From Randomized Controlled Trials. Front Pharmacol . 2020; 10:1577. [PubMed 32038251]

6. Negro A, Martelletti P. Gepants for the treatment of migraine. Expert Opin Investig Drugs . 2019; 28:555-567. [PubMed 31081399]

7. Hargreaves R, Olesen J. Calcitonin Gene-Related Peptide Modulators - The History and Renaissance of a New Migraine Drug Class. Headache . 2019; 59:951-970. [PubMed 31020659]

8. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 211765Orig1s000: Clinical pharmacology review(s). From FDA website. [Web]

9. Edvinsson L, Haanes KA, Warfvinge K et al. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol . 2018; 14:338-350. [PubMed 29691490]

10. Schuster NM, Rapoport AM. Calcitonin Gene-Related Peptide-Targeted Therapies for Migraine and Cluster Headache: A Review. Clin Neuropharmacol . 2017 Jul/Aug; 40:169-174. [PubMed 28644160]

12. American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache . 2019; 59:1-18. [PubMed 30536394]

13. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 212728Orig1s000: Summary review. From FDA website. [Web]

14. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 212728Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]

18. Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache . 2017; 57:47-55. [PubMed 28485848]

19. Mullin K, Kudrow D, Croop R et al. Potential for treatment benefit of small molecule CGRP receptor antagonist plus monoclonal antibody in migraine therapy. Neurology . 2020; 94:e2121-e2125. [PubMed 31932515]

20. Berman G, Croop R, Kudrow D et al. Safety of Rimegepant, an Oral CGRP Receptor Antagonist, Plus CGRP Monoclonal Antibodies for Migraine. Headache . 2020; 60:1734-1742. [PubMed 32799325]

21. Ailani J, Burch RC, Robbins MS et al. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache . 2021; 61:1021-1039. [PubMed 34160823]

22. 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. Lancet . 2021; 397:51-60. [PubMed 33338437]

23. Charles AC, Digre KB, Goadsby PJ, et al. Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: an American Headache Society position statement update. Headache. 2024;1-9. [Web]