Rimegepant

Inhibitors of CYP3A4 increase plasma concentrations of rimegepant. Concomitant administration of rimegepant with strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ritonavir) is not recommended. Concomitant administration of rimegepant with itraconazole resulted in a significant increase in rimegepant exposure (AUC by 4-fold and C_max 1.5-fold).

Inducers of CYP3A4 decrease plasma concentrations of rimegepant. Concomitant administration of rimegepant 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. Concomitant administration of rimegepant with rifampicin resulted in a significant decrease (AUC reduced by 80% and C_max by 64%) in rimegepant exposure, which may lead to loss of efficacy.

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.

Plasma concentrations (unbound AUC) of rimegepant were significantly higher in subjects with severe (Child-Pugh C) hepatic impairment. The use of rimegepant in patients with severe hepatic impairment should be avoided.

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. As a precautionary measure, it is preferable to avoid the use of rimegepant 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 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 rimegepant 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.

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

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 the following table. 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).

List of adverse reactions:

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.