UBROGEPANT: 2,531 Adverse Event Reports & Safety Profile

The active ingredient of UBRELVY is ubrogepant, a calcitonin gene-related peptide (CGRP) receptor antagonist. The chemical name of ubrogepant is (3' S )- N -((3 S ,5 S ,6 R )-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[ b ]pyridine-6,3'-pyrrolo[2,3- b ]pyridine]-3-carboxamide and has the following structural formula: The molecular formula is C 29 H 26 F 3 N 5 O 3 and molecular weight is 549.6. Ubrogepant is a white to off-white powder. It is freely soluble in ethanol, methanol, acetone, and acetonitrile; and is practically insoluble in water. UBRELVY is available as tablets for oral administration containing 50 mg or 100 mg ubrogepant. The inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, mannitol, microcrystalline cellulose, polyvinylpyrrolidone vinyl acetate copolymer, sodium chloride, sodium stearyl fumarate, and vitamin E polyethylene glycol succinate. The following structural formula for UBRELVY is ubrogepant, a calcitonin gene-related peptide (CGRP) receptor antagonist. The chemical name of ubrogepant is (3'S)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide.

AND USAGE UBRELVY is indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use UBRELVY is not indicated for the preventive treatment of migraine. UBRELVY is a calcitonin gene-related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura in adults. ( 1 ) Limitations of Use UBRELVY is not indicated for the preventive treatment of migraine. ( 1 )

AND ADMINISTRATION The recommended dose is 50 mg or 100 mg taken orally, as needed. ( 2.1 ) If needed, a second dose may be administered at least 2 hours after the initial dose. ( 2.1 ) The maximum dose in a 24-hour period is 200 mg. ( 2.1 )

Severe

Hepatic or Severe Renal Impairment: Recommended dose is 50 mg; if needed, a second 50 mg dose may be taken at least 2 hours after the initial dose. ( 2.2 , 8.6 , 8.7 )

2.1 Recommended Dosage The recommended dose of UBRELVY is 50 mg or 100 mg taken orally with or without food. If needed, a second dose may be taken at least 2 hours after the initial dose. The maximum dose in a 24-hour period is 200 mg. The safety of treating more than 8 migraines in a 30-day period has not been established.

2.2 Dosage Modification s Dosing modifications for concomitant use of specific drugs and for patients with hepatic or renal impairment are provided in Table 1.

Table

1: Dose Modifications for Drug Interactions and for Specific Populations Dosage Modifications Initi a l Dose Second Dose a (if needed)

Concomitant

Drug [see Drug Interactions ( 7 )] Moderate CYP3A4 Inhibitors ( 7.1 ) 50 mg Avoid within 24 hours Weak CYP3A4 Inhibitors ( 7.1 ) 50 mg 50 mg Strong CYP3A4 Inducers ( 7.2 ) Avoid concomitant use Weak & Moderate CYP3A4 Inducers ( 7.2 ) 100 mg 100 mg BCRP and/or P-gp only Inhibitors ( 7.3 ) 50 mg 50 mg Spec i fic Populations [see Use in Specific Populations ( 8 )]

Severe Hepatic

Impairment (Child-Pugh Class C) ( 8.6 ) 50 mg 50 mg Severe Renal Impairment (CLcr 15-29 mL/min) ( 8.7 ) 50 mg 50 mg End-Stage Renal Disease (CLcr <15 mL/min) ( 8.7 ) Avoid use a Second dose may be taken at least 2 hours after the initial dose

UBRELVY is contraindicated: With concomitant use of strong CYP3A4 inhibitors [see Drug Interactions ( 7.1 )] In patients with a history of serious hypersensitivity to ubrogepant or any component of UBRELVY. Reactions have included anaphylaxis, dyspnea, and facial or throat edema [see Warnings and Precautions ( 5.1 )] Concomitant use with strong CYP3A4 inhibitors. ( 4 ) History of serious hypersensitivity to ubrogepant or any component of UBRELVY. ( 4 )

REACTIONS The following clinically significant adverse reactions are described elsewhere in 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 2% and greater than placebo) were nausea and 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 UBRELVY was evaluated in 3,624 subjects who received at least one dose of UBRELVY. In two randomized, double-blind, placebo-controlled, Phase 3 trials in adult patients with migraine (Studies 1 and 2), a total of 1,439 patients received UBRELVY 50 mg or 100 mg <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . Of the UBRELVY-treated patients in these 2 studies, approximately 89% were female, 82% were White, 15% were Black, and 17% were of Hispanic or Latino ethnicity. The mean age at study entry was 41 years (range of 18-75 years). Long-term safety was assessed in 813 patients, dosing intermittently for up to 1 year in an open-label extension study. Patients were permitted to treat up to 8 migraines per month with UBRELVY. Of these 813 patients, 421 patients were exposed to 50 mg or 100 mg for at least 6 months, and 364 patients were exposed to these doses for at least one year, all of whom treated at least two migraine attacks per month, on average. In that study, 2.5% of patients were withdrawn from UBRELVY because of an adverse reaction. The most common adverse reaction resulting in discontinuation in the long-term safety study was nausea. Adverse reactions in Studies 1 and 2 are shown in Table 2.

Table

2: Adverse Reactions Occurring in At Least 2% and at a Frequency Greater than Placebo in Studies 1 and 2 Placebo (N= 984) % UBRELVY 50 mg (N=954) % UBRELVY 100 mg (N=485) % Nausea 2 2 4 Somnolence* 1 2 3 Dry Mouth 1 <1 2 *Somnolence includes the adverse reaction-related terms sedation and fatigue. 6 . 2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of UBRELVY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System

Disorders: Hypersensitivity (e.g., anaphylaxis, dyspnea, facial or throat edema, rash, urticaria, and pruritus) [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 )]

AND PRECAUTIONS Hypersensitivity Reactions: If a serious hypersensitivity reaction occurs, discontinue UBRELVY and initiate appropriate therapy. Severe hypersensitivity reactions have included anaphylaxis and dyspnea. These reactions can occur within minutes, hours, or 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, facial or throat edema, rash, urticaria, and pruritus, have been reported with use of UBRELVY. Hypersensitivity reactions can occur minutes, hours, or days after administration. Most reactions occurred within hours after dosing and were not serious, and some reactions led to discontinuation. If a serious or severe hypersensitivity reaction occurs, discontinue UBRELVY and institute appropriate therapy [see Contraindications ( 4 ) and Adverse Reactions ( 6.2 )] . 5. 2 Hyper tension Development of hypertension and worsening of pre-existing hypertension have been reported following the use of CGRP antagonists, including UBRELVY, 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. The CGRP antagonist was discontinued in many of the reported cases. Monitor patients treated with UBRELVY for new-onset hypertension, or worsening of pre-existing hypertension, and consider whether discontinuation of UBRELVY 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 UBRELVY. 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. UBRELVY 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.

INTERACTIONS Strong CYP3A4 Inducers: Should be avoided as concomitant use will result in reduction of ubrogepant exposure. ( 2.2 , 7.2 ) For additional dose modifications for moderate or weak CYP3A4 inhibitors and inducers or BCRP and/or P-gp only inhibitors, refer to section 2.2 . ( 7.1 , 7.2 , 7.3 )

7.1 CYP3A4 I nhibitors Co-administration of UBRELVY with ketoconazole, a strong CYP3A4 inhibitor, resulted in a significant increase in exposure of ubrogepant <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 ) ]</span> . UBRELVY should not be used with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) <span class="opacity-50 text-xs">[see Contraindication s ( 4 )]</span> . Co-administration of UBRELVY with verapamil, a moderate CYP3A4 inhibitor, resulted in an increase in ubrogepant exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 ) ]</span> . Dose adjustment is recommended with concomitant use of UBRELVY and moderate CYP3A4 inhibitors (e.g., cyclosporine, ciprofloxacin, fluconazole, fluvoxamine, grapefruit juice) <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> . No dedicated drug interaction study was conducted with ubrogepant and weak CYP3A4 inhibitors. Dose adjustment is recommended with concomitant use of UBRELVY with weak CYP3A4 inhibitors <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .

7.2 CYP3A4 I nducers Co-administration of UBRELVY with rifampin, a strong CYP3A4 inducer, resulted in a significant reduction in ubrogepant exposure [ s ee Clinical Pharmacology ( 12.3 ) ] . In patients taking strong CYP3A4 inducers (e.g., phenytoin, barbiturates, rifampin, St. John’s Wort), loss of ubrogepant efficacy is expected, and concomitant use should be avoided. Co-administration of UBRELVY with moderate or weak CYP3A4 inducers was not evaluated in a clinical study. Dose adjustment is recommended with concomitant use of UBRELVY and moderate or weak CYP3A4 inducers <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> . 7 .3 BCRP and / or P-gp Only Inhibitors Ubrogepant is a substrate of BCRP and P-gp efflux transporters. Use of BCRP and/or P-gp only inhibitors (e.g., quinidine, carvedilol, eltrombopag, curcumin) may increase the exposure of ubrogepant [ s ee Clinical Pharmacology ( 12.3 ) ] . Clinical drug interaction studies with inhibitors of these transporters were not conducted. Dose adjustment is recommended with BCRP and/or P-gp only inhibitors <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ) ]</span> .