Atogepant

Organic anion transporting polypeptide (OATP) inhibitors (e.g., rifampicin, ciclosporin, ritonavir) can significantly increase systemic exposure to atogepant. Co-administration of atogepant with single dose rifampicin resulted in increased exposure (C_max by 2.23-fold and AUC by 2.85-fold) of atogepant in healthy subjects.

Dose modification to 10 mg once daily is recommended.

Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir) can significantly increase systemic exposure to atogepant. Co-administration of atogepant with itraconazole resulted in increased exposure (C_max by 2.15-fold and AUC by 5.5-fold) of atogepant in healthy subjects.

Dose modification to 10 mg once daily is recommended.

In patients with severe renal impairment (creatinine clearance [CLcr] 15-29 mL/min), and in patients with end-stage renal disease (ESRD) (CLcr <15 mL/min), the recommended dose is 10 mg once daily. For patients with ESRD undergoing intermittent dialysis, atogepant should preferably be taken after dialysis.

There are limited data from the use of atogepant in pregnant women. Studies in animals have shown reproductive toxicity. Atogepant is not recommended during pregnancy and in women of childbearing potential not using contraception.

Pharmacokinetic data after single-dose administration showed minimal transfer of atogepant into breast milk.

There are no data on the effects of atogepant on the breastfed infant or the effects of atogepant on milk production.

The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for atogepant and any potential adverse effects on the breastfed infant from atogepant or from the underlying maternal condition.

Fertility

No human data on the effect of atogepant on fertility are available. Animal studies showed no impact on female and male fertility with atogepant treatment.

Atogepant has no or negligible influence on the ability to drive and use machines. However, it may cause somnolence in some patients. Patients should exercise caution before driving or using machinery until they are reasonably certain that atogepant does not adversely affect performance.

Summary of the safety profile

Safety was evaluated in 3 852 patients with migraine who received at least one dose of atogepant in clinical studies. Of these, 1 225 patients were exposed to atogepant for prophylaxis daily for at least 6 months and 826 patients were exposed for 12 months. 895 patients were exposed during 24 weeks on an as-needed basis for treatment of acute migraine attacks.

In 12-week, placebo-controlled prophylaxis clinical studies, 678 patients received at least one dose of atogepant 60 mg once daily, and 663 patients received placebo. In the placebo-controlled clinical study for acute treatment of migraine, 1 195 patients received at least one dose of atogepant 60 mg, and 1 177 patients received placebo; patients received both atogepant and placebo to treat qualifying migraines.

In placebo-controlled prophylaxis studies, the most commonly reported adverse reactions were nausea (9%), constipation (8%), and fatigue/somnolence (5%). Most of the reactions were mild or moderate in severity. The adverse reaction that most commonly led to discontinuation for prophylaxis was nausea (0.4%). Nausea (1.3%) was the most commonly reported adverse reaction for acute treatment.

Tabulated list of adverse reactions

Adverse reactions reported in clinical trials and from post-marketing experience are listed below by system organ class and frequency, most frequent reactions first. Frequencies are defined as follows: 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), or not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Adverse reactions identified with atogepant:

^* Defined in clinical trials as weight decrease of at least 7% at any point.
^** Cases of ALT/AST elevations (defined as ≥3 × upper limit of normal) temporally associated with atogepant were observed in clinical trials, including cases with a potential positive dechallenge history that resolved within 8 weeks of discontinuation. However, the overall frequency of liver enzyme elevations was similar in the atogepant and placebo groups.