AQUIPTA 10mg tablets medication leaflet

AQUIPTA 10 mg tablets

AQUIPTA 60 mg tablets

AQUIPTA 10 mg tablets

Each tablet contains 10 mg of atogepant.

AQUIPTA 60 mg tablets

Each tablet contains 60 mg of atogepant.

Each 60 mg tablet contains 31.5 mg sodium.

For the full list of excipients, see section 6.1.

Tablet

AQUIPTA 10 mg tablets

White to off-white, round biconvex tablet, diameter 6 mm, and debossed with “A” and “10” on oneside.

AQUIPTA 60 mg tablets

White to off-white, oval biconvex tablet, 16 mm x 9 mm, and debossed with “A60” on one side.

AQUIPTA is indicated for prophylaxis of migraine in adults who have at least 4 migraine days permonth.

The recommended dose is 60 mg atogepant once daily.

The tablets can be taken with or without meals.

A missed dose should be taken as soon as it is remembered. If it is forgotten for an entire day, themissed dose should be skipped and the next dose taken as scheduled.

Dosing modifications for concomitant use of specific medicinal products are provided in Table 1 (seesection 4.5).

Table 1: Dose modifications for interactions

Recommended

Dose modificationsonce daily dose

Strong CYP3A4 inhibitors 10 mg

Strong OATP inhibitors 10 mg

Population pharmacokinetic modelling suggests no clinically significant pharmacokinetic differencesbetween elderly and younger subjects. No dose adjustment is needed in elderly patients.

No dose adjustment is recommended for patients with mild or moderate renal impairment (seesection 5.2). In patients with severe renal impairment (creatinine clearance [CLcr] 15-29 mL/min), andin patients with end-stage renal disease (ESRD) (CLcr < 15 mL/min), the recommended dose is 10 mgonce daily. For patients with ESRD undergoing intermittent dialysis, AQUIPTA should preferably betaken after dialysis.

No dose adjustment is recommended for patients with mild or moderate hepatic impairment (seesection 5.2). Atogepant should be avoided in patients with severe hepatic impairment.

The safety and efficacy of atogepant in children (< 18 years of age) have not yet been established. Nodata are available.

AQUIPTA is for oral use. Tablets should be swallowed whole and should not be split, crushed, orchewed.

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

Serious hypersensitivity reactions

Serious hypersensitivity reactions, including anaphylaxis, dyspnoea, rash, pruritus, urticaria, and facialoedema, have been reported with use of AQUIPTA (see section 4.8). Most serious reactions haveoccurred within 24 hours of first use, however, some hypersensitivity reactions can occur days afteradministration. Patients should be warned about the symptoms associated with hypersensitivity. If ahypersensitivity reaction occurs, discontinue AQUIPTA and institute appropriate therapy.

Atogepant is not recommended in patients with severe hepatic impairment (see section 4.2).

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

AQUIPTA 60 mg tablets contain 31.5 mg sodium per tablet, equivalent to 1.6% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir) cansignificantly increase systemic exposure to atogepant. Co-administration of atogepant withitraconazole resulted in increased exposure (Cmax by 2.15-fold and AUC by 5.5-fold) of atogepant inhealthy subjects (see section 4.2). Changes in atogepant exposure when co-administered with weak ormoderate CYP3A4 inhibitors are not expected to be clinically significant.

Transporter inhibitors

Organic anion transporting polypeptide (OATP) inhibitors (e.g., rifampicin, ciclosporin, ritonavir) cansignificantly increase systemic exposure to atogepant. Co-administration of atogepant with single doserifampicin resulted in increased exposure (Cmax by 2.23-fold and AUC by 2.85-fold) of atogepant inhealthy subjects (see section 4.2).

Frequently co-administered medicinal products

Co-administration of atogepant with oral contraceptive components ethinyl estradiol andlevonorgestrel, paracetamol, naproxen, sumatriptan, or ubrogepant did not result in significantpharmacokinetic interactions for either atogepant or co-administered medicinal products. Co-administration with famotidine or esomeprazole did not result in clinically relevant changes ofatogepant exposure.

There are limited data from the use of atogepant in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). Atogepant is not recommended during pregnancy and inwomen of childbearing potential not using contraception.

Pharmacokinetic data after single-dose administration showed minimal transfer of atogepant intobreast milk (see section 5.2).

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

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

No human data on the effect of atogepant on fertility are available. Animal studies showed no impacton female and male fertility with atogepant treatment (see section 5.3).

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

Safety was evaluated in 2 657 patients with migraine who received at least one dose of atogepant inclinical studies. Of these, 1 225 patients were exposed to atogepant for at least 6 months and826 patients were exposed for 12 months.

In 12-week, placebo-controlled clinical studies, 678 patients received at least one dose of atogepant60 mg once daily, and 663 patients received placebo.

The most commonly reported adverse drug reactions were nausea (9%), constipation (8%), andfatigue/somnolence (5%). Most of the reactions were mild or moderate in severity. The adversereaction that most commonly led to discontinuation was nausea (0.4%).

Adverse reactions reported in clinical trials and from post-marketing experience are listed below bysystem 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 theavailable data). Within each frequency grouping, adverse reactions are presented in the order ofdecreasing seriousness.

Table 2. Adverse reactions identified with atogepant

System organ class Frequency Adverse reaction

Immune system disorders Not known Hypersensitivity (e.g., anaphylaxis,dyspnoea, rash, pruritus, urticaria, facialoedema)

Metabolism and nutrition disorders Common Decreased appetite

Gastrointestinal disorders Common Nausea,

General disorders and administration Common Fatigue/somnolencesite conditions

Investigations Common Weight decreased*

Uncommon ALT/AST increased**

* 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 atogepantwere observed in clinical trials, including cases with a potential positive dechallenge history that resolved within8 weeks of discontinuation. However, the overall frequency of liver enzyme elevations was similar in theatogepant and placebo groups.

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.

In clinical studies, atogepant was administered as single doses up to 300 mg and as multiple doses upto 170 mg once daily. Adverse reactions were comparable to those seen at lower doses, and no specifictoxicities were identified. There is no known antidote for atogepant. Treatment of an overdose shouldconsist of general supportive measures including monitoring of vital signs and observation of theclinical status of the patient.

Pharmacotherapeutic group: Analgesics, calcitonin gene-related peptide (CGRP) antagonists, ATCcode: N02CD07

Non-clinical receptor binding studies and in vitro functional studies point to an involvement of morethan one receptor type in the pharmacological effects of atogepant. Atogepant shows affinity to severalreceptors of the calcitonin/CGRP-receptor family. In view of the clinically relevant free plasmaconcentrations of atogepant (Cmax > 20 nM for a 60 mg dose) and the fact that CGRP and amylin-1receptors are considered to be involved in the pathophysiology of migraine, inhibitory effects ofatogepant at these receptors (Ki-value 26 pM and 2.4 nM, respectively) could be of clinical relevance.

However, the precise mechanism of action of atogepant in the prophylaxis of migraine remains to beestablished.

Atogepant was evaluated for the prophylaxis of migraine in two pivotal studies across the migrainespectrum in chronic and episodic migraine. The episodic migraine study (ADVANCE) enrolledpatients who met International Classification of Headache Disorders (ICHD) criteria for a diagnosis ofmigraine with or without aura. The chronic migraine study (PROGRESS) enrolled patients who alsomet ICHD criteria for chronic migraine. Both studies excluded patients with myocardial infarction,stroke, or transient ischemic attacks within six months prior to screening.

Episodic migraine

Atogepant was evaluated for the prophylaxis of episodic migraine (4 to 14 migraine days per month)in a randomised, multicentre, double-blind, placebo-controlled study (ADVANCE). Patients wererandomised to AQUIPTA 60 mg (N = 235) or placebo (N = 223) once daily for 12 weeks. Patientswere allowed to use acute headache treatments (i.e., triptans, ergotamine derivatives, NSAIDs,paracetamol and opioids) as needed. The use of a concomitant medicinal product that acts on the

CGRP pathway was not permitted for either acute or preventive treatment of migraine.

A total of 88% patients completed the 12-week double-blind study period. Patients had a mean age of42 years (range: 18 to 73 years), 4% were 65 years or older, 89% were female, and 83% were white.

The mean migraine frequency at baseline was approximately 8 migraine days per month and wassimilar across treatment groups.

The primary efficacy endpoint was the change from baseline in mean monthly migraine days (MMD)across the 12-week treatment period. Secondary endpoints controlled for multiplicity included thechange from baseline in mean monthly headache days, the change from baseline in mean monthlyacute medication use days, the proportion of patients achieving at least a 50% reduction from baselinein mean MMD (3 month average), and several patient-reported outcome measures assessingfunctioning. Statistically significant findings were demonstrated for AQUIPTA versus placebo for theprimary and secondary efficacy endpoints in ADVANCE, as summarized in Table 3.

Table 3: Efficacy endpoints in ADVANCE

AQUIPTA 60 mg Placebo

N=226 N=216

Monthly migraine days (MMD) across 12 weeks

Baseline 7.8 7.5

Mean change from baseline -4.1 -2.5

Difference from placebo -1.7p-value <0.001

Monthly headache days across 12 weeks

Baseline 9.0 8.5

Mean change from baseline -4.2 -2.5

Difference from placebo -1.7p-value <0.001

Monthly acute medication use days across 12 weeks

Baseline 6.9 6.5

Mean change from baseline -3.8 -2.3

Difference from placebo -1.4p-value <0.001≥ 50% MMD responders across 12 weeks% Responders 59 29

Odds ratio (95% CI) 3.55 (2.39, pct. 5.28)p-value <0.001

Figure 1 shows the mean change from baseline in MMD in ADVANCE. Patients treated with

AQUIPTA 60 mg once daily had greater mean decreases from baseline in MMD across the 12-weektreatment period compared to patients who received placebo. AQUIPTA 60 mg once daily resulted insignificant decreases from baseline in mean monthly migraine days within the first 4-week intervalcompared to placebo-treated patients.

Figure 1: Change from baseline in monthly migraine days in ADVANCE0.0

Baseline Weeks 1-4 Weeks 5-8 Weeks 9-12

- 0- Placebo AQUIPTA 60 mg once daily

Efficacy was sustained for up to one year in an open-label study in which 546 patients with episodicmigraine were randomised to receive AQUIPTA 60 mg once daily. 68% (373/546) of patientscompleted the treatment period. The reduction in the least-squares mean number of monthly migrainedays in the first month (weeks 1-4) was -3.8 days and improved to a least-squares mean reduction of -5.2 days in the last month (weeks 49-52). Approximately 84%, 70%, and 48% of patients reported≥ 50%, ≥ 75%, and 100% reduction in monthly migraine days at weeks 49-52, respectively.

Patients with previous failure to 2 to 4 classes of oral prophylactic treatments

In the ELEVATE study, 315 adult patients with episodic migraine who previously failed 2 to 4 classesof oral prophylactic treatments (e.g., topiramate, tricyclic antidepressants, beta-blockers) based onefficacy and/or tolerability were randomised 1:1 to receive either atogepant 60 mg (N = 157) orplacebo (N = 158) for 12 weeks. Results in this study were consistent with the main findings ofprevious episodic migraine efficacy studies and statistically significant for primary and secondaryefficacy endpoints including several patient-reported outcome measures assessing functioning.

Atogepant treatment led to a reduction of 4.2 days in mean MMD compared to 1.9 days in the placebogroup (p<0.001). 50.6% (78/154) of patients in the atogepant group achieved at least a 50% reductionfrom baseline in MMD compared to 18.1% (28/155) in the placebo group (odds ratio [95% CI]: 4.82[2.85, 8.14], p<0.001).

Chronic migraine

Atogepant was evaluated for the prophylaxis of chronic migraine (15 or more headache days permonth with at least 8 migraine days) in a randomised, multicentre, double-blind, placebo-controlledstudy (PROGRESS). Patients were randomised to AQUIPTA 60 mg (N = 262) or placebo (N = 259)once daily for 12 weeks. A subset of patients (11%) was allowed to use one concomitant migraineprophylaxis medicinal product (e.g., amitriptyline, propranolol, topiramate). Patients were allowed touse acute headache treatments (i.e., triptans, ergotamine derivatives, NSAIDs, paracetamol andopioids) as needed. Patients with acute medication overuse and medication overuse headache alsowere enrolled. The use of a concomitant medicinal product that acts on the CGRP pathway was notpermitted for either acute or preventive treatment of migraine.

Change from baseline in monthly migraine days(least-square mean ± standard error)

A total of 463 (89%) patients completed the 12-week double-blind study. Patients had a mean age of42 years (range: 18 to 74 years), 3% were 65 years or older, 87% were female, and 59% were white.

The mean migraine frequency at baseline was approximately 19 migraine days per month and wassimilar across treatment groups.

The primary efficacy endpoint was the change from baseline in mean MMD across the 12-weektreatment period. Secondary endpoints controlled for multiplicity included the change from baseline inmean monthly headache days, the change from baseline in mean monthly acute medication use days,the proportion of patients achieving at least a 50% reduction from baseline in mean MMD (3-monthaverage), and several patient-reported outcome measures assessing functioning. Statisticallysignificant findings were demonstrated for AQUIPTA versus placebo for the primary and secondaryefficacy endpoints for PROGRESS, as summarized in Table 4.

Table 4: Efficacy endpoints in PROGRESS

AQUIPTA 60 mg Placebo

N=257 N=249

Monthly migraine days (MMD) across 12 weeks

Baseline 19.2 19.0

Mean change from baseline -6.8 -5.1

Difference from placebo -1.7p-value 0.002

Monthly headache days across 12 weeks

Baseline 21.5 21.4

Mean change from baseline -6.9 -5.2

Difference from placebo -1.7p-value 0.002

Monthly acute medication use days across 12 weeks

Baseline 15.5 15.3

Mean change from baseline -6.2 -4.1

Difference from placebo -2.1p-value 0.002≥ 50% MMD responders across 12 weeks% Responders 40 27

Odds ratio (95% CI) 1.90 (1.29, 2.79)p-value 0.002

Figure 2 shows the mean change from baseline in MMD in PROGRESS. Patients treated with

AQUIPTA 60 mg once daily had a greater mean decrease from baseline in MMD across the 12-weektreatment period compared to patients who received placebo.

Figure 2: C hange from baseline in monthly migraine days in PROGRESSh

- 0.5.25

- SO

- SS

- CS

Baseline Weeks 1-4 Weeks 5-8 Weeks 9-12

Placebo AQUIPTA 60 mg once daily

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

AQUIPTA in one or more subsets of the paediatric population in prophylaxis of migraine headaches(see section 4.2 for information on paediatric use).

Following oral administration, atogepant is absorbed with peak plasma concentrations atapproximately 1 to 2 hours. Following once daily dosing, atogepant displays dose-proportionalpharmacokinetics up to 170 mg (approximately 3 times the highest recommended dose), with noaccumulation.

When atogepant was administered with a high-fat meal, AUC and Cmax were reduced byapproximately 18% and 22%, respectively, with no effect on median time to maximum atogepantplasma concentration. Atogepant was administered without regard to food in clinical efficacy studies.

Plasma protein binding of atogepant was not concentration-dependent in the range of 0.1 to 10 µM;the unbound fraction of atogepant was approximately 4.7% in human plasma. The mean apparentvolume of distribution of atogepant (Vz/F) after oral administration is approximately 292 L.

Atogepant is eliminated mainly through metabolism, primarily by CYP3A4. The parent compound(atogepant), and a glucuronide conjugate metabolite (M23) were the most prevalent circulatingcomponents in human plasma.

Change from baseline in monthly migraine days(least-square mean ± standard error)

Co-administration of atogepant with steady state rifampicin, a strong CYP3A4 inducer, resulted in asignificant decrease in exposure (Cmax by 30% and AUC by 60%) of atogepant in healthy subjects.

Co-administration of atogepant with steady-state topiramate, a mild CYP3A4 inducer, resulted in adecrease in exposure (Cmax by 24% and AUC by 25%) of atogepant.

In vitro, atogepant is not an inhibitor for CYP3A4, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, MAO-A, or

UGT1A1 at clinically relevant concentrations. Atogepant also is not an inducer of CYP1A2, CYP2B6,or CYP3A4 at clinically relevant concentrations.

The elimination half-life of atogepant is approximately 11 hours. The mean apparent oral clearance(CL/F) of atogepant is approximately 19 L/h. Following single oral dose of 50 mg 14C-atogepant tohealthy male subjects, 42% and 5% of the dose was recovered as unchanged atogepant in faeces andurine, respectively.

Atogepant is a substrate of P-gp, BCRP, OATP1B1, OATP1B3, and OAT1. Dose adjustment forconcomitant use with strong inhibitors of OATP is recommended based on a clinical interaction studywith a strong OATP inhibitor. Atogepant is not a substrate of OAT3, OCT2, or MATE1.

Atogepant is not an inhibitor of P-gp, BCRP, OAT1, OAT3, NTCP, BSEP, MRP3, or MRP4 atclinically relevant concentrations. Atogepant is a weak inhibitor of OATP1B1, OATP1B3, OCT1, and

MATE1, but no clinically relevant interactions are expected.

The renal route of elimination plays a minor role in the clearance of atogepant. Based on populationpharmacokinetic analysis, there is no significant difference in the pharmacokinetics of atogepant inpatients with mild or moderate renal impairment (CLcr 30-89 mL/min) relative to those with normalrenal function (CLcr  90 mL/min). As patients with severe renal impairment or end-stage renaldisease (ESRD; CLcr < 30 mL/min) have not been studied, use of atogepant 10 mg is recommended inthose patients.

In patients with pre-existing mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severehepatic impairment (Child-Pugh Class C), total atogepant exposure was increased by 24%, 15% and38%, respectively. However, unbound atogepant exposure was approximately 3-fold higher in patientswith severe hepatic impairment. The use of AQUIPTA in patients with severe hepatic impairmentshould be avoided.

Transfer into breast milk

In a study of 12 healthy lactating women administered a single oral dose of atogepant 60 mg between1 to 6 months postpartum, peak levels of atogepant in breast milk occurred between 1 to 3 hours afteradministration. The Cmax and AUC of atogepant in breast milk were significantly lower byapproximately 93% compared to women’s plasma. The mean relative infant dose was approximately0.19% (range 0.06 to 0.33%) of the maternal weight-adjusted dose with a mean milk-to-plasma ratioof 0.08 (0.02 to 0.10). The cumulative amount of atogepant excreted in breast milk over 24 hours wasminimal, at less than 0.01 mg.

Based on a population pharmacokinetic analysis, sex, race, and body weight did not have a significanteffect on the pharmacokinetics (Cmax and AUC) of atogepant. Therefore, no dose adjustments arewarranted based on these factors.

Notwithstanding marked interspecies differences in CGRP-receptor affinity of atogepant, non-clinicaldata reveal no special hazard for atogepant in humans based on conventional studies of safetypharmacology, repeat dose toxicity, genotoxicity, phototoxicity or carcinogenic potential.

Oral administration of atogepant to male and female rats prior to and during mating and continuing infemales to gestation day 7 resulted in no adverse effects on fertility or reproductive performance.

Plasma exposures (AUC) are up to approximately 15 times that in humans at the maximumrecommended human dose (MRHD).

Reproductive and developmental toxicology

Oral administration of atogepant to pregnant rats and rabbits during the period of organogenesisresulted in decreased foetal body weight in rats and an increased incidence of foetal visceral andskeletal variations at doses associated with minimal maternal toxicity. At the no-effect dose foradverse effects on embryofoetal development, plasma exposure (AUC) was approximately 4 times inrats and 3 times in rabbits that in humans at the MRHD of 60 mg/day.

Oral administration of atogepant to rats throughout gestation and lactation resulted in non-adversesignificant decreased pup body weight which persisted into adulthood. Plasma exposure (AUC) at theno-effect dose for pre- and postnatal development were approximately 5-times that in humans at the

MRHD. In lactating rats, oral dosing with atogepant resulted in levels of atogepant in milkapproximately 2-fold higher than those in maternal plasma.

Polyvinylpyrrolidone/Vinyl acetate copolymer

Vitamin E polyethylene glycol succinate

Mannitol

Microcrystalline cellulose

Sodium chloride

Croscarmellose sodium

Colloidal silicon dioxide

Sodium stearyl fumarate

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

AQUIPTA 10 mg tablets

Aluminium foil and PVC/PE/PCTFE blisters, each containing 7 tablets.

Packs containing 28 or 98 tablets.

AQUIPTA 60 mg tablets

Aluminium foil and PVC/PE/PCTFE blisters, each containing 7 tablets.

Packs containing 28 or 98 tablets.

Not all pack sizes may be marketed.

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

AbbVie Deutschland GmbH & Co. KG

Knollstrasse67061 Ludwigshafen

Germany

EU/1/23/1750/001

EU/1/23/1750/002

EU/1/23/1750/003

EU/1/23/1750/004

Date of first authorisation: 11 August 2023

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

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