Aquipta

AQUIPTA tablets 10 mg: White to off-white, round biconvex tablet, diameter 6 mm, and debossed with "A" and "10" on one side.
Each tablet contains 10 mg of atogepant.
AQUIPTA tablets 60 mg: White to off-white, oval biconvex tablet, 16 mm x 9 mm, and debossed with "A60" on one side.
Each tablet contains 60 mg of atogepant.
Excipient with known effect: Each 60 mg tablet contains 31.5 mg sodium.
Excipients/Inactive Ingredients: Polyvinylpyrrolidone/Vinyl acetate copolymer, Vitamin E polyethylene glycol succinate, Mannitol, Microcrystalline cellulose, Sodium chloride, Croscarmellose sodium, Colloidal silicon dioxide, Sodium stearyl fumarate.

Pharmacotherapeutic group: Analgesics, calcitonin gene-related peptide (CGRP) antagonists. ATC code: N02CD07.
Pharmacology: Pharmacodynamics: Mechanism of action: Non-clinical receptor binding studies and in vitro functional studies point to an involvement of more than one receptor type in the pharmacological effects of atogepant. Atogepant shows affinity to several receptors of the calcitonin/CGRP-receptor family. In view of the clinically relevant free plasma concentrations of atogepant (C_max > 20 nM for a 60 mg dose) and the fact that CGRP and amylin-1 receptors are considered to be involved in the pathophysiology of migraine, inhibitory effects of atogepant at these receptors (K_i-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 be established.
Clinical efficacy and safety: Atogepant was evaluated for the prophylaxis of migraine in two pivotal studies across the migraine spectrum in chronic and episodic migraine. The episodic migraine study (ADVANCE) enrolled patients who met International Classification of Headache Disorders (ICHD) criteria for a diagnosis of migraine with or without aura. The chronic migraine study (PROGRESS) enrolled patients who also met 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 were randomised to AQUIPTA 60 mg (N = 235) or placebo (N = 223) once daily for 12 weeks. Patients were 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 of 42 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 was similar 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 the change from baseline in mean 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 month average), and several patient-reported outcome measures assessing functioning. Statistically significant findings were demonstrated for AQUIPTA versus placebo for the primary and secondary efficacy endpoints in ADVANCE, as summarized in Table 1. (See Table 1.)

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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-week treatment period compared to patients who received placebo. AQUIPTA 60 mg once daily resulted in significant decreases from baseline in mean monthly migraine days within the first 4-week interval compared to placebo-treated patients. (See Figure 1.)

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Long-term efficacy: Efficacy was sustained for up to one year in an open-label study in which 546 patients with episodic migraine were randomised to receive AQUIPTA 60 mg once daily. 68% (373/546) of patients completed the treatment period. The reduction in the least-squares mean number of monthly migraine days 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.
Chronic migraine: Atogepant was evaluated for the prophylaxis of chronic migraine (15 or more headache days per month with at least 8 migraine days) in a randomised, multicentre, double-blind, placebo-controlled study (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 migraine prophylaxis medicinal product (e.g., amitriptyline, propranolol, topiramate). Patients were allowed to use acute headache treatments (i.e., triptans, ergotamine derivatives, NSAIDs, paracetamol and opioids) as needed. Patients with acute medication overuse and medication overuse headache also were enrolled. 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 463 (89%) patients completed the 12-week double-blind study. Patients had a mean age of 42 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 was similar across treatment groups.
The primary efficacy endpoint was the change from baseline in mean MMD across the 12-week treatment period. Secondary endpoints controlled for multiplicity included the change from baseline in mean 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-month average), and several patient-reported outcome measures assessing functioning. Statistically significant findings were demonstrated for AQUIPTA versus placebo for the primary and secondary efficacy endpoints for PROGRESS, as summarized in Table 2. (See Table 2.)

Click on icon to see table/diagram/image

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-week treatment period compared to patients who received placebo. (See Figure 2.)

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Pharmacokinetics: Absorption: Following oral administration, atogepant is absorbed with peak plasma concentrations at approximately 1 to 2 hours. Following once daily dosing, atogepant displays dose-proportional pharmacokinetics up to 170 mg (approximately 3 times the highest recommended dose), with no accumulation.
Effect of food: When atogepant was administered with a high-fat meal, AUC and C_max were reduced by approximately 18% and 22%, respectively, with no effect on median time to maximum atogepant plasma concentration. Atogepant was administered without regard to food in clinical efficacy studies.
Distribution: 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 apparent volume of distribution of atogepant (V_z/F) after oral administration is approximately 292 L.
Biotransformation: Atogepant is eliminated mainly through metabolism, primarily by CYP3A4. The parent compound (atogepant), and a glucuronide conjugate metabolite (M23) were the most prevalent circulating components in human plasma.
CYP3A4 inducers: Co-administration of atogepant with steady state rifampicin, a strong CYP3A4 inducer, resulted in a significant 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 a decrease 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.
Elimination: 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 to healthy male subjects, 42% and 5% of the dose was recovered as unchanged atogepant in faeces and urine, respectively.
Transporters: Atogepant is a substrate of P-gp, BCRP, OATP1B1, OATP1B3, and OAT1. Dose adjustment for concomitant use with strong inhibitors of OATP is recommended based on a clinical interaction study with 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 at clinically relevant concentrations. Atogepant is a weak inhibitor of OATP1B1, OATP1B3, OCT1, and MATE1, but no clinically relevant interactions are expected.
Special populations: Renal impairment: The renal route of elimination plays a minor role in the clearance of atogepant. Based on population pharmacokinetic analysis, there is no significant difference in the pharmacokinetics of atogepant in patients with mild or moderate renal impairment (CLcr 30-89 mL/min) relative to those with normal renal function (CLcr ≥ 90 mL/min). As patients with severe renal impairment or end-stage renal disease (ESRD; CLcr < 30 mL/min) have not been studied, use of atogepant 10 mg is recommended in those patients.
Hepatic impairment: In patients with pre-existing mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe hepatic impairment (Child-Pugh Class C), total atogepant exposure was increased by 24%, 15% and 38%, respectively. However, unbound atogepant exposure was approximately 3-fold higher in patients with severe hepatic impairment. The use of AQUIPTA in patients with severe hepatic impairment should be avoided.
Other special populations: Based on a population pharmacokinetic analysis, sex, race, and body weight did not have a significant effect on the pharmacokinetics (C_max and AUC) of atogepant. Therefore, no dose adjustments are warranted based on these factors.
Toxicology: Preclinical safety data: Notwithstanding marked interspecies differences in CGRP-receptor affinity of atogepant, non-clinical data reveal no special hazard for atogepant in humans based on conventional studies of safety pharmacology, repeat dose toxicity, genotoxicity, phototoxicity or carcinogenic potential.
Impairment of fertility: Oral administration of atogepant to male and female rats prior to and during mating and continuing in females 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 maximum recommended human dose (MRHD).
Reproductive and developmental toxicology: Oral administration of atogepant to pregnant rats and rabbits during the period of organogenesis resulted in decreased foetal body weight in rats and an increased incidence of foetal visceral and skeletal variations at doses associated with minimal maternal toxicity. At the no-effect dose for adverse effects on embryofoetal development, plasma exposure (AUC) was approximately 4 times in rats 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-adverse significant decreased pup body weight which persisted into adulthood. Plasma exposure (AUC) at the no-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 milk approximately 2-fold higher than those in maternal plasma.

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

Posology: The recommended dose is 60 mg atogepant once daily.
The tablets can be taken with or without meals.
Missed dose: A missed dose should be taken as soon as it is remembered. If it is forgotten for an entire day, the missed dose should be skipped and the next dose taken as scheduled.
Dose modifications: Dosing modifications for concomitant use of specific medicinal products are provided in Table 3 (see Interactions). (See Table 3.)

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Special populations: Elderly: Population pharmacokinetic modelling suggests no clinically significant pharmacokinetic differences between elderly and younger subjects. No dose adjustment is needed in elderly patients.
Renal impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment (see Pharmacology: Pharmacokinetics under Actions). 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, AQUIPTA should preferably be taken after dialysis.
Hepatic impairment: No dose adjustment is recommended for patients with mild or moderate hepatic impairment (see Pharmacology: Pharmacokinetics under Actions). Atogepant should be avoided in patients with severe hepatic impairment.
Paediatric population: The safety and efficacy of atogepant in children (< 18 years of age) have not yet been established. No data are available.
Method of administration: AQUIPTA is for oral use. Tablets should be swallowed whole and should not be split, crushed, or chewed.

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

Hypersensitivity to the active substance or to any of the excipients listed in Excipients/Inactive Ingredients under Description.

Atogepant is not recommended in patients with severe hepatic impairment (see Dosage & Administration).
Excipients with known effect: AQUIPTA tablets 10 mg contain less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
AQUIPTA tablets 60 mg contain 31.5 mg sodium per tablet, equivalent to 1.6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Effects on ability to drive and use machines: 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.

Pregnancy: There are limited data from the use of atogepant in pregnant women. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). Atogepant is not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feeding: It is unknown whether atogepant is excreted in human milk. Available toxicological data in animals have shown excretion of atogepant in milk (see Pharmacology: Toxicology: Preclinical safety data under Actions). A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from atogepant therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
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 Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of the safety profile: Safety was evaluated in 2 657 patients with migraine who received at least one dose of atogepant in clinical studies. Of these, 1 225 patients were exposed to atogepant for at least 6 months and 826 patients were exposed for 12 months.
In 12-week, placebo-controlled clinical studies, 678 patients received at least one dose of atogepant 60 mg once daily, and 663 patients received placebo.
The most commonly reported adverse drug 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 was nausea (0.4%).
Tabulated list of adverse reactions: Adverse reactions reported in clinical trials and from post-marketing experience are listed as follows 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. (See Table 4.)

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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 according to local requirements.

CYP3A4 inhibitors: 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 (see Dosage & Administration). Changes in atogepant exposure when co-administered with weak or moderate CYP3A4 inhibitors are not expected to be clinically significant.
Transporter inhibitors: 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 (see Dosage & Administration).
Frequently co-administered medicinal products: Co-administration of atogepant with oral contraceptive components ethinyl estradiol and levonorgestrel, paracetamol, naproxen, sumatriptan, or ubrogepant did not result in significant pharmacokinetic interactions for either atogepant or co-administered medicinal products. Co-administration with famotidine or esomeprazole did not result in clinically relevant changes of atogepant exposure.

Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.

Store at or below 30°C.

Antimigraine Preparations

N02CD07 - atogepant ; Belongs to the class of calcitonin gene-related peptide (CGRP) antagonists preparations. Used to relieve migraine.

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