In Vitro studies
Rimegepant is a substrate of CYP3A4 and CYP2C9 (see 9.4 Drug-Drug Interactions). Rimegepant is not an inhibitor of CYP1A2, 2B6, 2C9, 2C19, 2D6, or UGT1A1 at clinically relevant concentrations. However, rimegepant is a weak inhibitor of CYP3A4 with time-dependent inhibition. Rimegepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.
In vitro, rimegepant is a substrate of BCRP and P-gp efflux transporters. Inhibitors of P-gp and BCRP efflux transporters increase plasma concentrations of rimegepant. Rimegepant may be co-administered with BCRP transporter inhibitors and with weak to moderate P-gp only inhibitors. Strong P-gp inhibitors may be co-administered no more frequently than once every 48 hours, based on a clinical interaction study with a potent dual P-gp and BCRP inhibitor (cyclosporine) and with a selective P-gp inhibitor (quinidine) resulted in significant increases of similar magnitude in rimegepant exposure (AUC and Cmax by 1.6 and 1.4 fold with cyclosporine, and by 1.6 and 1.7 fold with quinidine, respectively) (see 9.4 Drug-Drug Interactions).
Rimegepant is not a substrate of OATP1B1 or OATP1B3. Considering its low renal clearance, rimegepant was not evaluated as a 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 a weak inhibitor of OATP1B1 and OAT3.
Rimegepant is an inhibitor of OATP1B3, OCT2, and MATE1. No clinical drug interactions are expected for NURTEC ODT with these transporters at clinically relevant concentrations (see 9.4 Drug-Drug Interactions).
The effect of rimegepant on sexual activity, driving, and operating machinery has not been studied.
The interaction of rimegepant with cigarette smoking, cannabis use, and/or alcohol consumption has not been studied.
| [Proper/Common name] | Source of Evidence | Effect | Clinical Comment |
|---|---|---|---|
| CYP3A4 Inhibitors (e.g., clarithromycin, itraconazole, ritonavir, diltiazem, erythromycin, fluconazole, grapefruit juice) | In vivo | Concomitant administration of 75 mg rimegepant (single dose) with itraconazole, a strong CYP3A4 inhibitor, at steady state resulted in increased exposures of rimegepant (AUC by 4-fold and Cmax by ~1.5-fold). The concomitant administration of rimegepant with a moderate inhibitor of CYP3A4 (e.g., fluconazole), at steady state, increased rimegepant exposures (AUC) by 1.8-fold. No dedicated drug interaction study was conducted to assess the effect of concomitant administration of a weak inhibitor of CYP3A4 on the pharmacokinetics of rimegepant. Concomitant administration of rimegepant with a weak inhibitor of CYP3A4 is not anticipated to have a clinically significant impact on rimegepant exposures. | Concomitant administration of NURTEC ODT with strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ritonavir) should be avoided . Exercise caution during concomitant administration of rimegepant with moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, fluconazole). Another dose of NURTEC ODT within 48 hours should be avoided when it is concomitantly administered with moderate inhibitors of CYP3A4 (e.g., fluconazole). |
| CYP3A4 Inducers (e.g., phenobarbital, rifampicin, St John’s wort (Hypericum perforatum), bosentan, efavirenz, modafinil) | In vivo | Concomitant administration of 75 mg rimegepant (single dose) with rifampin, a strong CYP3A4 inducer, at steady state, resulted in decreased exposures of rimegepant (AUC by 80% and Cmax by 64%), which can lead to loss of efficacy. The effects of moderate or weak inducers of CYP3A4 on the pharmacokinetics of rimegepant are unknown. However, since rimegepant is a substrate for CYP3A4, drugs that are moderate inducers of CYP3A4 can also cause significant reduction in rimegepant exposure resulting in loss of efficacy. Clinically significant interaction is not anticipated with concomitant administration of weak inducers of CYP3A4 and rimegepant. | Concomitant administration of NURTEC ODT with strong CYP3A4 inducers (e.g., phenobarbital, rifampicin, St John’s wort (Hypericum perforatum)) or moderate CYP3A4 inducers (e.g., bosentan, efavirenz, modafinil) is not recommended. The effect of CYP3A4 induction may last for up to 2 weeks after discontinuation of the strong or moderate CYP3A4 inducer. |
| BCRP and/or P-gp only Inhibitors (e.g., cyclosporine, verapamil, quinidine). | In vivo | Concomitant administration of 75 mg rimegepant (single dose) with a single 200 mg dose of cyclosporine, a strong inhibitor of the P-gp and BCRP transporters, resulted in 1.6-fold and 1.4-fold increase in rimegepant AUC and Cmax, respectively. Upon concomitant administration of a single 75 mg dose of rimegepant and a single 600 mg dose of quinidine, a strong inhibitor of P-gp only, rimegepant AUC and Cmax increased by approximately 1.6 fold and 1.7 fold, respectively. Based on the totality of the results, BCRP inhibition is not anticipated to significantly affect rimegepant exposures. | Avoid a second dose of NURTEC ODT within 48 hours after concomitant administration of the first dose with strong inhibitors of P-gp (e.g., cyclosporine, verapamil, quinidine). |
Other drugs
CYP2C9 inhibitors:
Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9. Increase in the exposure of rimegepant can be attributed to combined inhibition of CYP2C9 and CYP3A4. In a drug-drug interaction study in healthy adult subjects, administration of a single 75 mg dose of rimegepant concurrent with steady state fluconazole (400 mg QD) increased AUC of rimegepant by approximately 1.8-fold while its Cmax did not change significantly.
MATE1 substrates:
In a dedicated drug interaction study in healthy nondiabetic adult subjects, steady state administration of rimegepant 75 mg with metformin 500 mg, a MATE1 transporter substrate, at steady state, resulted in no clinically significant impact on either metformin pharmacokinetics or on glucose utilization.
CYP3A4 substrates and pharmacodynamic interactions:
In dedicated drug interaction studies in healthy adult subjects, rimegepant did not have a clinically significant effect on the pharmacokinetics of oral contraceptives (norelgestromin, ethinyl estradiol or midazolam (a sensitive CYP3A4 substrate) (see 10.2 Pharmacodynamics).
In another drug interaction study in healthy adult subjects, steady state administration of oral rimegepant 75 mg did not affect sumatriptan (OCT1 substrate) pharmacokinetics (2 x 6 mg administered subcutaneously within one hour). Also, single-dose administration of sumatriptan did not have any meaningful effect on rimegepant pharmacokinetics.
Other calcitonin gene-related peptide (CGRP) Receptor Antagonists:
In a clinical study of two other CGRP receptor antagonists, a significant increase in cases of constipation was reported when these CGRP receptor antagonists were co-administered. Concomitant use of rimegepant with other CGRP receptor antagonists is not recommended.
Following administration of NURTEC ODT under fed conditions Tmax was delayed by approximately 1 to 1.5 hours. Consumption of a high-fat meal 30 minutes before administration of NURTEC ODT under or on top of the tongue decreased rimegepant AUCT by 32% and 38%, and Cmax by 42% and 53%, respectively. Similarly, consumption of a low-fat meal 30 min before administration of NURTEC ODT under the tongue decreased rimegepant AUCT and Cmax by approximately 28% and 36%, respectively, compared with administration under fasting conditions.
NURTEC ODT was administered without regard to food in clinical safety and efficacy studies. It is not known whether there is any impact on efficacy when there is a reduction in rimegepant exposure when administered with food.
See 9.4 Drug-Drug Interactions regarding concomitant use with St. John’s wort (a CYP3A4 inducer).
Interactions of NURTEC ODT with laboratory tests have not been studied.
)In Vitro studies
Rimegepant is a substrate of CYP3A4 and CYP2C9 (see 9.4 Drug-Drug Interactions). Rimegepant is not an inhibitor of CYP1A2, 2B6, 2C9, 2C19, 2D6, or UGT1A1 at clinically relevant concentrations. However, rimegepant is a weak inhibitor of CYP3A4 with time-dependent inhibition. Rimegepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.
In vitro, rimegepant is a substrate of BCRP and P-gp efflux transporters. Inhibitors of P-gp and BCRP efflux transporters increase plasma concentrations of rimegepant. Rimegepant may be co-administered with BCRP transporter inhibitors and with weak to moderate P-gp only inhibitors. Strong P-gp inhibitors may be co-administered no more frequently than once every 48 hours, based on a clinical interaction study with a potent dual P-gp and BCRP inhibitor (cyclosporine) and with a selective P-gp inhibitor (quinidine) resulted in significant increases of similar magnitude in rimegepant exposure (AUC and Cmax by 1.6 and 1.4 fold with cyclosporine, and by 1.6 and 1.7 fold with quinidine, respectively) (see 9.4 Drug-Drug Interactions).
Rimegepant is not a substrate of OATP1B1 or OATP1B3. Considering its low renal clearance, rimegepant was not evaluated as a 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 a weak inhibitor of OATP1B1 and OAT3.
Rimegepant is an inhibitor of OATP1B3, OCT2, and MATE1. No clinical drug interactions are expected for NURTEC ODT with these transporters at clinically relevant concentrations (see 9.4 Drug-Drug Interactions).
The effect of rimegepant on sexual activity, driving, and operating machinery has not been studied.
The interaction of rimegepant with cigarette smoking, cannabis use, and/or alcohol consumption has not been studied.
| [Proper/Common name] | Source of Evidence | Effect | Clinical Comment |
|---|---|---|---|
| CYP3A4 Inhibitors (e.g., clarithromycin, itraconazole, ritonavir, diltiazem, erythromycin, fluconazole, grapefruit juice) | In vivo | Concomitant administration of 75 mg rimegepant (single dose) with itraconazole, a strong CYP3A4 inhibitor, at steady state resulted in increased exposures of rimegepant (AUC by 4-fold and Cmax by ~1.5-fold). The concomitant administration of rimegepant with a moderate inhibitor of CYP3A4 (e.g., fluconazole), at steady state, increased rimegepant exposures (AUC) by 1.8-fold. No dedicated drug interaction study was conducted to assess the effect of concomitant administration of a weak inhibitor of CYP3A4 on the pharmacokinetics of rimegepant. Concomitant administration of rimegepant with a weak inhibitor of CYP3A4 is not anticipated to have a clinically significant impact on rimegepant exposures. | Concomitant administration of NURTEC ODT with strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ritonavir) should be avoided . Exercise caution during concomitant administration of rimegepant with moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, fluconazole). Another dose of NURTEC ODT within 48 hours should be avoided when it is concomitantly administered with moderate inhibitors of CYP3A4 (e.g., fluconazole). |
| CYP3A4 Inducers (e.g., phenobarbital, rifampicin, St John’s wort (Hypericum perforatum), bosentan, efavirenz, modafinil) | In vivo | Concomitant administration of 75 mg rimegepant (single dose) with rifampin, a strong CYP3A4 inducer, at steady state, resulted in decreased exposures of rimegepant (AUC by 80% and Cmax by 64%), which can lead to loss of efficacy. The effects of moderate or weak inducers of CYP3A4 on the pharmacokinetics of rimegepant are unknown. However, since rimegepant is a substrate for CYP3A4, drugs that are moderate inducers of CYP3A4 can also cause significant reduction in rimegepant exposure resulting in loss of efficacy. Clinically significant interaction is not anticipated with concomitant administration of weak inducers of CYP3A4 and rimegepant. | Concomitant administration of NURTEC ODT with strong CYP3A4 inducers (e.g., phenobarbital, rifampicin, St John’s wort (Hypericum perforatum)) or moderate CYP3A4 inducers (e.g., bosentan, efavirenz, modafinil) is not recommended. The effect of CYP3A4 induction may last for up to 2 weeks after discontinuation of the strong or moderate CYP3A4 inducer. |
| BCRP and/or P-gp only Inhibitors (e.g., cyclosporine, verapamil, quinidine). | In vivo | Concomitant administration of 75 mg rimegepant (single dose) with a single 200 mg dose of cyclosporine, a strong inhibitor of the P-gp and BCRP transporters, resulted in 1.6-fold and 1.4-fold increase in rimegepant AUC and Cmax, respectively. Upon concomitant administration of a single 75 mg dose of rimegepant and a single 600 mg dose of quinidine, a strong inhibitor of P-gp only, rimegepant AUC and Cmax increased by approximately 1.6 fold and 1.7 fold, respectively. Based on the totality of the results, BCRP inhibition is not anticipated to significantly affect rimegepant exposures. | Avoid a second dose of NURTEC ODT within 48 hours after concomitant administration of the first dose with strong inhibitors of P-gp (e.g., cyclosporine, verapamil, quinidine). |
Other drugs
CYP2C9 inhibitors:
Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9. Increase in the exposure of rimegepant can be attributed to combined inhibition of CYP2C9 and CYP3A4. In a drug-drug interaction study in healthy adult subjects, administration of a single 75 mg dose of rimegepant concurrent with steady state fluconazole (400 mg QD) increased AUC of rimegepant by approximately 1.8-fold while its Cmax did not change significantly.
MATE1 substrates:
In a dedicated drug interaction study in healthy nondiabetic adult subjects, steady state administration of rimegepant 75 mg with metformin 500 mg, a MATE1 transporter substrate, at steady state, resulted in no clinically significant impact on either metformin pharmacokinetics or on glucose utilization.
CYP3A4 substrates and pharmacodynamic interactions:
In dedicated drug interaction studies in healthy adult subjects, rimegepant did not have a clinically significant effect on the pharmacokinetics of oral contraceptives (norelgestromin, ethinyl estradiol or midazolam (a sensitive CYP3A4 substrate) (see 10.2 Pharmacodynamics).
In another drug interaction study in healthy adult subjects, steady state administration of oral rimegepant 75 mg did not affect sumatriptan (OCT1 substrate) pharmacokinetics (2 x 6 mg administered subcutaneously within one hour). Also, single-dose administration of sumatriptan did not have any meaningful effect on rimegepant pharmacokinetics.
Other calcitonin gene-related peptide (CGRP) Receptor Antagonists:
In a clinical study of two other CGRP receptor antagonists, a significant increase in cases of constipation was reported when these CGRP receptor antagonists were co-administered. Concomitant use of rimegepant with other CGRP receptor antagonists is not recommended.
Following administration of NURTEC ODT under fed conditions Tmax was delayed by approximately 1 to 1.5 hours. Consumption of a high-fat meal 30 minutes before administration of NURTEC ODT under or on top of the tongue decreased rimegepant AUCT by 32% and 38%, and Cmax by 42% and 53%, respectively. Similarly, consumption of a low-fat meal 30 min before administration of NURTEC ODT under the tongue decreased rimegepant AUCT and Cmax by approximately 28% and 36%, respectively, compared with administration under fasting conditions.
NURTEC ODT was administered without regard to food in clinical safety and efficacy studies. It is not known whether there is any impact on efficacy when there is a reduction in rimegepant exposure when administered with food.
See 9.4 Drug-Drug Interactions regarding concomitant use with St. John’s wort (a CYP3A4 inducer).
Interactions of NURTEC ODT with laboratory tests have not been studied.
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