4.1. Therapeutic indications

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.

4.2. Posology and method of administration

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.

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.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Hypersensitivity reactions, including dyspnoea and rash, have occurred in less than 1% of patients treated with rimegepant in clinical studies (see section 4.8). Hypersensitivity reactions, including serious hypersensitivity such as anaphylactic reaction, have been reported in the clinical and post‑marketing settings (see section 4.8). Some hypersensitivity reactions can occur days after administration. If a hypersensitivity reaction occurs, rimegepant should be discontinued and appropriate 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 is experienced 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.

4.5. Interaction with other medicinal products and other forms of interaction

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).

4.6. Fertility, pregnancy and lactation

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)

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The most common adverse reaction was nausea for acute treatment (1.2%) and for migraine prophylaxis (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.

Tabulated list of adverse reactions

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

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 treatment.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.