Qulipta

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.

4 CONTRAINDICATIONS QULIPTA is contraindicated in patients with a history of hypersensitivity to atogepant or any of the components of QULIPTA. Reactions have included anaphylaxis and dyspnea [see Warnings and Precautions ( 5.1 )] . Patients with a history of hypersensitivity to atogepant or to any of the components of QULIPTA. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: If a hypersensitivity reaction occurs, discontinue QULIPTA and initiate appropriate therapy. Severe hypersensitivity reactions have included anaphylaxis and dyspnea. These reactions can occur days after administration. ( 5.1 ) Hypertension: New-onset or worsening of pre-existing hypertension may occur. ( 5.2 ) Raynaud’s phenomenon: New-onset or worsening of pre-existing Raynaud’s phenomenon may occur. ( 5.3 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, dyspnea, rash, pruritus, urticaria, and facial edema, have been reported with use of QULIPTA [see Adverse Reactions ( 6.2 )] . Hypersensitivity reactions can occur days after administration. If a hypersensitivity reaction occurs, discontinue QULIPTA and institute appropriate therapy [see Contraindications ( 4 )] . 5. 2 Hyper tension Development of hypertension and worsening of pre-existing hypertension have been reported following the use of CGRP antagonists, including QULIPTA, in the postmarketing setting. Some of the patients who developed new-onset hypertension had risk factors for hypertension. There were cases requiring initiation of pharmacological treatment for hypertension and, in some cases, hospitalization. Hypertension may occur at any time during treatment, but was most frequently reported within 7 days of therapy initiation. QULIPTA was discontinued in many of the reported cases. Monitor patients treated with QULIPTA for new-onset hypertension, or worsening of pre-existing hypertension, and consider whether discontinuation of QULIPTA is warranted if evaluation fails to establish an alternative etiology or blood pressure is inadequately controlled. 5. 3 Raynaud’s Phenomenon Development of Raynaud’s phenomenon and recurrence or worsening of pre-existing Raynaud’s phenomenon have been reported in the postmarketing setting following the use of CGRP antagonists, including QULIPTA. In reported cases with small molecule CGRP antagonists, symptom onset occurred a median of 1.5 days following dosing. Many of the cases reported serious outcomes, including hospitalizations and disability, generally related to debilitating pain. In most reported cases, discontinuation of the CGRP antagonist resulted in resolution of symptoms. QULIPTA should be discontinued if signs or symptoms of Raynaud’s phenomenon develop, and patients should be evaluated by a healthcare provider if symptoms do not resolve. Patients with a history of Raynaud’s phenomenon should be monitored for, and informed about the possibility of, worsening or recurrence of signs and symptoms.

7 DRUG INTERACTIONS Recommended dosage modifications: Strong CYP3A4 Inhibitors ( 2.2 , 7.1 ): Episodic or chronic migraine: 10 mg once daily Strong CYP3A4 Inducers ( 2.2 , 7.2 ): Episodic migraine: 60 mg once daily (monitor for reduced efficacy). Chronic migraine: Not recommended. Moderate CYP3A4 Inducers ( 2.2 , 7.2 ): Episodic migraine: 60 mg once daily. Chronic migraine: Not recommended. Weak CYP3A4 Inducers ( 2.2 , 7.2 ): Episodic migraine: 30 mg or 60 mg once daily. Chronic migraine: 60 mg once daily. OATP Inhibitors ( 2.2 , 7.3 ): Episodic migraine: 10 mg or 30 mg once daily. Chronic migraine: 30 mg once daily. 7.1 CYP3A4 Inhibitors Coadministration of QULIPTA with itraconazole, a strong CYP3A4 inhibitor, resulted in a significant increase in exposure of atogepant in healthy subjects [see Clinical Pharmacology ( 12.3 )] . The recommended dosage of QULIPTA with concomitant use of strong CYP3A4 inhibitors is 10 mg once daily [see Dosage and Administration ( 2.2 ) ] . No dosage adjustment of QULIPTA is needed with concomitant use of moderate or weak CYP3A4 inhibitors. 7.2 CYP3A4 Inducers Coadministration of QULIPTA with steady-state rifampin, a strong CYP3A4 inducer and OATP1B1 and OATP1B3 inhibitor, resulted in a significant decrease in exposure of atogepant in healthy subjects [see Clinical Pharmacology ( 12.3 )] . Concomitant administration of QULIPTA with moderate inducers of CYP3A4 can also result in decreased exposure of atogepant. Coadministration of QULIPTA with steady-state topiramate, a weak CYP3A4 inducer, resulted in decreased exposure of atogepant in healthy subjects [see Clinical Phar macology ( 12.3 )] . For episodic migraine, the recommended dosage of QULIPTA with concomitant use of strong or moderate CYP3A4 inducers is 60 mg once daily. During concomitant use of QULIPTA with strong CYP3A4 inducers, monitor monthly for signs of reduced efficacy, and consider alternative therapies if a reduction in efficacy is observed. The recommended dosage of QULIPTA with concomitant use of weak CYP3A4 inducers is 30 mg or 60 mg once daily [see Dosage and Administration ( 2.2 ) ] . For chronic migraine, concomitant use of strong or moderate CYP3A4 inducers with QULIPTA is not recommended. The recommended dosage of QULIPTA with concomitant use of weak CYP3A4 inducers is 60 mg once daily. Monitor monthly for signs of reduced efficacy, and consider alternative therapies if a reduction in efficacy is observed [see Dosage and Administration ( 2.2 ) ] . 7 .3 OATP Inhibitors Coadministration of QULIPTA with single dose rifampin, an OATP inhibitor, resulted in a significant increase in exposure of atogepant in healthy subjects [see Clinical Pharmacology ( 12.3 )] . For episodic migraine, the recommended dosage of QULIPTA with concomitant use of OATP inhibitors is 10 mg or 30 mg once daily. For chronic migraine, the recommended dosage of QULIPTA with concomitant use of OATP inhibitors is 30 mg once daily [see Dosage and Administration ( 2.2 ) ] .

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 )]

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors outcomes in women who become pregnant while taking QULIPTA. Patients should be encouraged to enroll by calling 1-833-277-0206 or visiting http://empresspregnancyregistry.com . Risk Summary There are no adequate data on the developmental risk associated with the use of QULIPTA in pregnant women. In animal studies, oral administration of atogepant during the period of organogenesis (rats and rabbits) or throughout pregnancy and lactation (rats) resulted in adverse developmental effects (decreased fetal and offspring body weight in rats; increased incidence of fetal structural variations in rabbits) at exposures greater than those used clinically [see Data ] . In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The estimated rate of major birth defects (2.2%-2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy. Data Animal Data Oral administration of atogepant (0, 5, 15, 125, or 750 mg/kg/day) to pregnant rats during the period of organogenesis resulted in decreases in fetal body weight and in skeletal ossification at the two highest doses tested (125 and 750 mg/kg), which were not associated with maternal toxicity. At the no-effect dose (15 mg/kg/day) for adverse effects on embryofetal development, plasma exposure (AUC) was approximately 4 times that in humans at the maximum recommended human dose (MRHD) of 60 mg/day. Oral administration of atogepant (0, 30, 90, or 130 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in an increase in fetal visceral and skeletal variations at the highest dose tested (130 mg/kg/day), which was associated with minimal maternal toxicity. At the no-effect dose (90 mg/kg/day) for adverse effects on embryofetal development, plasma exposure (AUC) was approximately 3 times that in humans at the MRHD. Oral administration of atogepant (0, 15, 45, or 125 mg/kg/day) to rats throughout gestation and lactation resulted in decreased pup body weight at the highest dose tested (125 mg/kg/day), which persisted into adulthood. At the no-effect dose (45 mg/kg/day) for adverse effects on pre- and postnatal development, plasma exposure (AUC) was approximately 5 times that in humans at the MRHD.