rimegepant: prescribing information – dosing, contraindications, interactions, side effects

VYDURA is indicated for the
• Acute treatment of migraine with or without aura in adults;
• Preventive treatment of episodic migraine in adults who have at least 4 migraine attacks per month.

Posology

Acute treatment of migraine
The recommended dose is 75 mg rimegepant, as needed, once daily.

Prophylaxis of migraine
The recommended dose is 75 mg rimegepant every other day or every day. Dosing regimen selection should be individualised to the patient based on efficacy and tolerability.

The maximum dose per day is 75 mg rimegepant.

VYDURA can be taken with or without meals.

Concomitant medicinal products
Another dose of rimegepant should be avoided within 48 hours when it is concomitantly administered with moderate inhibitors of CYP3A4 or with strong inhibitors of P-gp (see section 4.5).

Special populations

Elderly (aged 65 and over)
There is limited experience with rimegepant in patients aged 65 years or older. No dose adjustment is required as the pharmacokinetics of rimegepant are not affected by age (see section 5.2).

Renal impairment
No dose adjustment is required in patients with mild, moderate, or severe renal impairment. Severe renal impairment resulted in a > 2-fold increase in unbound AUC but less than a 50% increase in total AUC (see section 5.2). Caution should be exercised during frequent use in patients with severe renal impairment. Rimegepant has not been studied in patients with end-stage renal disease and in patients on dialysis. Use of rimegepant in patients with end-stage renal disease (CLcr < 15 ml/min) should be avoided.

Hepatic impairment
No dose adjustment is required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Plasma concentrations (unbound AUC) of rimegepant were significantly higher in subjects with severe (Child-Pugh C) hepatic impairment (see section 5.2). The use of rimegepant in patients with severe hepatic impairment should be avoided.

Paediatric population
The safety and efficacy of VYDURA in paediatric patients (< 18 years of age) have not been established. No data are available.

Method of administration

VYDURA is for oral use.

The oral lyophilisate should be placed on the tongue or under the tongue. It will disintegrate in the mouth and can be taken without liquid.

Patients should be advised to use dry hands when opening the blister and referred to the package leaflet for complete instructions.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile

The most common adverse reaction for acute treatment of migraine was nausea (1.2%). Most of the reactions were mild or moderate in severity. Hypersensitivity, including dyspnoea and severe rash, occurred in less than 1% of patients treated.

For migraine prophylaxis, the most common adverse reactions were nausea (3.3% for every other day dosing regimen; 3.5% for every day dosing regimen) and constipation (1.0% for every other day dosing regimen; 3.5% for every day dosing regimen). Most of the reactions were mild or moderate in severity.

Tabulated list of adverse reactions

Adverse reaction frequencies for migraine prophylaxis are derived from pooled data from 831 participants, of whom 229 participants received rimegepant every day for 12 weeks and 602 participants received rimegepant every other day for 12 weeks.

Adverse reactions are listed by MedDRA system organ class in Table 1. The corresponding frequency category for each drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000);
very rare (<1/10 000).

Table 1 : List of Adverse Reactions
System Organ Class
Adverse Reaction
Frequency
Acute Treatment
Immune system disorders
Anaphylactic reactiona
Hypersensitivity, including dyspnoea and severe rash
Uncommon
Uncommon
Gastrointestinal disorders
Nausea
Common
Prophylaxis
Immune system disorders
Anaphylactic reactiona
Hypersensitivitya
Not known
Not known
Gastrointestinal disorders
Nausea, Constipation
Common a Adverse Drug Reactions (ADR) identified post-marketing.

Long-term safety
Long-term safety of rimegepant was assessed in two one year, open-label extensions; 1662 patients received rimegepant for at least 6 months and 740 received rimegepant for 12 months for acute or prophylactic (every other day plus as needed dosing) treatment.

An additional open-label safety study of prophylactic treatment with every day dosing was conducted in 250 patients receiving rimegepant for up to 24 weeks.

Description of selected adverse reactions

Hypersensitivity reactions
Hypersensitivity, including dyspnoea and severe rash, occurred in less than 1% of patients treated in clinical studies. Hypersensitivity reactions can occur days after administration, and delayed serious hypersensitivity has occurred.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

<0.0001a

0.0181b

0.0130b
*n=number of responders/N=number of patients in that treatment group a Significant p-value in hierarchical testing b Nominal p-value in hierarchical testing MBS: most bothersome symptom

Figure 1 presents the percentage of patients achieving migraine pain freedom within 2 hours following treatment in Study 1.

Figure 1: Percentage of Patients Achieving Pain Freedom within 2 Hours in Study 1

Figure 2 presents the percentage of patients achieving MBS freedom within 2 hours in Study 1.

Figure 2: Percentage of Patients Achieving MBS Freedom within 2 Hours in Study 1

The incidence of photophobia and phonophobia was reduced at 2 hours following administration of VYDURA 75 mg as compared to placebo in all 3 studies.

Clinical efficacy: prophylaxis

Study 4
The efficacy of rimegepant was evaluated as a prophylactic treatment of migraine in a randomized, double-blind, placebo-controlled study (Study 4).

Study 4 included male and female adults with at least a 1-year history of migraine (with or without aura). Patients had a history of 4 to 18 migraine attacks of moderate to severe pain intensity per 4-week period within the 12 weeks prior to the screening visit. 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 study. The study randomized patients to receive rimegepant 75 mg (N=373) or placebo (N=374) for up to 12 weeks. Patients were instructed to take randomized treatment once every other day (EOD) for the 12-week treatment period. Patients were allowed to use other acute treatments for migraine (e.g., triptans, NSAIDs, paracetamol, antiemetics) as needed. Approximately 22% of patients were taking preventive medicinal products for migraine at baseline. Patients were allowed to continue in an open-label extension study for an additional 12 months.

The primary efficacy endpoint for Study 4 was the change from baseline in the mean number of monthly migraine days (MMDs) during Weeks 9 through 12 of the double-blind treatment phase.
Secondary endpoints included the achievement of a ≥ 50% reduction from baseline in monthly moderate or severe migraine days.

Rimegepant 75 mg dosed EOD demonstrated statistically significant improvements for key efficacy endpoints compared to placebo, as summarized in Table 3 and shown graphically in Figure 3.

Table 3: Key Efficacy Endpoints for Study 4

Rimegepant
75 mg EOD
Placebo
EOD
Monthly Migraine Days (MMD) Weeks 9 through 12
N=348
N=347
Change from baseline
-4.3
-3.5
Change compared to placebo
-0.8

p-value
0.010a

≥ 50% Reduction in Moderate or Severe MMDs
Weeks 9 through 12
N=348
N=347
% Responders

Rimegepant is a substrate of CYP3A4, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters (see section 5.2).

CYP3A4 inhibitors

Inhibitors of CYP3A4 increase plasma concentrations of rimegepant. Concomitant administration of rimegepant with strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ritonavir) is not

recommended (see section 4.4). Concomitant administration of rimegepant with itraconazole resulted in a significant increase in rimegepant exposure (AUC by 4-fold and Cmax 1.5-fold).

Concomitant administration of rimegepant with medicinal products that moderately inhibit CYP3A4 (e.g., diltiazem, erythromycin, fluconazole) may increase exposure to rimegepant. Concomitant administration of rimegepant with fluconazole resulted in increased exposures of rimegepant (AUC by 1.8-fold) with no relevant effect on Cmax. Another dose of rimegepant within 48 hours should be avoided when it is concomitantly administered with moderate inhibitors of CYP3A4 (e.g., fluconazole) (see section 4.2).

CYP3A4 inducers

Inducers of CYP3A4 decrease plasma concentrations of rimegepant. Concomitant administration of VYDURA 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 (see section 4.4). The effect of CYP3A4 induction may last for up to 2 weeks after discontinuation of the strong or moderate CYP3A4 inducer. Concomitant administration of rimegepant with rifampicin resulted in a significant decrease (AUC reduced by 80% and Cmax by 64%) in rimegepant exposure, which may lead to loss of efficacy.

P-gp and BCRP only inhibitors

Inhibitors of P-gp and BCRP efflux transporters may increase plasma concentrations of rimegepant.
Another dose of VYDURA within 48 hours should be avoided when it is concomitantly administered with strong inhibitors of P-gp (e.g., cyclosporine, verapamil, quinidine) (see section 4.2). Concomitant administration of rimegepant with cyclosporine (a potent P-gp and BCRP inhibitor) or with quinidine (a selective P-gp inhibitor) resulted in a significant increase of similar magnitude in rimegepant exposure (AUC and Cmax by > 50%, but less than two-fold).

Pregnancy

There are limited data from the use of rimegepant in pregnant women. Animal studies demonstrate that rimegepant is not embryocidal, and no teratogenic potential has been observed at clinically relevant exposures. Adverse effects on embryo-foetal development (decreased foetal body weight and increased skeletal variations in rats) were only observed at exposure levels associated with maternal toxicity (approximately 200 times greater than clinical exposures) following administration of rimegepant during pregnancy (see section 5.3). As a precautionary measure, it is preferable to avoid the use of VYDURA during pregnancy.

Breast-feeding

In a single center study of 12 breast-feeding women treated with a single dose of rimegepant 75 mg, minimal concentrations of rimegepant were observed in breast milk. The relative percentage of a maternal dose estimated to reach the infant is less than 1%. There are no data on the effects on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for VYDURA and any potential adverse reactions on the breastfed infant from rimegepant or from the underlying maternal condition.

Fertility

Animal studies showed no clinically relevant impact on female and male fertility (see section 5.3)

VYDURA has no or negligible influence on the ability to drive and use machines.

There is limited clinical experience with rimegepant overdose. No overdose symptoms have been reported. Treatment of an overdose of rimegepant should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. No specific antidote for the treatment of rimegepant overdose is available. Rimegepant is unlikely to be significantly removed by dialysis because of high serum protein binding.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Analgesics, calcitonin gene-related peptide (CGRP) antagonists, ATC code: N02CD06

Mechanism of action

Rimegepant selectively binds with high affinity to the human calcitonin gene-related peptide (CGRP) receptor and antagonizes CGRP receptor function.

The relationship between pharmacodynamic activity and the mechanism(s) by which rimegepant exerts its clinical effects is unknown.

Clinical efficacy: acute treatment

The efficacy of VYDURA for the acute treatment of migraine with and without aura in adults was studied in three randomized, double-blind, placebo-controlled trials (Studies 1-3). Patients were instructed to treat a migraine of moderate to severe headache pain intensity. Rescue medicinal products (i.e., NSAIDs, paracetamol, and/or an antiemetic) was allowed 2 hours after the initial treatment. Other forms of rescue medicinal products such as triptans were not allowed within 48 hours of initial treatment. Approximately 14% of patients were taking preventive medicinal products for migraine at baseline. None of the patients in Study 1 were on concomitant preventive medicinal products that act on the calcitonin gene-related peptide pathway.

The primary efficacy analyses were conducted in patients who treated a migraine with moderate to severe pain. Pain freedom was defined as a reduction of moderate or severe headache pain to no headache pain, and most bothersome symptom (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 at 2 hours after a single dose was statistically significantly greater in patients who received VYDURA compared to those who received placebo (Table 2). In addition, statistically significant effects of VYDURA compared to placebo were demonstrated for the additional efficacy endpoints of pain relief at 2 hours, sustained pain freedom from 2 to 48 hours, use of rescue medication within 24 hours, and ability to function normally at 2 hours after dosing. Pain relief was defined as a reduction in migraine pain from moderate or severe severity to mild or none. Pivotal single attack, double-blind, placebo-controlled studies 2 & 3 were conducted in patients with migraine who received one 75 mg rimegepant bioequivalent dosage form.

Table 2: Migraine Efficacy Endpoints for Acute Treatment Studies

Study 1
Study 2
Study 3

VYDURA
75 mg
Placebo
Rimegepant
75 mg
Placebo
Rimegepant
75 mg
Placebo
Pain Free at 2 hours

n/N*
142/669
74/682
105/537
64/535
104/543
77/541
% Responders

Absorption

Following oral administration, rimegepant is absorbed with the maximum concentration at 1.5 hours.
Following a supratherapeutic dose of 300 mg, the absolute oral bioavailability of rimegepant was approximately 64%.

Effects of food
Following administration of rimegepant under fed conditions with a high-fat or low-fat meal, Tmax was delayed by 1 to 1.5 hours. A high-fat meal reduced Cmax by 41 to 53% and AUC by 32 to 38%. A low-fat meal reduced Cmax by 36% and AUC by 28%. Rimegepant was administered without regard to food in clinical safety and efficacy studies.

Distribution

The steady state volume of distribution of rimegepant is 120 l. Plasma protein binding of rimegepant is approximately 96%.

Biotransformation

Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9. Rimegepant is the primary form (~77%) with no major metabolites (i.e., > 10%) detected in plasma.

Based on in vitro studies, rimegepant is not an inhibitor of CYP1A2, 2B6, 2C8, 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.

Elimination

The 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%).

Transporters
In vitro, rimegepant is a substrate of P-gp and BCRP efflux transporters. Inhibitors of P-gp and BCRP efflux transporters may increase plasma concentrations of rimegepant (see section 4.5).

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.