Atogepant

1 INDICATIONS AND USAGE QULIPTA is indicated for the preventive treatment of migraine in adults. QULIPTA is a calcitonin gene-related peptide receptor antagonist indicated for the preventive treatment of migraine in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION QULIPTA is taken orally with or without food. ( 2.1 ) For episodic migraine, the recommended dosage is 10 mg, 30 mg, or 60 mg taken once daily. ( 2.1 ) For chronic migraine, the recommended dosage is 60 mg taken once daily. ( 2.1 ) Severe Renal Impairment or End-Stage Renal Disease ( 2.2 , 8.6 ): Episodic migraine: 10 mg once daily. Chronic migraine: Not recommended. 2.1 Recommended Dosage QULIPTA is taken orally with or without food. Episodic Migraine The recommended dosage of QULIPTA for episodic migraine is 10 mg, 30 mg, or 60 mg taken once daily. Chronic Migraine The recommended dosage of QULIPTA for chronic migraine is 60 mg taken once daily. 2.2 Dosage Modification s Dosage modifications and usage recommendations for episodic and chronic migraine with concomitant use of specific drugs and for patients with renal impairment are provided in Table 1. Table 1 : Dos age Modifications for Drug Interactions and for Specific Populations Dosage Modifications Recommended Once Daily Dosage for Episodic Migraine Usage and Recommended Once Daily Dosage for Chronic Migraine Concomitant Drug [see Drug Interactions ( 7 )] Strong CYP3A4 Inhibitors ( 7.1 ) 10 mg 10 mg Strong CYP3A4 Inducers ( 7.2 ) 60 mg a Not recommended Moderate CYP3A4 Inducers ( 7.2 ) 60 mg Not recommended Weak CYP3A4 Inducers ( 7.2 ) 30 mg or 60 mg 60 mg a OATP Inhibitors ( 7.3 ) 10 mg or 30 mg 30 mg Renal Impairment [see Use in Specific Populations ( 8 )] Severe Renal Impairment and End-Stage Renal Disease (CLcr <30 mL/min) ( 8.6 ) 10 mg Not recommended a Coadministration decreases atogepant exposure. Monitor for reduced efficacy.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Hypertension [see Warnings and Precautions ( 5.2 )] Raynaud’s Phenomenon [see Warnings and Precautions ( 5.3 )] The most common adverse reactions (at least 4% and greater than placebo) are nausea, constipation, and fatigue/somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of QULIPTA was evaluated in 2657 patients with migraine who received at least one dose of QULIPTA. Of these, 1225 patients were exposed to QULIPTA for at least 6 months, and 826 patients were exposed for 12 months. In the 12-week, placebo-controlled clinical studies (Studies 1, 2, and 3), 314 patients received at least one dose of QULIPTA 10 mg once daily, 411 patients received at least one dose of QULIPTA 30 mg once daily, 678 patients received at least one dose of QULIPTA 60 mg once daily, and 663 patients received placebo [see Clinical Studies ( 14 ) ] . Approximately 88% were female, 75% were White, 13% were Black, 10% were Asian, and 10% were of Hispanic or Latino ethnicity. The mean age at study entry was 41 years (range 18 to 74 years). The most common adverse reactions (incidence at least 4% and greater than placebo) are nausea, constipation, and fatigue/somnolence. Table 2 summarizes the adverse reactions that occurred during Studies 1, 2, and 3. Table 2: Adverse Reactions Occurring with an Incidence of At Least 2% for QULIPTA and Greater than Placebo in Studies 1, 2, and 3 * Placebo (N= 663 ) % QULIPTA 10 mg (N=314) % QULIPTA 30 mg (N=411) % QULIPTA 60 mg (N= 678 ) % Nausea 3 5 6 9 Constipation 2 6 6 8 Fatigue/Somnolence 4 4 4 5 Decreased Appetite <1 2 1 3 Dizziness 2 2 2 3 * 10 mg and 30 mg incidence from Studies 1 and 2; 60 mg pooled incidence from Studies 1, 2, and 3. The adverse reactions that most commonly led to discontinuation of QULIPTA in these studies were nausea (0.6%), constipation (0.5%), and fatigue/somnolence (0.2%). Liver Enzyme Elevations In Study 1, Study 2, and Study 3, the rate of transaminase elevations over 3 times the upper limit of normal was similar between patients treated with QULIPTA (0.9%) and those treated with placebo (1.2%). However, there were cases with transaminase elevations over 3 times the upper limit of normal that were temporally associated with QULIPTA treatment; these were asymptomatic and resolved within 8 weeks of discontinuation. There were no cases of severe liver injury or jaundice. Decreases in Body Weight In Study 1, Study 2, and Study 3, the proportion of patients with a weight decrease of at least 7% at any point was 2.5% for placebo, 3.8% for QULIPTA 10 mg, 3.2% for QULIPTA 30 mg, and 5.3% for QULIPTA 60 mg. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of QULIPTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders : Hypersensitivity (e.g., anaphylaxis, dyspnea, rash, pruritus, urticaria, facial edema) [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] Vascular Disorders: Hypertension [see Warnings and Precautions ( 5.2 )] , Raynaud’s phenomenon [see Warnings and Precautions ( 5.3 )]

12.3 Pharmacokinetics Absorption Following oral administration of QULIPTA, atogepant is absorbed with peak plasma concentrations at approximately 1 to 2 hours. Atogepant displays dose-proportional pharmacokinetics up to 170 mg per day (approximately 3 times the highest recommended dosage), with no accumulation. Effect of Food When QULIPTA was administered with a high-fat meal, the food effect was not significant (AUC and C max were reduced by approximately 18% and 22%, respectively, with no effect on median time to maximum atogepant plasma concentration). QULIPTA 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 (Vz/F) after oral administration is approximately 292 L . Elimination Metabolism 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. Excretion The elimination half-life of atogepant is approximately 11 hours. The mean apparent oral clearance (CL/F) of atogepant is approximately 19 L/hr. Following single oral dose of 50 mg 14 C-atogepant to healthy male subjects, 42% and 5% of the dose was recovered as unchanged atogepant in feces and urine, respectively. Specific Populations Patients with Renal Impairment The renal route of elimination plays a minor role in the clearance of atogepant. Based on a 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). Patients with severe renal impairment or end-stage renal disease (ESRD; CLcr <30 mL/min) have not been studied [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 ) ] . Patients with Hepatic Impairment In patients with pre-existing mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment, the total atogepant exposure was increased by 24%, 15%, and 38%, respectively. Due to a potential for liver injury in patients with severe hepatic impairment, avoid use of QULIPTA in patients with severe hepatic impairment [see Use in Specific Populations ( 8.7 )] . Other Specific Populations Based on a population pharmacokinetic analysis, age, 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. Drug Interactions In Vitro Studies Enzymes In vitro, atogepant is not an inhibitor for CYPs 3A4, 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 at clinically relevant concentrations. Atogepant does not inhibit MAO-A or UGT1A1 at clinically relevant concentrations. Atogepant is not anticipated to be a clinically significant perpetrator of drug-drug interactions through CYP450s, MAO-A, or UGT1A1 inhibition. Atogepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations. Transporters Atogepant is a substrate of P-gp, BCRP, OATP1B1, OATP1B3, and OAT1. Dose adjustment for concomitant use of QULIPTA with inhibitors of OATP is recommended based on a clinical interaction study with a OATP inhibitor [see Dosage and Administration ( 2.2 )] . Coadministration of atogepant with BCRP and/or P-gp inhibitors is not expected to increase the exposure of atogepant. 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. No clinical drug interactions are expected for atogepant as a perpetrator with these transporters. In Vivo Studies CYP3A4 Inhibitors Co-administration of QULIPTA with itraconazole, a strong CYP3A4 inhibitor, resulted in a clinically significant increase (C max by 2.15-fold and AUC by 5.5-fold) in the exposure of atogepant in healthy subjects [see Drug Interactions ( 7.1 )] . Physiologically based pharmacokinetic (PBPK) modeling suggested co-administration of QULIPTA with moderate or weak CYP3A4 inhibitors increase atogepant AUC by 1.7- and 1.1-fold, respectively. The changes in atogepant exposure when coadministered with weak or moderate CYP3A4 inhibitors are not expected to be clinically significant. CYP3A4 Inducers Co-administration of QULIPTA with rifampin, a strong CYP3A4 inducer, decreased atogepant AUC by 60% and C max by 30% in healthy subjects [see Drug Interactions ( 7.2 )] . The observed change in atogepant exposures is a composite effect of inhibition of OATP1B1 and OATP1B3 transporters as well as induction of CYP3A4 and P-gp. No dedicated drug interaction studies were conducted to assess concomitant use with moderate CYP3A4 inducers. Moderate inducers of CYP3A4 can decrease atogepant exposure [see Drug Interactions ( 7.2 )] . Co-administration of QULIPTA with topiramate, a weak inducer of CYP3A4, decreased atogepant mean steady-state AUC 0-τ by 25% and mean steady-state C max by 24% in healthy subjects [ see Drug Interactions ( 7.2 ) ]. BCRP/OATP/P-gp Inhibitors Co-administration of QULIPTA with single dose rifampin, an OATP inhibitor, increased atogepant AUC by 2.85-fold and C max by 2.23-fold in healthy subjects [see Drug Interactions ( 7.3 )] . Co-administration of QULIPTA with quinidine, a P-gp inhibitor, increased atogepant AUC by 26% and C max by 4% in healthy subjects. The changes in atogepant exposure when co-administered with P-gp inhibitors are not expected to be clinically significant. PBPK modeling suggests that co-administration of QULIPTA with BCRP inhibitors increases atogepant exposure by 1.2-fold. This increase is not expected to be clinically significant. Other Drug Interaction Evaluations Co-administration of QULIPTA with oral contraceptive components ethinyl estradiol and levonorgestrel, famotidine, esomeprazole, acetaminophen, naproxen, sumatriptan, or ubrogepant did not result in significant pharmacokinetic interactions for either atogepant or co-administered drugs. Co-administration of QULIPTA with topiramate did not result in clinically significant changes in the pharmacokinetics of topiramate.