USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Exposures were significantly higher in subjects with severe hepatic impairment. Avoid use in patients with severe hepatic impairment (Child-Pugh C). 8.6) Exposures were significantly higher in subjects with severe hepatic impairment. Avoid use in patients with severe hepatic impairment (Child-Pugh C). 8.6) 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NURTEC ODT during pregnancy. For more information, healthcare providers or patients are encouraged to contact: 1-877-366-0324, email nurtecpregnancyregistryppd.com, or visit nurtecpregnancyregistry.com.. Risk SummaryThere are no adequate data on the developmental risk associated with the use of NURTEC ODT in pregnant women. In animal studies, oral administration of rimegepant during organogenesis resulted in adverse effects on development in rats (decreased fetal body weight and increased incidence of fetal variations) at exposures greater than those used clinically and which were associated with maternal toxicity. The evaluation of developmental effects following oral administration of rimegepant throughout pregnancy and lactation was inadequate (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. The estimated rate of major birth defects (2.2 to 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.. Clinical Considerations. Disease-Associated Maternal and/or Embryo/Fetal RiskPublished data have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy.. Data. Animal DataOral administration of rimegepant (0, 10, 60, or 300 mg/kg/day) to pregnant rats during the period of organogenesis resulted in decreased fetal body weight and an increased incidence of fetal variations at the highest dose tested (300 mg/kg/day), which was associated with maternal toxicity. Plasma exposures (AUC) at the no-effect dose (60 mg/kg/day) for adverse effects on embryofetal development were approximately 45 times that in humans at the maximum recommended human dose (MRHD) of 75 mg/day.Oral administration of rimegepant (0, 10, 25, or 50 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in no adverse effects on embryofetal development. The highest dose tested (50 mg/kg/day) was associated with plasma exposures (AUC) approximately 10 times that in humans at the MRHD.The prenatal and postnatal development study in rats, in which rimegepant (0, 10, 25, or 60 mg/kg/day) was orally administered throughout gestation and lactation, was inadequate to assess for adverse effects of rimegepant during these periods of development.. 8.2 Lactation. There are no data on the presence of rimegepant or its metabolites in human milk, the effects of rimegepant on the breastfed infant, or the effects of rimegepant on milk production. There are no animal data on the excretion of rimegepant in milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for NURTEC ODT and any potential adverse effects on the breastfed infant from NURTEC ODT or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. 8.5 Geriatric Use. In pharmacokinetic studies, no clinically significant pharmacokinetic differences were observed between elderly and younger subjects. Clinical studies of NURTEC ODT did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.. 8.6 Hepatic Impairment. No dosage adjustment of NURTEC ODT is required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Plasma concentrations of rimegepant were significantly higher in subjects with severe (Child-Pugh C) hepatic impairment. Avoid use of NURTEC ODT in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)] . 8.7 Renal Impairment. No dosage adjustment of NURTEC ODT is required in patients with mild, moderate, or severe renal impairment. NURTEC ODT has not been studied in patients with end-stage renal disease and in patients on dialysis. Avoid use of NURTEC ODT in patients with end-stage renal disease (CLcr 15 mL/min) [see Clinical Pharmacology (12.3)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong CYP3A4 Inhibitors: Avoid concomitant administration. 7.1) Moderate CYP3A4 Inhibitors: Avoid another dose within 48 hours when administered with moderate CYP3A4 inhibitor. 7.1) Strong and Moderate CYP3A Inducers: Avoid concomitant administration. 7.2) Potent Inhibitors of P-gp: Avoid another dose of NURTEC ODT within 48 hours when administered with potent P-gp inhibitor. 7.3) Strong CYP3A4 Inhibitors: Avoid concomitant administration. 7.1) Moderate CYP3A4 Inhibitors: Avoid another dose within 48 hours when administered with moderate CYP3A4 inhibitor. 7.1) Strong and Moderate CYP3A Inducers: Avoid concomitant administration. 7.2) Potent Inhibitors of P-gp: Avoid another dose of NURTEC ODT within 48 hours when administered with potent P-gp inhibitor. 7.3) 7.1 CYP3A4 Inhibitors. Concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4 results in significant increase in rimegepant exposure. Avoid concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4 [see Clinical Pharmacology (12.3)] Concomitant administration of NURTEC ODT with moderate inhibitors of CYP3A4 may result in increased exposure of rimegepant. Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with moderate inhibitors of CYP3A4 [see Clinical Pharmacology (12.3)] . 7.2 CYP3A Inducers. Concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A can result in significant reduction in rimegepant exposure, which may lead to loss of efficacy of NURTEC ODT. Avoid concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A [see Clinical Pharmacology (12.3)] . 7.3 P-gp Inhibitors. Concomitant administration of NURTEC ODT with potent inhibitors of P-gp (e.g., amiodarone, cyclosporine, lapatinib, quinidine, ranolazine) may result in increased exposure of rimegepant. Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with potent inhibitors of P-gp [see Clinical Pharmacology (12.3)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:Hypersensitivity Reactions [see Warnings and Precautions (5.1)] Hypersensitivity Reactions [see Warnings and Precautions (5.1)] Acute treatment of migraine: the adverse reaction reported in >= 1% of patients treated with NURTEC ODT is nausea. 6.1) Preventive treatment of episodic migraine: adverse reactions reported in >= 2% for rimegepant and >= 1% higher than placebo are nausea and abdominal pain/dyspepsia. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Biohaven Pharmaceuticals Inc. at 1-833-4BIOHVN or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.. Acute Treatment of MigraineThe safety of NURTEC ODT for the acute treatment of migraine in adults has been evaluated in randomized, double-blind, placebo-controlled trial (Study 1) in 682 patients with migraine who received one 75 mg dose of NURTEC ODT [see Clinical Studies (14)] Approximately 85% were female, 74% were White, 21% were Black, and 17% were Hispanic or Latino. The mean age at study entry was 40 years (range 18-75 years of age). Long-term safety was assessed in an open-label extension study using different oral dosage form of rimegepant. That study evaluated 1,798 patients, dosing intermittently for up to one year, including 1,131 patients who were exposed to rimegepant 75 mg for at least months, and 863 who were exposed for at least one year, all of whom treated an average of at least two migraine attacks per month.The most common adverse reaction in Study was nausea (2% in patients who received NURTEC ODT compared to 0.4% of patients who received placebo).Hypersensitivity, including dyspnea and severe rash, occurred in less than 1% of patients treated with NURTEC ODT [see Contraindications (4) and Warnings and Precautions (5.1)] . Preventive Treatment of Episodic MigraineThe safety of NURTEC ODT for the preventive treatment of episodic migraine in adults has been established in randomized, double-blind, placebo-controlled trial with an open-label extension (Study 2) using different oral dosage form of rimegepant [see Clinical Studies (14)] In the 12-week, double-blind treatment period, 370 patients with migraine received one 75 mg dose of rimegepant every other day Approximately 81% were female, 80% were White, 17% were Black, and 28% were Hispanic or Latino. The mean age at study entry was 41 years (range 18-74 years of age). Long-term safety was assessed in an open-label extension study that included 603 patients who were treated for up to one year. Overall, 527 patients were exposed to rimegepant 75 mg for at least months, and 311 were exposed for at least one year. The most common adverse reactions (occurring in at least 2% of rimegepant-treated patients and at frequency of at least 1% higher than placebo) in Study were nausea (2.7% in patients who received rimegepant compared with 0.8% of patients who received placebo) and abdominal pain/dyspepsia (2.4% in patients who received rimegepant compared with 0.8% of patients who received placebo).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Rimegepant is calcitonin gene-related peptide receptor antagonist.. 12.2 Pharmacodynamics. The relationship between pharmacodynamic activity and the mechanism(s) by which rimegepant exerts its clinical effects is unknown.No clinically relevant differences in resting blood pressure were observed when rimegepant was concomitantly administered with sumatriptan (12 mg subcutaneous, given as two mg doses separated by one hour) compared with sumatriptan alone to healthy volunteers.. Cardiac ElectrophysiologyAt single dose times the recommended dose, rimegepant does not prolong the QT interval to any clinically relevant extent.. 12.3 Pharmacokinetics. AbsorptionFollowing oral administration of NURTEC ODT, rimegepant is absorbed with the maximum concentration at 1.5 hours. The absolute oral bioavailability of rimegepant is approximately 64%.. Effects of FoodFollowing administration of NURTEC ODT under fed conditions with high-fat or low-fat meal, max was delayed by approximately to 1.5 hours. high-fat meal reduced max by 42 to 53% and AUC by 32 to 38%. low-fat meal reduced max by 36% and AUC by 28%. NURTEC ODT was administered without regard to food in clinical safety and efficacy studies. The impact of the reduction in rimegepant exposure because of administration with food on its efficacy is unknown. DistributionThe steady state volume of distribution of rimegepant is 120 L. Plasma protein binding of rimegepant is approximately 96%.. Elimination. MetabolismRimegepant is primarily metabolized by CYP3A4 and to lesser extent by CYP2C9.Rimegepant is primarily eliminated in unchanged form (~77% of the dose) with no major metabolites (i.e., 10%) detected in plasma.. ExcretionThe elimination half-life of rimegepant is approximately 11 hours in healthy subjects. Following oral administration of 14C]-rimegepant to healthy male subjects, 78% of the total radioactivity was recovered in feces and 24% in urine. Unchanged rimegepant is the major single component in excreted feces (42%) and urine (51%). Specific Populations. Renal ImpairmentIn dedicated clinical study comparing the pharmacokinetics of rimegepant in subjects with mild (estimated creatinine clearance [CLcr] 60-89 mL/min), moderate (CLcr 30-59 mL/min), and severe (CLcr 15-29 mL/min) renal impairment to that with normal subjects (healthy matched control), the exposure of rimegepant following single 75 mg dose was approximately 40% higher in subjects with moderate renal impairment. However, there was no clinically meaningful difference in the exposure of rimegepant in subjects with severe renal impairment compared to subjects with normal renal function (CLcr >= 90mL/min). NURTEC ODT has not been studied in patients with end-stage renal disease (CLcr 15 mL/min) [see Use in Specific Populations (8.7)]. Hepatic ImpairmentIn dedicated clinical study comparing the pharmacokinetics of rimegepant in subjects with mild, moderate, and severe hepatic impairment to that with normal subjects (healthy matched control), the exposure of rimegepant (C max and AUC) following single 75 mg dose was approximately 2-fold higher in subjects with severe impairment (Child-Pugh class C). There were no clinically meaningful differences in the exposure of rimegepant in subjects with mild (Child-Pugh class A) and moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function [see Use in Specific Populations (8.6)]. Other Specific PopulationsNo clinically significant differences in the pharmacokinetics of rimegepant were observed based on age, sex, race/ethnicity, body weight, or CYP2C9 genotype [see Clinical Pharmacology (12.5)]. Drug Interaction Studies. In Vitro Studies. EnzymesRimegepant is substrate of CYP3A4 and CYP2C9 (see In Vivo Studies). Rimegepant is not an inhibitor of CYP1A2, 2B6, 2C9, 2C19, 2D6, or UGT1A1 at clinically relevant concentrations. However, rimegepant is weak inhibitor of CYP3A4 with time-dependent inhibition. Rimegepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations. Enzymes. TransportersRimegepant is substrate of P-gp and BCRP (see In Vivo Studies) Rimegepant is not substrate of OATP1B1 or OATP1B3. Considering its low renal clearance, rimegepant was not evaluated as substrate of the OAT1, OAT3, OCT2, MATE1, or MATE2-K.Rimegepant is not an inhibitor of P-gp, BCRP, OAT1, or MATE2-K at clinically relevant concentrations. It is weak inhibitor of OATP1B1 and OAT3. Rimegepant is an inhibitor of OATP1B3, OCT2, and MATE1. In dedicated interaction study, concomitant administration of 75 mg rimegepant at steady state with metformin, MATE1 transporter substrate, at steady state resulted in no clinically significant impact on either metformin pharmacokinetics or on glucose utilization. No clinical drug interactions are expected for NURTEC ODT with OATP1B3 or OCT2, at clinically relevant concentrations.. Transporters. In Vivo Studies. CYP3A4 InhibitorsIn dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with itraconazole, strong CYP3A4 inhibitor, at steady state resulted in increased exposures of rimegepant (AUC by 4-fold and max by ~1.5-fold) [see Drug Interactions (7.1)]. No dedicated drug interaction study was conducted to assess the effect of concomitant administration of weak inhibitor of CYP3A4 on the pharmacokinetics of rimegepant. The concomitant administration of rimegepant with moderate inhibitor of CYP3A4 may increase rimegepant exposures (AUC) by less than 2-fold [see Drug Interactions (7.1)]. Concomitant administration of rimegepant with weak inhibitor of CYP3A4 is not expected to have clinically significant impact on rimegepant exposures. CYP3A InducersIn dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with rifampin, strong CYP3A4 inducer, at steady state resulted in decreased exposures of rimegepant (AUC by 80% and max by 64%), which may lead to loss of efficacy [see Drug Interactions (7.2)] No dedicated drug interaction study was conducted to assess the effect of concomitant administration of moderate or weak inducer of CYP3A4 on the pharmacokinetics of rimegepant Since rimegepant is moderately sensitive substrate for CYP3A4, drugs that are moderate inducers of CYP3A4 can also cause significant reduction in rimegepant exposure resulting in loss of efficacy [see Drug Interactions (7.2)] Clinically significant interaction is not expected with concomitant administration of weak inducers of CYP3A4 and rimegepant. CYP2C9 InhibitorsIn dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with fluconazole, combined moderate CYP3A4 and CYP2C9 inhibitor, resulted in increased exposures of rimegepant (AUC by 1.8-fold) with no relevant effect on max. Rimegepant is primarily metabolized by CYP3A4 and to lesser extent by CYP2C9. Increase in the exposure of rimegepant can be attributed to combined inhibition of CYP2C9 and CYP3A4 with fluconazole administration suggesting minor contribution from CYP2C9. Thus, CYP2C9 inhibition alone is not expected to significantly affect rimegepant exposures. P-gp and BCRP InhibitorsIn dedicated drug interaction study, concomitant administration of NURTEC ODT 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 (AUC and max by 1.6 and 1.4 fold with cyclosporine, and by 1.6 and 1.7 fold with quinidine, respectively) [see Drug Interactions (7.3)]. Therefore, concomitant administration of NURTEC ODT with BCRP inhibitors is not expected to have clinically significant impact on rimegepant exposures. Other Drugs: No significant pharmacokinetic interactions were observed when rimegepant was concomitantly administered with oral contraceptives (norelgestromin, ethinyl estradiol), midazolam (a sensitive CYP3A4 substrate), metformin (a MATE1 substrate), or sumatriptan [see Clinical Pharmacology (12.2)]. 12.5 Pharmacogenomics. CYP2C9 activity is reduced in individuals with genetic variants such as the CYP2C92 and CYP2C93 alleles. Rimegepant Cmax and AUC0-inf were similar in CYP2C9 intermediate metabolizers (i.e., 1/2, 2/2, 1/3, n=43) as compared to normal metabolizers (i.e., 1/1, N=72). Adequate PK data are not available from CYP2C9 poor metabolizers (i.e., 2/3). Since the contribution of CYP2C9 to rimegepant metabolism is considered minor, CYP2C9 polymorphism is not expected to significantly affect its exposure.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Acute Treatment of Migraine. The efficacy of NURTEC ODT for the acute treatment of migraine with and without aura in adults was demonstrated in randomized, double-blind, placebo-controlled trial: Study (NCT03461757). Patients in the study were randomized to receive 75 mg of NURTEC ODT (N=732) or placebo (N=734). Patients were instructed to treat migraine of moderate to severe headache pain intensity. Rescue medication (i.e., NSAIDs, acetaminophen, and/or an antiemetic) was allowed hours after the initial treatment. Other forms of rescue medication such as triptans were not allowed within 48 hours of initial treatment. Approximately 14% of patients were taking preventive medications for migraine at baseline. None of the patients in Study were on concomitant preventive medication that act on the CGRP pathway.The primary efficacy analyses were conducted in patients who treated migraine with moderate to severe pain. NURTEC ODT 75 mg demonstrated an effect on pain freedom and most bothersome symptom (MBS) freedom at two hours after dosing, compared to placebo. Pain freedom was defined as reduction of moderate or severe headache pain to no headache pain, and MBS freedom was defined as the absence of the self-identified MBS (i.e., photophobia, phonophobia, or nausea). Among patients who selected an MBS, the most commonly selected symptom was photophobia (54%), followed by nausea (28%), and phonophobia (15%).In Study 1, the percentage of patients achieving headache pain freedom and MBS freedom two hours after single dose was statistically significantly greater in patients who received NURTEC ODT compared to those who received placebo (Table 1).Table 1: Efficacy Endpoints for the Acute Treatment of Migraine in Study 1Study 1NURTEC ODT 75 mg PlaceboPain Free at hours n/N n=number of responders/N=number of patients in that treatment group 142/66974/682 Responders21.210.9 Difference from placebo (%)10.3 p-value<0.001MBS Free at hours n/N 235/669183/682 Responders35.126.8 Difference from placebo (%)8.3 p-value0.001Figure presents the percentage of patients achieving migraine pain freedom within hours following treatment in Study 1.Figure 1: Percentage of Patients Achieving Pain Freedom within Hours in Study 1Figure presents the percentage of patients achieving MBS freedom within hours in Study 1.Figure 2: Percentage of Patients Achieving MBS Freedom within Hours in Study 1In Study 1, statistically significant effects of NURTEC ODT compared to placebo were demonstrated for the additional efficacy endpoints of pain relief at hours, sustained pain freedom 2-48 hours, use of rescue medication within 24 hours, and the percentage of patients reporting normal function at two hours after dosing (Table 2). Pain relief was defined as reduction in migraine pain from moderate or severe severity to mild or none. The measurement of the percentage of patients reporting normal function at two hours after dosing was derived from single text questionnaire, asking patients to select one response on 4-point scale; normal function, mild impairment, severe impairment, or required bedrest.Table 2: Additional Acute Treatment of Migraine Efficacy Endpoints in Study 1Study 1NURTEC ODT 75 mg PlaceboPain Relief at hours n/N n=number of responders/N=number of patients in that treatment group 397/669295/682 Responders59.343.3 Difference from placebo16.1 p-value<0.001Sustained Pain Freedom 2-48 hours n/N 90/66937/682 Responders13.55.4 Difference from placebo8.0 p-value<0.001Use of Rescue Medication within 24 hours This analysis includes only the use of NSAIDs, acetaminophen, or antiemetics, within 24 hours post-dose; the use of triptans, or other acute migraine medication, was not allowed. n/N 95/669199/682 Responders14.229.2 Difference from placebo-15.0 p-value<0.001Percentage of Patients Reporting Normal Function at hours n/N 255/669176/682 Responders38.125.8 Difference from placebo12.3 p-value<0.001The incidence of photophobia and phonophobia was reduced following administration of NURTEC ODT 75 mg as compared to placebo.. Figure 1. Figure 2. 14.2 Preventive Treatment of Episodic Migraine. The efficacy of NURTEC ODT for the preventive treatment of episodic migraine in adults was demonstrated in one randomized, double-blind, placebo-controlled trial of different oral dosage form of rimegepant (Study 2; NCT03732638).Study enrolled adult patients with at least 1-year history of migraine (with or without aura). Patients 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 into the trial. Patients were randomized to receive every other day dosing of rimegepant 75 mg (N=373) or placebo (N=374) for 12 weeks. Patients were allowed to use acute headache treatments (i.e., triptans, NSAIDs, acetaminophen, antiemetics, muscle relaxants, and aspirin) as needed. Approximately 10% of patients were taking one preventive medication for migraine at baseline. The use of concomitant medication that acts on the CGRP pathway was not permitted for either the acute or preventive treatment of migraine.The study excluded patients with myocardial infarction, acute coronary syndrome, percutaneous coronary intervention, cardiac surgery, stroke, or transient ischemic attack within six months of screening.The primary efficacy endpoint for Study was the change from baseline in the mean number of monthly migraine days (MMDs) during Weeks through 12 of the double-blind treatment phase.The percentage of patients who achieved at least 50% reduction from baseline in moderate to severe MMDs during Weeks through 12 of the double-blind treatment phase compared to placebo was also evaluated. Rimegepant 75 mg dosed every other day demonstrated statistically significant improvements for these efficacy endpoints compared to placebo, as summarized in Table 3.Table 3: Efficacy Endpoints for the Preventive Treatment of Episodic Migraine in Study 2Rimegepant 75 mg Every Other Day Placebo Every Other Day Monthly Migraine Days (MMD), Weeks 9-12N=348N=347Change from baseline-4.3-3.5Change from placebo-0.8p-value0.010>= 50% Responders (Moderate to Severe MMDs), Weeks 9-12 N=348N=347% Responders49.141.5Difference from placebo7.6p-value0.044Figure 3: Change from Baseline in Monthly Migraine Days in Study a aLeast-square means and 95% confidence intervals are presented. Figure 4: Distribution of Change from Baseline in Mean Monthly Migraine Days at Month by Treatment Group in Study a aFigure excludes patients with missing data. Figure : Change from Baseline in Monthly Migraine Days in Study 2a. Figure : Distribution of Change from Baseline in Mean Monthly Migraine Days at Month by Treatment Group in Study 2a.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.. Acute Treatment of MigraineThe safety of NURTEC ODT for the acute treatment of migraine in adults has been evaluated in randomized, double-blind, placebo-controlled trial (Study 1) in 682 patients with migraine who received one 75 mg dose of NURTEC ODT [see Clinical Studies (14)] Approximately 85% were female, 74% were White, 21% were Black, and 17% were Hispanic or Latino. The mean age at study entry was 40 years (range 18-75 years of age). Long-term safety was assessed in an open-label extension study using different oral dosage form of rimegepant. That study evaluated 1,798 patients, dosing intermittently for up to one year, including 1,131 patients who were exposed to rimegepant 75 mg for at least months, and 863 who were exposed for at least one year, all of whom treated an average of at least two migraine attacks per month.The most common adverse reaction in Study was nausea (2% in patients who received NURTEC ODT compared to 0.4% of patients who received placebo).Hypersensitivity, including dyspnea and severe rash, occurred in less than 1% of patients treated with NURTEC ODT [see Contraindications (4) and Warnings and Precautions (5.1)] . Preventive Treatment of Episodic MigraineThe safety of NURTEC ODT for the preventive treatment of episodic migraine in adults has been established in randomized, double-blind, placebo-controlled trial with an open-label extension (Study 2) using different oral dosage form of rimegepant [see Clinical Studies (14)] In the 12-week, double-blind treatment period, 370 patients with migraine received one 75 mg dose of rimegepant every other day Approximately 81% were female, 80% were White, 17% were Black, and 28% were Hispanic or Latino. The mean age at study entry was 41 years (range 18-74 years of age). Long-term safety was assessed in an open-label extension study that included 603 patients who were treated for up to one year. Overall, 527 patients were exposed to rimegepant 75 mg for at least months, and 311 were exposed for at least one year. The most common adverse reactions (occurring in at least 2% of rimegepant-treated patients and at frequency of at least 1% higher than placebo) in Study were nausea (2.7% in patients who received rimegepant compared with 0.8% of patients who received placebo) and abdominal pain/dyspepsia (2.4% in patients who received rimegepant compared with 0.8% of patients who received placebo).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended dosage for acute treatment of migraine: 75 mg taken orally, as needed. 2.1) The safety of using more than 18 doses in 30-day period has not been established. 2.1) Recommended dosage for preventive treatment of episodic migraine: 75 mg taken orally every other day. 2.2) The maximum dose in 24-hour period is 75 mg. 2.1) Recommended dosage for acute treatment of migraine: 75 mg taken orally, as needed. 2.1) The safety of using more than 18 doses in 30-day period has not been established. 2.1) Recommended dosage for preventive treatment of episodic migraine: 75 mg taken orally every other day. 2.2) The maximum dose in 24-hour period is 75 mg. 2.1) 2.1 Recommended Dosing for Acute Treatment of Migraine. The recommended dose of NURTEC ODT is 75 mg taken orally, as needed.The maximum dose in 24-hour period is 75 mg. The safety of using more than 18 doses in 30-day period has not been established.. 2.2 Recommended Dosing for Preventive Treatment of Episodic Migraine. The recommended dosage of NURTEC ODT is 75 mg taken orally every other day.. 2.3 Administration Information. Instruct the patient on the following administration instructions:Use dry hands when opening the blister pack.Peel back the foil covering of one blister and gently remove the orally disintegrating tablet (ODT). Do not push the ODT through the foil.As soon as the blister is opened, remove the ODT and place on the tongue; alternatively, the ODT may be placed under the tongue.The ODT will disintegrate in saliva so that it can be swallowed without additional liquid.Take the ODT immediately after opening the blister pack. Do not store the ODT outside the blister pack for future use.. Use dry hands when opening the blister pack.. Peel back the foil covering of one blister and gently remove the orally disintegrating tablet (ODT). Do not push the ODT through the foil.. As soon as the blister is opened, remove the ODT and place on the tongue; alternatively, the ODT may be placed under the tongue.. The ODT will disintegrate in saliva so that it can be swallowed without additional liquid.. Take the ODT immediately after opening the blister pack. Do not store the ODT outside the blister pack for future use.. 2.4 Concomitant Administration with Strong or Moderate CYP3A4 Inhibitors. Avoid concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4. Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with moderate inhibitors of CYP3A4 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)] . 2.5 Concomitant Administration with Strong or Moderate CYP3A Inducers. Avoid concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A, which may lead to loss of efficacy of NURTEC ODT [see Drug Interactions (7.2), Clinical Pharmacology (12.3)] . 2.6 Concomitant Administration with Potent Inhibitors of P-gp. Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with potent inhibitors of P-gp [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFollowing oral administration of NURTEC ODT, rimegepant is absorbed with the maximum concentration at 1.5 hours. The absolute oral bioavailability of rimegepant is approximately 64%.. Effects of FoodFollowing administration of NURTEC ODT under fed conditions with high-fat or low-fat meal, max was delayed by approximately to 1.5 hours. high-fat meal reduced max by 42 to 53% and AUC by 32 to 38%. low-fat meal reduced max by 36% and AUC by 28%. NURTEC ODT was administered without regard to food in clinical safety and efficacy studies. The impact of the reduction in rimegepant exposure because of administration with food on its efficacy is unknown. DistributionThe steady state volume of distribution of rimegepant is 120 L. Plasma protein binding of rimegepant is approximately 96%.. Elimination. MetabolismRimegepant is primarily metabolized by CYP3A4 and to lesser extent by CYP2C9.Rimegepant is primarily eliminated in unchanged form (~77% of the dose) with no major metabolites (i.e., 10%) detected in plasma.. ExcretionThe elimination half-life of rimegepant is approximately 11 hours in healthy subjects. Following oral administration of 14C]-rimegepant to healthy male subjects, 78% of the total radioactivity was recovered in feces and 24% in urine. Unchanged rimegepant is the major single component in excreted feces (42%) and urine (51%). Specific Populations. Renal ImpairmentIn dedicated clinical study comparing the pharmacokinetics of rimegepant in subjects with mild (estimated creatinine clearance [CLcr] 60-89 mL/min), moderate (CLcr 30-59 mL/min), and severe (CLcr 15-29 mL/min) renal impairment to that with normal subjects (healthy matched control), the exposure of rimegepant following single 75 mg dose was approximately 40% higher in subjects with moderate renal impairment. However, there was no clinically meaningful difference in the exposure of rimegepant in subjects with severe renal impairment compared to subjects with normal renal function (CLcr >= 90mL/min). NURTEC ODT has not been studied in patients with end-stage renal disease (CLcr 15 mL/min) [see Use in Specific Populations (8.7)]. Hepatic ImpairmentIn dedicated clinical study comparing the pharmacokinetics of rimegepant in subjects with mild, moderate, and severe hepatic impairment to that with normal subjects (healthy matched control), the exposure of rimegepant (C max and AUC) following single 75 mg dose was approximately 2-fold higher in subjects with severe impairment (Child-Pugh class C). There were no clinically meaningful differences in the exposure of rimegepant in subjects with mild (Child-Pugh class A) and moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function [see Use in Specific Populations (8.6)]. Other Specific PopulationsNo clinically significant differences in the pharmacokinetics of rimegepant were observed based on age, sex, race/ethnicity, body weight, or CYP2C9 genotype [see Clinical Pharmacology (12.5)]. Drug Interaction Studies. In Vitro Studies. EnzymesRimegepant is substrate of CYP3A4 and CYP2C9 (see In Vivo Studies). Rimegepant is not an inhibitor of CYP1A2, 2B6, 2C9, 2C19, 2D6, or UGT1A1 at clinically relevant concentrations. However, rimegepant is weak inhibitor of CYP3A4 with time-dependent inhibition. Rimegepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations. Enzymes. TransportersRimegepant is substrate of P-gp and BCRP (see In Vivo Studies) Rimegepant is not substrate of OATP1B1 or OATP1B3. Considering its low renal clearance, rimegepant was not evaluated as substrate of the OAT1, OAT3, OCT2, MATE1, or MATE2-K.Rimegepant is not an inhibitor of P-gp, BCRP, OAT1, or MATE2-K at clinically relevant concentrations. It is weak inhibitor of OATP1B1 and OAT3. Rimegepant is an inhibitor of OATP1B3, OCT2, and MATE1. In dedicated interaction study, concomitant administration of 75 mg rimegepant at steady state with metformin, MATE1 transporter substrate, at steady state resulted in no clinically significant impact on either metformin pharmacokinetics or on glucose utilization. No clinical drug interactions are expected for NURTEC ODT with OATP1B3 or OCT2, at clinically relevant concentrations.. Transporters. In Vivo Studies. CYP3A4 InhibitorsIn dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with itraconazole, strong CYP3A4 inhibitor, at steady state resulted in increased exposures of rimegepant (AUC by 4-fold and max by ~1.5-fold) [see Drug Interactions (7.1)]. No dedicated drug interaction study was conducted to assess the effect of concomitant administration of weak inhibitor of CYP3A4 on the pharmacokinetics of rimegepant. The concomitant administration of rimegepant with moderate inhibitor of CYP3A4 may increase rimegepant exposures (AUC) by less than 2-fold [see Drug Interactions (7.1)]. Concomitant administration of rimegepant with weak inhibitor of CYP3A4 is not expected to have clinically significant impact on rimegepant exposures. CYP3A InducersIn dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with rifampin, strong CYP3A4 inducer, at steady state resulted in decreased exposures of rimegepant (AUC by 80% and max by 64%), which may lead to loss of efficacy [see Drug Interactions (7.2)] No dedicated drug interaction study was conducted to assess the effect of concomitant administration of moderate or weak inducer of CYP3A4 on the pharmacokinetics of rimegepant Since rimegepant is moderately sensitive substrate for CYP3A4, drugs that are moderate inducers of CYP3A4 can also cause significant reduction in rimegepant exposure resulting in loss of efficacy [see Drug Interactions (7.2)] Clinically significant interaction is not expected with concomitant administration of weak inducers of CYP3A4 and rimegepant. CYP2C9 InhibitorsIn dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with fluconazole, combined moderate CYP3A4 and CYP2C9 inhibitor, resulted in increased exposures of rimegepant (AUC by 1.8-fold) with no relevant effect on max. Rimegepant is primarily metabolized by CYP3A4 and to lesser extent by CYP2C9. Increase in the exposure of rimegepant can be attributed to combined inhibition of CYP2C9 and CYP3A4 with fluconazole administration suggesting minor contribution from CYP2C9. Thus, CYP2C9 inhibition alone is not expected to significantly affect rimegepant exposures. P-gp and BCRP InhibitorsIn dedicated drug interaction study, concomitant administration of NURTEC ODT 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 (AUC and max by 1.6 and 1.4 fold with cyclosporine, and by 1.6 and 1.7 fold with quinidine, respectively) [see Drug Interactions (7.3)]. Therefore, concomitant administration of NURTEC ODT with BCRP inhibitors is not expected to have clinically significant impact on rimegepant exposures. Other Drugs: No significant pharmacokinetic interactions were observed when rimegepant was concomitantly administered with oral contraceptives (norelgestromin, ethinyl estradiol), midazolam (a sensitive CYP3A4 substrate), metformin (a MATE1 substrate), or sumatriptan [see Clinical Pharmacology (12.2)].

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NURTEC ODT during pregnancy. For more information, healthcare providers or patients are encouraged to contact: 1-877-366-0324, email nurtecpregnancyregistryppd.com, or visit nurtecpregnancyregistry.com.. Risk SummaryThere are no adequate data on the developmental risk associated with the use of NURTEC ODT in pregnant women. In animal studies, oral administration of rimegepant during organogenesis resulted in adverse effects on development in rats (decreased fetal body weight and increased incidence of fetal variations) at exposures greater than those used clinically and which were associated with maternal toxicity. The evaluation of developmental effects following oral administration of rimegepant throughout pregnancy and lactation was inadequate (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. The estimated rate of major birth defects (2.2 to 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.. Clinical Considerations. Disease-Associated Maternal and/or Embryo/Fetal RiskPublished data have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy.. Data. Animal DataOral administration of rimegepant (0, 10, 60, or 300 mg/kg/day) to pregnant rats during the period of organogenesis resulted in decreased fetal body weight and an increased incidence of fetal variations at the highest dose tested (300 mg/kg/day), which was associated with maternal toxicity. Plasma exposures (AUC) at the no-effect dose (60 mg/kg/day) for adverse effects on embryofetal development were approximately 45 times that in humans at the maximum recommended human dose (MRHD) of 75 mg/day.Oral administration of rimegepant (0, 10, 25, or 50 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in no adverse effects on embryofetal development. The highest dose tested (50 mg/kg/day) was associated with plasma exposures (AUC) approximately 10 times that in humans at the MRHD.The prenatal and postnatal development study in rats, in which rimegepant (0, 10, 25, or 60 mg/kg/day) was orally administered throughout gestation and lactation, was inadequate to assess for adverse effects of rimegepant during these periods of development.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION. PATIENT INFORMATIONNURTEC(R) ODT (NUR-tek)(rimegepant)orally disintegrating tablets (ODT), for sublingual or oral use What is NURTEC ODTNURTEC ODT is prescription medicine used in adults for the:acute treatment of migraine attacks with or without aurapreventive treatment of episodic migraineIt is not known if NURTEC ODT is safe and effective in children.Do not take NURTEC ODT if you are:allergic to rimegepant, NURTEC ODT, or any of the ingredients in NURTEC ODT.See the end of this leaflet for complete list of ingredients in NURTEC ODT. Before you take NURTEC ODT, tell your healthcare provider about all of your medical conditions, including if you:have liver problems.have kidney problems.are pregnant or plan to become pregnant. It is not known if NURTEC ODT will harm your unborn baby. There is pregnancy exposure registry for women who take NURTEC ODT during pregnancy. The study is named MONITOR (Migraine Observational NURTEC Pregnancy Registry). registry is study. The purpose of this registry is to collect information about your health and the health of your baby. Your healthcare provider can help you enroll in this registry. You may also enroll yourself or get more information about the registry by calling 1-877-366-0324, emailing nurtecpregnancyregistryppd.com, or by visiting nurtecpregnancyregistry.com.are breastfeeding or plan to breastfeed. It is not known if NURTEC ODT passes into your breast milk.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should take NURTEC ODT Take NURTEC ODT exactly how your healthcare provider tells you to.For the acute treatment of migraine attacks when they occur, NURTEC ODT can be taken time each day as needed. You should not take more than tablet in 24 hours. It is not known if it is safe to take more than 18 doses of NURTEC ODT in 30 days. For the preventive treatment of episodic migraine, take NURTEC ODT time every other day.To take NURTEC ODT: Use dry hands when opening the blister pack.Peel back the foil covering of one blister and gently remove NURTEC ODT. Do not push NURTEC ODT through the foil.As soon as the blister is opened, remove NURTEC ODT and place on or under the tongue.NURTEC ODT will dissolve and no drink or water is needed.Take NURTEC ODT immediately after opening the blister pack. Do not store NURTEC ODT outside the blister pack for future use. If you take too much NURTEC ODT, go to the nearest emergency room right away.What are the possible side effects of NURTEC ODTNURTEC ODT may cause serious side effects including:Allergic reactions. Allergic reactions, including trouble breathing and rash, can happen after you take NURTEC ODT. This can happen days after you take NURTEC ODT. Call your healthcare provider or get emergency help right away if you have any of the following symptoms, which may be part of an allergic reaction: Swelling of the face, mouth, tongue, or throatTrouble breathingThe most common side effect of NURTEC ODT in acute treatment of migraine attacks with or without aura is:nauseaThe most common side effects of NURTEC ODT in preventive treatment of episodic migraine are:nauseastomach painindigestionThese are not the only possible side effects of NURTEC ODT. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800 FDA-1088. How should store NURTEC ODTStore NURTEC ODT in the blister package that it comes in.Store NURTEC ODT at room temperature between 68F to 77F (20C to 25C).Keep NURTEC ODT and all medicines out of the reach of children.General information about the safe and effective use of NURTEC ODT:Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use NURTEC ODT for condition for which it was not prescribed. Do not give NURTEC ODT to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about NURTEC ODT that is written for health professionals. What are the ingredients in NURTEC ODTActive ingredient in NURTEC ODT: rimegepantInactive ingredients in NURTEC ODT: benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, menthyl acetate, sucralose, and vanillinManufactured for:Biohaven Pharmaceuticals, Inc.New Haven, CT 06510 USANURTEC and NURTEC ODT are registered trademarks of Biohaven Pharmaceutical Ireland DAC. Biohaven is trademark of Biohaven Pharmaceutical Holding Company Ltd.For more information, go to www.nurtec.com or call 1-833-4NURTEC.This Patient Information has been approved by the U.S. Food and Drug Administration Revised: 12/2021. acute treatment of migraine attacks with or without aura. preventive treatment of episodic migraine. allergic to rimegepant, NURTEC ODT, or any of the ingredients in NURTEC ODT.. have liver problems.. have kidney problems.. are pregnant or plan to become pregnant. It is not known if NURTEC ODT will harm your unborn baby. There is pregnancy exposure registry for women who take NURTEC ODT during pregnancy. The study is named MONITOR (Migraine Observational NURTEC Pregnancy Registry). registry is study. The purpose of this registry is to collect information about your health and the health of your baby. Your healthcare provider can help you enroll in this registry. You may also enroll yourself or get more information about the registry by calling 1-877-366-0324, emailing nurtecpregnancyregistryppd.com, or by visiting nurtecpregnancyregistry.com.. are breastfeeding or plan to breastfeed. It is not known if NURTEC ODT passes into your breast milk.. Take NURTEC ODT exactly how your healthcare provider tells you to.. For the acute treatment of migraine attacks when they occur, NURTEC ODT can be taken time each day as needed. You should not take more than tablet in 24 hours. It is not known if it is safe to take more than 18 doses of NURTEC ODT in 30 days. It is not known if it is safe to take more than 18 doses of NURTEC ODT in 30 days.. For the preventive treatment of episodic migraine, take NURTEC ODT time every other day.. To take NURTEC ODT: Use dry hands when opening the blister pack.Peel back the foil covering of one blister and gently remove NURTEC ODT. Do not push NURTEC ODT through the foil.As soon as the blister is opened, remove NURTEC ODT and place on or under the tongue.NURTEC ODT will dissolve and no drink or water is needed.Take NURTEC ODT immediately after opening the blister pack. Do not store NURTEC ODT outside the blister pack for future use. Use dry hands when opening the blister pack.. Peel back the foil covering of one blister and gently remove NURTEC ODT. Do not push NURTEC ODT through the foil.. As soon as the blister is opened, remove NURTEC ODT and place on or under the tongue.. NURTEC ODT will dissolve and no drink or water is needed.. Take NURTEC ODT immediately after opening the blister pack. Do not store NURTEC ODT outside the blister pack for future use.. If you take too much NURTEC ODT, go to the nearest emergency room right away.. Allergic reactions. Allergic reactions, including trouble breathing and rash, can happen after you take NURTEC ODT. This can happen days after you take NURTEC ODT. Call your healthcare provider or get emergency help right away if you have any of the following symptoms, which may be part of an allergic reaction: Swelling of the face, mouth, tongue, or throat. Trouble breathing. nausea. nausea. stomach pain. indigestion. Store NURTEC ODT in the blister package that it comes in.. Store NURTEC ODT at room temperature between 68F to 77F (20C to 25C).