4.1. Therapeutic indications

AQUIPTA is indicated for:

• Acute treatment of migraine with or without aura in adults

• Prophylaxis of migraine in adults who have at least 4 migraine days per month

4.2. Posology and method of administration

Posology

The maximum dose per day for AQUIPTA is 60 mg.

For acute treatment of migraine as needed, the recommended dose for AQUIPTA is 60 mg.

For prophylaxis of migraine, the recommended dose for AQUIPTA is 60 mg taken orally once daily with or without food. A missed dose should be taken right away. If it is almost time for the next dose, patients should be instructed to skip the missed dose and take the next dose as scheduled.

Dose modifications

Dosing modifications for concomitant use of specific drugs are provided in Table 1 (see section 4.5).

Table 1: Dose modifications for drug interactions

Dosage modifications

Recommended once daily dose

Strong CYP3A4 inhibitors

10 mg

Strong OATP inhibitors

10 mg

Special populations

Elderly (≥65 years)

There is limited data available in the elderly with no data available in patients over 80 years of age. Population pharmacokinetic modelling suggests no clinically significant pharmacokinetic differences between elderly and younger subjects. No dose adjustment of AQUIPTA is needed in elderly patients.

Hepatic impairment

Avoid use of AQUIPTA in patients with severe hepatic impairment. No dose adjustment is recommended for patients with mild or moderate hepatic impairment (see section 5.2).

Renal impairment

In patients with severe renal impairment (CLcr 15-29 mL/min), and in patients with end-stage renal disease (ESRD) (CLcr <15 mL/min), the recommended dosage of AQUIPTA is 10 mg once daily. For patients with ESRD undergoing intermittent dialysis, AQUIPTA should preferably be taken after dialysis. No dose adjustment is recommended for patients with mild or moderate renal impairment (see section 5.2).

Paediatric population

The safety and efficacy of atogepant in children have not yet been established. No data are available.

Method of administration

AQUIPTA is to be taken orally once daily with or without food.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.4).

4.4. Special warnings and precautions for use

Hypersensitivity reactions, including anaphylaxis, dyspnoea, rash, pruritus, urticaria, and facial oedema, have been reported with use of AQUIPTA (see section 4.8). Some hypersensitivity reactions can occur days after administration. If a hypersensitivity reaction occurs, discontinue AQUIPTA and institute appropriate therapy (see section 4.3).

Excipients

AQUIPTA 10 mg tablets contain less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

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

CYP3A4 Inhibitors

Co-administration of AQUIPTA with itraconazole, a strong CYP3A4 inhibitor, resulted in a significant increase in exposure of atogepant in healthy subjects. The recommended dosage of AQUIPTA with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, indinavir, nelfinavir, ritonavir, saquinavir) is 10 mg once daily. No dosage adjustment of AQUIPTA is needed with concomitant use of moderate or weak CYP3A4 inhibitors.

OATP Inhibitors

Co-administration of AQUIPTA with single dose rifampicin, an OATP inhibitor, resulted in a significant increase in exposure of atogepant in healthy subjects. The recommended dosage of AQUIPTA with concomitant use of strong OATP inhibitors (e.g., rifampicin, atazanavir, ritonavir, tipranavir, ciclosporin, telmisartan) is 10 mg once daily.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are limited data from the use of atogepant in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). AQUIPTA is not recommended during pregnancy.

Breast-feeding

In a study of 12 breast-feeding women administered a single oral dose of atogepant 60 mg, transfer of atogepant into breast milk was minimal. The relative infant dose was approximately 0.19% of the maternal weight-adjusted dose with a milk-to-plasma ratio of 0.08. The cumulative amount of atogepant excreted in breast milk over 24 hours was minimal, at less than 0.01 mg.

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 (see section 5.3).

4.7. Effects on ability to drive and use machines

AQUIPTA 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.

4.8. Undesirable effects

Summary of the safety profile

The safety of AQUIPTA was evaluated in 3 852 patients with migraine who received at least one dose of AQUIPTA. Of these, 1 225 patients were exposed to AQUIPTA 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, 314 patients received at least one dose of AQUIPTA 10 mg once daily, 411 patients received at least one dose of AQUIPTA 30 mg once daily, 343 patients received at least one dose of AQUIPTA 30 mg twice daily, 678 patients received at least one dose of AQUIPTA 60 mg once daily, 91 patients received at least one dose of AQUIPTA 60 mg twice 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 AQUIPTA 60 mg, and 1 177 patients received placebo; patients received both AQUIPTA and placebo to treat qualifying migraines.

In placebo-controlled prophylaxis studies, the most commonly reported adverse reactions were nausea (7%), constipation (7%), and fatigue/somnolence (5%). The majority of the cases were mild, and none were serious. The adverse reaction that most commonly led to discontinuation for prophylaxis was nausea (0.6%). Nausea (1.3%) was the most commonly reported adverse reaction for acute treatment.

Tabulated list of adverse reactions

Table 2 lists adverse reactions for which a causal relationship between AQUIPTA and the adverse event is at least a reasonable possibility. Given the lower exposure in the setting of acute treatment of migraine, adverse drug reactions may not occur or may not be as frequent as when used for the prophylaxis of migraine.

The adverse reactions are listed below by system organ class and frequency. 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) or very rare (<1/10 000).

Table 2: Adverse drug reactions identified with AQUIPTA*

System Organ Class

Frequency

Adverse Reaction

Immune system disorders

Common

Hypersensitivity (e.g., dyspnoea, rash, pruritus, urticaria, facial oedema)

Rare

Anaphylaxis

Metabolism and nutrition disorders

Common

Decreased appetite

Gastrointestinal disorders

Common

Nausea, constipation

General disorders and administration site conditions

Common

Fatigue/somnolence

Investigations

Common

Weight decreased

Uncommon

ALT/AST increased

* Frequency categories are based on once daily administration. Given the lower exposure in the setting of acute treatment of migraine, adverse drug reactions may not occur or may not be as frequent as when used for the prophylaxis of migraine.

Description of selected adverse reactions

Liver enzyme elevations

In placebo-controlled prophylaxis studies, the rate of transaminase elevations over 3 times the upper limit of normal was similar between patients treated with AQUIPTA (0.9%) and those treated with placebo (1.2%). In the placebo-controlled period of the study for acute treatment of migraine, transaminase elevations over 3 times the upper limit of normal were not seen in patients treated with AQUIPTA, though cases with a possible relationship to AQUIPTA were seen in the open-label period. There were cases with transaminase elevations over 3 times the upper limit of normal that were temporally associated with AQUIPTA treatment; these were asymptomatic and resolved within 8 weeks of discontinuation. There were no cases of severe liver injury or jaundice in these clinical studies.

Changes in body weight

In placebo-controlled prophylaxis studies, the proportion of patients with a weight decrease of at least 7% at any point was 2.5% for placebo, 3.8% for AQUIPTA 10 mg once daily, 3.2% for AQUIPTA 30 mg once daily, 5.3% for AQUIPTA 30 mg twice daily, 5.3% for AQUIPTA 60 mg once daily, and 6.8% for AQUIPTA 60 mg twice daily.

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

4.9. Overdose

There is no known antidote for AQUIPTA. Treatment of an overdose of AQUIPTA should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.