VYDURA 75mg oral lyophilisate medication leaflet

VYDURA 75 mg oral lyophilisate

Each oral lyophilisate contains rimegepant sulfate, equivalent to 75 mg rimegepant.

For the full list of excipients, see section 6.1.

Oral lyophilisate

The oral lyophilisate is white to off-white, circular, diameter 14 mm and debossed with the symbol .

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 permonth.

The recommended dose is 75 mg rimegepant, as needed, once daily.

The recommended dose is 75 mg rimegepant every other day.

The maximum dose per day is 75 mg rimegepant.

VYDURA can be taken with or without meals.

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

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

No dose adjustment is required in patients with mild, moderate, or severe renal impairment. Severerenal 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 renalimpairment. Rimegepant has not been studied in patients with end-stage renal disease and in patientson dialysis. Use of rimegepant in patients with end-stage renal disease (CLcr < 15 ml/min) should beavoided.

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 insubjects with severe (Child-Pugh C) hepatic impairment (see section 5.2). The use of rimegepant inpatients with severe hepatic impairment should be avoided.

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

VYDURA is for oral use.

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

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

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

Hypersensitivity reactions, including dyspnoea and rash, have occurred in less than 1% of patientstreated with rimegepant in clinical studies (see section 4.8). Hypersensitivity reactions, includingserious hypersensitivity such as anaphylactic reaction, have been reported in the clinical andpost-marketing settings (see section 4.8). Some hypersensitivity reactions can occur days afteradministration. If a hypersensitivity reaction occurs, rimegepant should be discontinued andappropriate therapy should be initiated.

VYDURA is not recommended:

- in patients with severe hepatic impairment (see section 4.2);

- in patients with end-stage renal disease (CLcr < 15 ml/min) (see section 4.2);

- for concomitant use with strong inhibitors of CYP3A4 (see section 4.5);

- for concomitant use with strong or moderate inducers of CYP3A4 (see section 4.5).

Medication overuse headache (MOH)

Overuse of any type of medicinal products for headaches can make them worse. If this situation isexperienced or suspected, medical advice should be obtained, and treatment should be discontinued.

The diagnosis of MOH should be suspected in patients who have frequent or daily headaches despite(or because of) the regular use of medicinal products for acute headache.

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

Inhibitors of CYP3A4 increase plasma concentrations of rimegepant. Concomitant administration ofrimegepant with strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ritonavir) is notrecommended (see section 4.4). Concomitant administration of rimegepant with itraconazole resultedin 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. Concomitantadministration of rimegepant with fluconazole resulted in increased exposures of rimegepant (AUC by1.8-fold) with no relevant effect on Cmax. Another dose of rimegepant within 48 hours should beavoided when it is concomitantly administered with moderate inhibitors of CYP3A4 (e.g.,fluconazole) (see section 4.2).

Inducers of CYP3A4 decrease plasma concentrations of rimegepant. Concomitant administration of

VYDURA with strong CYP3A4 inducers (e.g., phenobarbital, rifampicin, St John’s wort (Hypericumperforatum)) 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 ofthe strong or moderate CYP3A4 inducer. Concomitant administration of rimegepant with rifampicinresulted in a significant decrease (AUC reduced by 80% and Cmax by 64%) in rimegepant exposure,which may lead to loss of efficacy.

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 administeredwith strong inhibitors of P-gp (e.g., cyclosporine, verapamil, quinidine) (see section 4.2). Concomitantadministration 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 rimegepantexposure (AUC and Cmax by > 50%, but less than two-fold).

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

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 amaternal dose estimated to reach the infant is less than 1%. There are no data on the effects on milkproduction. The developmental and health benefits of breast-feeding should be considered along withthe mother’s clinical need for VYDURA and any potential adverse reactions on the breastfed infantfrom rimegepant or from the underlying maternal condition.

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.

The most common adverse reaction was nausea for acute treatment (1.2%) and for migraineprophylaxis (1.4%). Most of the reactions were mild or moderate in severity. Hypersensitivity,including dyspnoea and severe rash, occurred in less than 1% of patients treated.

Adverse reactions are listed by MedDRA system organ class in Table 1. The corresponding frequencycategory 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 Uncommon

Hypersensitivity, including dyspnoea and severe Uncommonrash

Gastrointestinal disorders Nausea Common

Immune system disorders Anaphylactic reactiona Not known

Hypersensitivitya Not known

Gastrointestinal disorders Nausea Commona Adverse Drug Reactions (ADR) identified post-marketing.

Long-term safety of rimegepant was assessed in two one year, open-label extensions; 1662 patientsreceived rimegepant for at least 6 months and 740 received rimegepant for 12 months for acute orprophylactic treatment.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is limited clinical experience with rimegepant overdose. No overdose symptoms have beenreported. Treatment of an overdose of rimegepant should consist of general supportive measuresincluding monitoring of vital signs and observation of the clinical status of the patient. No specificantidote for the treatment of rimegepant overdose is available. Rimegepant is unlikely to besignificantly removed by dialysis because of high serum protein binding.

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

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 rimegepantexerts its clinical effects is unknown.

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

The primary efficacy analyses were conducted in patients who treated a migraine with moderate tosevere pain. Pain freedom was defined as a reduction of moderate or severe headache pain to noheadache pain, and most bothersome symptom (MBS) freedom was defined as the absence of theself-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%), andphonophobia (15%).

In Study 1, the percentage of patients achieving headache pain freedom and MBS freedom at 2 hoursafter a single dose was statistically significantly greater in patients who received VYDURA comparedto those who received placebo (Table 2). In addition, statistically significant effects of VYDURAcompared 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 tofunction normally at 2 hours after dosing. Pain relief was defined as a reduction in migraine pain frommoderate or severe severity to mild or none. Pivotal single attack, double-blind, placebo-controlledstudies 2 & 3 were conducted in patients with migraine who received one 75 mg rimegepantbioequivalent dosage form.

Table 2: Migraine Efficacy Endpoints for Acute Treatment Studies

Study 1 Study 2 Study 3

VYDURA Placebo Rimegepant Placebo Rimegepant Placebo75 mg 75 mg 75 mg

Pain Free at 2 hoursn/N* 142/669 74/682 105/537 64/535 104/543 77/541% Responders 21.2 10.9 19.6 12.0 19.2 14.2

Difference compared to 10.3 7.6 4.9placebo (%)p-value <0.0001 a 0.0006a 0.0298 a

MBS Free at 2 hoursn/N* 235/669 183/682 202/537 135/535 199/543 150/541% Responders 35.1 26.8 37.6 25.2 36.6 27.7

Difference compared to 8.3 12.4 8.9placebo (%)p-value 0.0009 a <0.0001 a 0.0016 a

Pain Relief at 2 hoursn/N* 397/669 295/682 312/537 229/535 304/543 247/541% Responders 59.3 43.3 58.1 42.8 56.0 45.7

Difference compared to 16.1 15.3 10.3placebop-value <0.0001a <0.0001a 0.0006a

Sustained Pain

Freedom 2 to 48 hoursn/N* 90/669 37/682 53/537 32/535 63/543 39/541% Responders 13.5 5.4 9.9 6.0 11.6 7.2

Difference compared to 8.0 3.9 4.4placebo (%)p-value <0.0001a 0.0181b 0.0130b

*n=number of responders/N=number of patients in that treatment groupa Significant p-value in hierarchical testingb Nominal p-value in hierarchical testing

MBS: most bothersome symptom

Figure 1 presents the percentage of patients achieving migraine pain freedom within 2 hours followingtreatment 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.

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 withoutaura). Patients had a history of 4 to 18 migraine attacks of moderate to severe pain intensity per4-week period within the 12 weeks prior to the screening visit. Patients experienced an average of10.9 headache days during the 28-day observational period, which included an average of 10.2migraine days, prior to randomization into the study. The study randomized patients to receiverimegepant 75 mg (N=373) or placebo (N=374) for up to 12 weeks. Patients were instructed to takerandomized treatment once every other day (EOD) for the 12-week treatment period. Patients wereallowed 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 atbaseline. Patients were allowed to continue in an open-label extension study for an additional12 months.

The primary efficacy endpoint for Study 4 was the change from baseline in the mean number ofmonthly 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 monthlymoderate or severe migraine days.

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

Table 3: Key Efficacy Endpoints for Study 4

Rimegepant Placebo75 mg EOD EOD

Monthly Migraine Days (MMD) Weeks 9 through 12 N=348 N=347

Change from baseline -4.3 -3.5

Change compared to placebo -0.8p-value 0.010a≥ 50% Reduction in Moderate or Severe MMDs N=348 N=347

Weeks 9 through 12% Responders 49.1 41.5

Difference compared to placebo 7.6p-value 0.044aa Significant p-value in hierarchical testing

Figure 3: Change from Baseline in Monthly Migraine Days in Study 4

Patients participating in Study 4 were allowed to continue in an open-label extension study for anadditional 12 months. Efficacy was sustained for up to 1 year in an open-label study extension inwhich patients received rimegepant 75 mg every other day plus as needed on non-scheduled dosingdays (Figure 4). A portion composed of 203 patients assigned to rimegepant completed the overall16-month treatment period. In these patients, the overall mean reduction from baseline in the numberof MMDs averaged over the 16-month treatment period was 6.2 days.

Figure 4: Longitudinal Plot of the Change in Mean Number of Monthly Migraine Days (MMDs)from the Observation Period Over Time during Double-Blind Treatment (Months 1 to 3) andduring Treatment with Open-label Rimegepant (Months 4 to 16)

The European Medicines Agency has waived the obligation to submit the results of studies with

VYDURA in all subsets of the paediatric population in the prophylactic treatment of migraineheadaches (see section 4.2 for information on paediatric use).

The European Medicines Agency has deferred the obligation to submit the results of studies with

VYDURA in one or more subsets of the paediatric population in the acute treatment of migraine (seesection 4.2 for information on paediatric use).

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 wasapproximately 64%.

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

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

Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9. Rimegepant isthe 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 CYP3A4with time-dependent inhibition. Rimegepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 atclinically relevant concentrations.

The elimination half-life of rimegepant is approximately 11 hours in healthy subjects. Following oraladministration of [14C]-rimegepant to healthy male subjects, 78% of the total radioactivity wasrecovered in feces and 24% in urine. Unchanged rimegepant is the major single component in excretedfeces (42%) and urine (51%).

In vitro, rimegepant is a substrate of P-gp and BCRP efflux transporters. Inhibitors of P-gp and BCRPefflux 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.

Rimegepant is not an inhibitor of P-gp, BCRP, OAT1, or MATE2-K at clinically relevantconcentrations. It is a weak inhibitor of OATP1B1 and OAT3.

Rimegepant is an inhibitor of OATP1B3, OCT2, and MATE1. Concomitant administration ofrimegepant with metformin, a MATE1 transporter substrate, resulted in no clinically significantimpact on either metformin pharmacokinetics or on glucose utilization. No clinical drug interactionsare expected for rimegepant with OATP1B3 or OCT2, at clinically relevant concentrations.

Rimegepant exhibits greater than dose proportional increases in exposure following single oraladministration, which appears to be related to a dose-dependant increase in bioavailability.

No clinically significant differences in the pharmacokinetics of rimegepant were observed based onage, sex, race/ethnicity, body weight, migraine status, or CYP2C9 genotype.

In a 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 pooled control), a lessthan 50% increase in total rimegepant exposure was observed following a single 75 mg dose. Theunbound AUC of rimegepant was 2.57-fold higher in subjects with severe renal impairment.

VYDURA has not been studied in patients with end-stage renal disease (CLcr < 15 ml/min).

In a 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), theexposure of rimegepant (unbound AUC) following a single 75 mg dose was 3.89-fold higher insubjects with severe impairment (Child-Pugh class C). There were no clinically meaningfuldifferences in the exposure of rimegepant in subjects with mild (Child-Pugh class A) and moderatehepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function.

Non-clinical data reveal no special hazard for rimegepant in humans based on conventional studies ofsafety pharmacology, repeat-dose toxicity, genotoxicity, phototoxicity, reproduction or development,or carcinogenic potential.

Rimegepant-related effects at higher doses in repeat-dose studies included hepatic lipidosis in miceand rats, intravascular hemolysis in rats and monkeys, and emesis in monkeys. These findings wereobserved only at exposures considered sufficiently in excess of the maximum human exposureindicating little relevance to clinical use (≥ 12 times [mice] and ≥ 49 times [rats] for hepatic lipidosis,≥ 95 times [rats] and ≥ 9 times [monkeys] for intravascular hemolysis, and ≥ 37 times for emesis[monkeys]).

In a fertility study in rats, rimegepant-related effects were noted only at the high dose of150 mg/kg/day (decreased fertility and increased pre-implantation loss) that produced maternaltoxicity and systemic exposures ≥ 95 times the maximum human exposure. Oral administration ofrimegepant during organogenesis resulted in foetal effects in rats but not rabbits. In rats, decreasedfoetal body weight and increased incidence of foetal variations were observed only at the highest doseof 300 mg/kg/day that produced maternal toxicity at exposures approximately 200 times the maximumhuman exposure. Additionally, rimegepant had no effects on pre- and postnatal development in rats atdoses up to 60 mg/kg/day (≥ 24 times the maximum human exposure) or on growth, development, orreproductive performance of juvenile rats at doses up to 45 mg/kg/day (≥ 14 times the maximumhuman exposure).

gelatinmannitol (E421)mint flavoursucralose

Not applicable.

4 years

Do not store above 30 °C.

Store in the original package in order to protect from moisture.

Unit dose blisters made of polyvinyl chloride (PVC), oriented polyamide (OPA) and aluminium foiland sealed with a peelable aluminum foil.

Unit dose 2 x 1 oral lyophilisates.

Unit dose 8 x 1 oral lyophilisates.

Unit dose 16 x 1 oral lyophilisates.

Not all pack sizes may be marketed.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/22/1645/001

EU/1/22/1645/002

EU/1/22/1645/003

Date of first authorisation: 25 April 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.