ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. The most common adverse reactions (at least 2% and greater than placebo) were nausea and somnolence. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Allergan 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 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 trials in adult patients with migraine (Studies and 2), total of 1,439 patients received UBRELVY 50 mg or 100 mg [see Clinical Studies 14 )] Of the UBRELVY-treated patients in these 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 year in an open-label extension study. Patients were permitted to treat up to migraines per month with UBRELVY. Of these 813 patients, 421 patients were exposed to 50 mg or 100 mg for at least 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 In that study, 2.5% of patients were withdrawn from UBRELVY because of an adverse reaction.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 and are shown in Table 2. Table 2: Adverse Reactions Occurring in At Least 2% and at Frequency Greater than Placebo in Studies and 2Placebo(N= 984)%UBRELVY 50 mg(N=954)%UBRELVY 100 mg(N=485)%Nausea224Somnolence123Dry Mouth1<12 Somnolence includes the adverse reaction-related terms sedation and fatigue.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenicityTwo-year oral carcinogenicity studies of ubrogepant were conducted in mice (0, 5, 15, or 50 mg/kg/day) and rats (0, 10, 30, or 100 mg/kg in males; 0, 10, 30, or 150 mg/kg in females). There was no evidence of drug-related tumors in either species. The highest dose tested in mice is similar to the maximum recommended human dose (200 mg/day) on body surface area (mg/m2) basis. Plasma exposure (AUC) at the highest dose tested in rats is approximately 25 times that in humans at the maximum recommended human dose (MRHD) of 200 mg/day.MutagenicityUbrogepant was negative in in vitro (Ames, chromosomal aberration test in Chinese Hamster Ovary cells) and in vivo (rat bone marrow micronucleus) assays.Impairment of FertilityOral administration of ubrogepant (0, 20, 80, or 160 mg/kg/day) to male and female rats (mated with drug-naive females and males, respectively) resulted in no adverse effects on fertility or reproductive performance. Plasma exposures (AUC) at the highest dose tested are approximately 30 times that in humans at the MRHD.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ubrogepant is calcitonin gene-related peptide receptor antagonist. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyAt dose times the maximum recommended daily dose, UBRELVY does not prolong the QT interval to any clinically relevant extent.. 12.3 Pharmacokinetics AbsorptionFollowing oral administration of UBRELVY, ubrogepant is absorbed with peak plasma concentrations at approximately 1.5 hours. Ubrogepant displays dose-proportional pharmacokinetics within the recommended dose range [see Dosage and Administration 2.1 )] Effect of FoodWhen UBRELVY was administered with high-fat meal, the time to maximum ubrogepant plasma concentration was delayed by hours and resulted in 22% reduction in Cmax with no change in AUC. UBRELVY was administered without regard to food in clinical efficacy studies [see Dosage and Administration 2.1 )]. DistributionPlasma protein binding of ubrogepant is 87% in vitro. The mean apparent central volume of distribution of ubrogepant (V/F) after single dose oral administration is approximately 350 L.Elimination MetabolismUbrogepant is eliminated mainly through metabolism, primarily by CYP3A4. The parent compound (ubrogepant), and glucuronide conjugate metabolites were the most prevalent circulating components in human plasma. The glucuronide metabolites are not expected to contribute to the pharmacological activity of ubrogepant since they were reported as about 6000-fold less potent in the CGRP receptor binding assay.ExcretionThe elimination half-life of ubrogepant is approximately 5-7 hours. The mean apparent oral clearance (CL/F) of ubrogepant is approximately 87 L/hr. Ubrogepant is excreted mostly via the biliary/fecal route, while the renal route is minor route of elimination. Following single oral dose administration of [14C]-ubrogepant to healthy male subjects, 42% and 6% of the dose was recovered as unchanged ubrogepant in feces and urine, respectively.Specific PopulationsPatients with Renal Impairment Population pharmacokinetic analysis based on pooled data from clinical studies was used to evaluate the effect of renal impairment characterized based on estimated creatinine clearance (CLcr) using the Cockcroft-Gault (C-G) equation. Renal impairment did not reveal significant difference in the pharmacokinetics of ubrogepant 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 ESRD (eGFR <30 mL/min) have not been studied. Dose adjustment in patients with severe renal impairment (CLcr 15-29 mL/min) is recommended based on ADME information and conservative assumption that severe renal impairment is unlikely to cause more than two-fold increase in exposure of ubrogepant [see Dosage and Administration 2.2 )]. No dosing recommendations can be made for patients with ESRD (CLcr<15 mL/min).Patients with 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), ubrogepant exposure was increased by 7%, 50%, and 115%, respectively. Patients with severe hepatic impairment require dose adjustments [see Dosage and Administration 2.2 )].Other Specific PopulationsBased on population pharmacokinetic analysis, age, sex, race, and body weight did not have significant effect on the pharmacokinetics (Cmax and AUC) of ubrogepant. Therefore, no dose adjustments are warranted based on these factors. Drug InteractionsIn Vitro StudiesEnzymesUbrogepant is not an inhibitor of CYP1A2, 2B6, or 3A4. Ubrogepant is weak inhibitor of CYP2C8, 2C9, 2D6, 2C19, MAO-A, and UGT1A1. The in vitro inhibition potential is not expected to be clinically significant. Ubrogepant is not an inducer of CYP1A2, 2B6, or 3A4 at clinically relevant concentrations. TransportersUbrogepant is substrate of BCRP and P-gp transporters in-vitro; therefore, use of inhibitors of BCRP and/or P-gp may increase the exposure of ubrogepant. Dose adjustment for concomitant use of UBRELVY with inhibitors of BCRP and/or P-gp is recommended based on ADME and clinical interaction studies with CYP3A4/P-gp inhibitors that show the highest predicted potential increase in exposure of ubrogepant is not expected to be more than two-fold [see Dosage and Administration 2.2 and Drug Interactions 7.3)]. Ubrogepant is weak substrate of OATP1B1, OATP1B3, and OAT1, but not substrate of OAT3. It is not an inhibitor of P-gp, BCRP, BSEP, MRP3, MRP4, OAT1, OAT3, or NTCP transporters, but is weak inhibitor of OATP1B1, OATP1B3, and OCT2 transporters. Dose adjustments are needed only for P-gp, or BCRP inhibitors. No clinical drug interactions are expected for UBRELVY with other transporters. In Vivo Studies CYP3A4 Inhibitors [see Dosage and Administration 2.2 ), Contraindications 4 ), and Dr ug Interactions 7.1)]:Co-administration of UBRELVY with ketoconazole, strong CYP3A4 inhibitor, resulted in 9.7-fold and 5.3-fold increase in AUCinf and Cmax of ubrogepant, respectively. Co-administration of UBRELVY with verapamil, moderate CYP3A4 inhibitor, resulted in about 3.5-fold and 2.8-fold increase in AUCinf and Cmax of ubrogepant, respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors. The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold.CYP3A4 Inducers [see Dosage and Administration 2.2 and Drug Interactions 7.2)]:Co-administration of UBRELVY with rifampin, strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with weak or moderate CYP3A4 inducers. Dose adjustment for concomitant use of UBRELVY with weak or moderate CYP3A4 inducers is recommended based on conservative prediction of 50% reduction in exposure of ubrogepant.Other Drug-Drug Interaction Evaluations:No significant pharmacokinetic interactions were observed for either ubrogepant or co-administered drugs when UBRELVY was administered with oral contraceptives (containing norgestimate and ethinyl estradiol), acetaminophen, naproxen, sumatriptan, or esomeprazole (a proton pump inhibitor).

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. The efficacy of UBRELVY for the acute treatment of migraine was demonstrated in two randomized, double-blind, placebo-controlled trials [Study (NCT02828020) and Study (NCT02867709)]. Study randomized patients to placebo (n=559) or UBRELVY 50 mg (n=556) or 100 mg (n=557) and Study randomized patients to placebo (n=563) or UBRELVY 50 mg (n=562). In all studies, patients were instructed to treat migraine with moderate to severe headache pain intensity. second dose of study medication (UBRELVY or placebo), or the patients usual acute treatment for migraine, was allowed between to 48 hours after the initial treatment for non-responding or recurrent migraine headache. Up to 23% of patients were taking preventive medications for migraine at baseline. None of these patients were on concomitant preventive medication that act on the CGRP pathway.The primary efficacy analyses were conducted in patients who treated migraine with moderate to severe pain. The efficacy of UBRELVY was established by an effect on pain freedom at hours post-dose and most bothersome symptom (MBS) freedom at hours post-dose, compared to placebo, for Studies and 2. Pain freedom was defined as reduction of moderate or severe headache pain to no pain, and MBS freedom was defined as the absence of the self-identified MBS (i.e., photophobia, phonophobia, or nausea). Among patients who selected an MBS, the most commonly selected was photophobia (56%), followed by phonophobia (24%), and nausea (19%).In both studies, the percentage of patients achieving headache pain freedom and MBS freedom hours post-dose was significantly greater among patients receiving UBRELVY compared to those receiving placebo (see Table 3). Table also presents the results of the analyses of the percentage of patients achieving pain relief at hours (defined as reduction in migraine pain from moderate or severe to mild or none) post-dose and the percentage of patients achieving sustained pain freedom between to 24 hours post-dose.The incidence of photophobia and phonophobia was reduced following administration of UBRELVY at both doses (50 mg and 100 mg) as compared to placebo.Table 3: Migraine Efficacy Endpoints for Study and Study 2Study 1Study 2UBRELVY50 mgUBRELVY 100 mgPlaceboUBRELVY 50 mgPlaceboPain Free at hoursN422448456464456% Responders19.221.211.821.814.3Difference from placebo (%)7.49.47.5p value0.002<0.0010.007Most Bothersome Symptom Free at hoursN420448454463456% Responders38.637.727.838.927.4Difference from placebo (%)10.89.911.5p value<0.001<0.001<0.001 Pain Relief at hoursN422448456464456% Responders60.761.449.162.748.2p value<0.001<0.001<0.001Sustained Pain Freedom 2-24 hoursN418441452457451% Responders12.715.48.614.48.2p valueNS0.0020.005 Not statistically significant (NS) Figure presents the percentage of patients achieving migraine pain freedom within hours following treatment in Studies and 2. Figure 1: Percentage of Patients Achieving Pain Freedom within Hours in Pooled Studies and 2a The 100 mg arm was only included in Study 1.Figure presents the percentage of patients achieving MBS freedom within hours in Studies and 2.Figure 2: Percentage of Patients Achieving MBS Freedom within Hours in Pooled Studies and 2a The 100 mg arm was only included in Study 1.. Figure 1: Percentage of Patients Achieving Pain Freedom within Hours in Pooled Studies and 2. Figure 2: Percentage of Patients Achieving MBS Freedom within Hours in Pooled Studies and 2.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied UBRELVY 50 mg is supplied as white to off-white, capsule-shaped, biconvex tablets debossed with U50 on one side in unit-dose packets (each packet contains tablet):Box of 10 Packets, NDC: 0023-6498-10 Box of 16 Packets, NDC: 0023-6498-16 Box of 30 Packets, NDC: 0023-6498-30UBRELVY 100 mg is supplied as white to off-white capsule-shaped, biconvex tablets debossed with U100 on one side in unit-dose packets (each packet contains tablet): Box of 10 Packets, NDC: 0023-6501-10 Box of 16 Packets, NDC: 0023-6501-16 Box of 30 Packets, NDC: 0023-6501-30. Box of 10 Packets, NDC: 0023-6498-10 Box of 16 Packets, NDC: 0023-6498-16 Box of 30 Packets, NDC: 0023-6498-30. Box of 10 Packets, NDC: 0023-6501-10 Box of 16 Packets, NDC: 0023-6501-16 Box of 30 Packets, NDC: 0023-6501-30. 16.2 Storage and Handling Store between 20C and 25C (68F and 77F): excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature ].

INDICATIONS & USAGE SECTION.


1 INDICATIONS 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 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).

CLINICAL TRIALS EXPERIENCE SECTION.


6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 trials in adult patients with migraine (Studies and 2), total of 1,439 patients received UBRELVY 50 mg or 100 mg [see Clinical Studies 14 )] Of the UBRELVY-treated patients in these 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 year in an open-label extension study. Patients were permitted to treat up to migraines per month with UBRELVY. Of these 813 patients, 421 patients were exposed to 50 mg or 100 mg for at least 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 and are shown in Table 2. Table 2: Adverse Reactions Occurring in At Least 2% and at Frequency Greater than Placebo in Studies and 2Placebo(N= 984)%UBRELVY 50 mg(N=954)%UBRELVY 100 mg(N=485)%Nausea224Somnolence123Dry Mouth1<12 Somnolence includes the adverse reaction-related terms sedation and fatigue.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS UBRELVY is contraindicated with concomitant use of strong CYP3A4 inhibitors [see Drug Interactions 7.1 )].. Concomitant use with strong CYP3A4 inhibitors. (4).

DESCRIPTION SECTION.


11 DESCRIPTION The active ingredient of UBRELVY is ubrogepant, calcitonin gene-related peptide (CGRP) receptor antagonist. The chemical name of ubrogepant is (3S)-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 has the following structural formula:The molecular formula is C29H26F3N5O3 and molecular weight is 549.6. Ubrogepant is 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 polyethylene glycol succinate.. The following structural formula for UBRELVY is ubrogepant, calcitonin gene-related peptide (CGRP) receptor antagonist. The chemical name of ubrogepant is (3S)-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.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION o The recommended dose is 50 mg or 100 mg taken orally, as needed. (2.1)o If needed, second dose may be administered at least hours after the initial dose. (2.1)o The maximum dose in 24-hour period is 200 mg. (2.1)o Severe Hepatic or Severe Renal Impairment: Recommended dose is 50 mg; if needed, second 50 mg dose may be taken at least 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, second dose may be taken at least hours after the initial dose. The maximum dose in 24-hour period is 200 mg. The safety of treating more than migraines in 30-day period has not been established.. 2.2 Dosage Modifications 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 PopulationsDosage ModificationsInitial DoseSecond Dosea(if needed)Concomitant Drug [see Drug Interactions (7)] Moderate CYP3A4 Inhibitors 7.1 50 mgAvoid within 24 hours Weak CYP3A4 Inhibitors 7.1 50 mg50 mg Strong CYP3A4 Inducers 7.2 Avoid concomitant use Weak Moderate CYP3A4 Inducers 7.2 100 mg100 mg BCRP and/or P-gp only Inhibitors 7.3 50 mg50 mgSpecific Populations [see Use in Specific Populations (8)] Severe Hepatic Impairment (Child-Pugh Class C) 8.6 50 mg50 mg Severe Renal Impairment (CLcr 15-29 mL/min) 8.7 50 mg50 mg End-Stage Renal Disease (CLcr <15 mL/min) 8.7 Avoid usea Second dose may be taken at least hours after the initial dose.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS UBRELVY 50 mg is supplied as white to off-white, capsule-shaped, biconvex tablets debossed with U50 on one side.UBRELVY 100 mg is supplied as white to off-white, capsule-shaped, biconvex tablets debossed with U100 on one side.. Tablets: 50 mg and 100 mg (3).

DRUG INTERACTIONS SECTION.


7 DRUG 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). 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 nhibitors Co-administration of UBRELVY with ketoconazole, strong CYP3A4 inhibitor, resulted in significant increase in exposure of ubrogepant [see Clinical Pharmacology 12.3 ]. UBRELVY should not be used with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) [see Contraindication ( )]. Co-administration of UBRELVY with verapamil, moderate CYP3A4 inhibitor, resulted in an increase in ubrogepant exposure [see Clinical Pharmacology 12.3 ]. Dose adjustment is recommended with concomitant use of UBRELVY and moderate CYP3A4 inhibitors (e.g., cyclosporine, ciprofloxacin, fluconazole, fluvoxamine, grapefruit juice) [see Dosage and Administration 2.2 )].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 [see Dosage and Administration 2.2 )].. 7.2 CYP3A4 nducers Co-administration of UBRELVY with rifampin, strong CYP3A4 inducer, resulted in significant reduction in ubrogepant exposure s ee Clinical Pharmacology 12.3 ]. In patients taking strong CYP3A4 inducers (e.g., phenytoin, barbiturates, rifampin, St. Johns 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 clinical study. Dose adjustment is recommended with concomitant use of UBRELVY and moderate or weak CYP3A4 inducers [see Dosage and Administration 2.2 )].. 7.3 BCRP and or P- gp Only Inhibitors Ubrogepant is 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 [see Dosage and Administration 2.2 ].

GERIATRIC USE SECTION.


8.5 Geriatric Use. In pharmacokinetic studies, no clinically significant pharmacokinetic differences were observed between elderly and younger subjects. Clinical studies of UBRELVY did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).Drug InteractionsInform patients that UBRELVY may interact with certain other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription medications, over-the-counter medications, or herbal products [see Contraindication ( ), and Drug Interactions 7.1 7.2 7.3 )]. Advise patients to inform their healthcare provider of grapefruit juice intake because dosage modification is recommended with co-administration. Pregnancy Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant [see Use in Specific Populations 8.1 )]. LactationInform patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations 8.2 )] Manufactured by: Forest Laboratories Ireland Ltd.,Dublin, IrelandDistributed by: Allergan USA, Inc.Madison, NJ 07940(C) 2021 Allergan. All rights reserved.UBRELVY(R) is registered trademark of Allergan Pharmaceuticals International Limited.Allergan(R) and its design are trademarks of Allergan, Inc.Patented. See www.allergan.com/patentsv1.3USPI6498.

LACTATION SECTION.


8.2 Lactation There are no data on the presence of ubrogepant in human milk, the effects of ubrogepant on the breastfed infant, or the effects of ubrogepant on milk production. In lactating rats, oral dosing with ubrogepant resulted in levels of ubrogepant in milk comparable to peak plasma concentrations. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for UBRELVY and any potential adverse effects on the breastfed infant from UBRELVY or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action Ubrogepant is calcitonin gene-related peptide receptor antagonist.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenicityTwo-year oral carcinogenicity studies of ubrogepant were conducted in mice (0, 5, 15, or 50 mg/kg/day) and rats (0, 10, 30, or 100 mg/kg in males; 0, 10, 30, or 150 mg/kg in females). There was no evidence of drug-related tumors in either species. The highest dose tested in mice is similar to the maximum recommended human dose (200 mg/day) on body surface area (mg/m2) basis. Plasma exposure (AUC) at the highest dose tested in rats is approximately 25 times that in humans at the maximum recommended human dose (MRHD) of 200 mg/day.MutagenicityUbrogepant was negative in in vitro (Ames, chromosomal aberration test in Chinese Hamster Ovary cells) and in vivo (rat bone marrow micronucleus) assays.Impairment of FertilityOral administration of ubrogepant (0, 20, 80, or 160 mg/kg/day) to male and female rats (mated with drug-naive females and males, respectively) resulted in no adverse effects on fertility or reproductive performance. Plasma exposures (AUC) at the highest dose tested are approximately 30 times that in humans at the MRHD.

OVERDOSAGE SECTION.


10 OVERDOSAGE. The elimination half-life of ubrogepant is approximately to hours; therefore, monitoring of patients after overdose with UBRELVY should continue for at least 24 hours, or while symptoms or signs persist.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL. NDC 0023-6498-02Ubrelvy(ubrogepant) tablet50 mgRx onlycontains Tablet NDC 0023-6498-02Ubrelvy(ubrogepant) tablet50 mgRx onlycontains Tablet. NDC 0023-6498-02Ubrelvy(ubrogepant) tablet50 mgRx onlycontains Tablet.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.

PHARMACODYNULLMICS SECTION.


12.2 Pharmacodynamics. Cardiac ElectrophysiologyAt dose times the maximum recommended daily dose, UBRELVY does not prolong the QT interval to any clinically relevant extent.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics AbsorptionFollowing oral administration of UBRELVY, ubrogepant is absorbed with peak plasma concentrations at approximately 1.5 hours. Ubrogepant displays dose-proportional pharmacokinetics within the recommended dose range [see Dosage and Administration 2.1 )] Effect of FoodWhen UBRELVY was administered with high-fat meal, the time to maximum ubrogepant plasma concentration was delayed by hours and resulted in 22% reduction in Cmax with no change in AUC. UBRELVY was administered without regard to food in clinical efficacy studies [see Dosage and Administration 2.1 )]. DistributionPlasma protein binding of ubrogepant is 87% in vitro. The mean apparent central volume of distribution of ubrogepant (V/F) after single dose oral administration is approximately 350 L.Elimination MetabolismUbrogepant is eliminated mainly through metabolism, primarily by CYP3A4. The parent compound (ubrogepant), and glucuronide conjugate metabolites were the most prevalent circulating components in human plasma. The glucuronide metabolites are not expected to contribute to the pharmacological activity of ubrogepant since they were reported as about 6000-fold less potent in the CGRP receptor binding assay.ExcretionThe elimination half-life of ubrogepant is approximately 5-7 hours. The mean apparent oral clearance (CL/F) of ubrogepant is approximately 87 L/hr. Ubrogepant is excreted mostly via the biliary/fecal route, while the renal route is minor route of elimination. Following single oral dose administration of [14C]-ubrogepant to healthy male subjects, 42% and 6% of the dose was recovered as unchanged ubrogepant in feces and urine, respectively.Specific PopulationsPatients with Renal Impairment Population pharmacokinetic analysis based on pooled data from clinical studies was used to evaluate the effect of renal impairment characterized based on estimated creatinine clearance (CLcr) using the Cockcroft-Gault (C-G) equation. Renal impairment did not reveal significant difference in the pharmacokinetics of ubrogepant 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 ESRD (eGFR <30 mL/min) have not been studied. Dose adjustment in patients with severe renal impairment (CLcr 15-29 mL/min) is recommended based on ADME information and conservative assumption that severe renal impairment is unlikely to cause more than two-fold increase in exposure of ubrogepant [see Dosage and Administration 2.2 )]. No dosing recommendations can be made for patients with ESRD (CLcr<15 mL/min).Patients with 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), ubrogepant exposure was increased by 7%, 50%, and 115%, respectively. Patients with severe hepatic impairment require dose adjustments [see Dosage and Administration 2.2 )].Other Specific PopulationsBased on population pharmacokinetic analysis, age, sex, race, and body weight did not have significant effect on the pharmacokinetics (Cmax and AUC) of ubrogepant. Therefore, no dose adjustments are warranted based on these factors. Drug InteractionsIn Vitro StudiesEnzymesUbrogepant is not an inhibitor of CYP1A2, 2B6, or 3A4. Ubrogepant is weak inhibitor of CYP2C8, 2C9, 2D6, 2C19, MAO-A, and UGT1A1. The in vitro inhibition potential is not expected to be clinically significant. Ubrogepant is not an inducer of CYP1A2, 2B6, or 3A4 at clinically relevant concentrations. TransportersUbrogepant is substrate of BCRP and P-gp transporters in-vitro; therefore, use of inhibitors of BCRP and/or P-gp may increase the exposure of ubrogepant. Dose adjustment for concomitant use of UBRELVY with inhibitors of BCRP and/or P-gp is recommended based on ADME and clinical interaction studies with CYP3A4/P-gp inhibitors that show the highest predicted potential increase in exposure of ubrogepant is not expected to be more than two-fold [see Dosage and Administration 2.2 and Drug Interactions 7.3)]. Ubrogepant is weak substrate of OATP1B1, OATP1B3, and OAT1, but not substrate of OAT3. It is not an inhibitor of P-gp, BCRP, BSEP, MRP3, MRP4, OAT1, OAT3, or NTCP transporters, but is weak inhibitor of OATP1B1, OATP1B3, and OCT2 transporters. Dose adjustments are needed only for P-gp, or BCRP inhibitors. No clinical drug interactions are expected for UBRELVY with other transporters. In Vivo Studies CYP3A4 Inhibitors [see Dosage and Administration 2.2 ), Contraindications 4 ), and Dr ug Interactions 7.1)]:Co-administration of UBRELVY with ketoconazole, strong CYP3A4 inhibitor, resulted in 9.7-fold and 5.3-fold increase in AUCinf and Cmax of ubrogepant, respectively. Co-administration of UBRELVY with verapamil, moderate CYP3A4 inhibitor, resulted in about 3.5-fold and 2.8-fold increase in AUCinf and Cmax of ubrogepant, respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors. The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold.CYP3A4 Inducers [see Dosage and Administration 2.2 and Drug Interactions 7.2)]:Co-administration of UBRELVY with rifampin, strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with weak or moderate CYP3A4 inducers. Dose adjustment for concomitant use of UBRELVY with weak or moderate CYP3A4 inducers is recommended based on conservative prediction of 50% reduction in exposure of ubrogepant.Other Drug-Drug Interaction Evaluations:No significant pharmacokinetic interactions were observed for either ubrogepant or co-administered drugs when UBRELVY was administered with oral contraceptives (containing norgestimate and ethinyl estradiol), acetaminophen, naproxen, sumatriptan, or esomeprazole (a proton pump inhibitor).

PREGNULLNCY SECTION.


8.1 Pregnancy. Risk SummaryThere are no adequate data on the developmental risk associated with the use of UBRELVY in pregnant women. In animal studies, adverse effects on embryofetal development were observed following administration of ubrogepant during pregnancy (increased embryofetal mortality in rabbits) or during pregnancy and lactation (decreased body weight in offspring in rats) at doses greater than those used clinically and which were associated with maternal toxicity 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 ConsiderationsDisease-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.DataAnimal DataOral administration of ubrogepant (0, 1.5, 5, 25, 125 mg/kg/day) to pregnant rats during the period of organogenesis resulted in no adverse effects on embryofetal development. Plasma exposure (AUC) at the highest dose tested is approximately 45 times that in humans at the maximum recommended human dose (MRHD) of 200 mg/day.In pregnant rabbits, ubrogepant (0, 15, 45, 75, or 250 mg/kg/day) was administered orally throughout organogenesis in two separate studies. In both studies, the highest dose tested (250 mg/kg/day) was associated with maternal toxicity. In the first study, ubrogepant produced abortion and increased embryofetal mortality in surviving litters at the high dose (250 mg/kg/day). In the second study, excessive maternal toxicity at the high dose (250 mg/kg/day) resulted in early termination and lack of fetal data for that dose group. Plasma exposure (AUC) at the highest no-effect dose (75 mg/kg/day) for adverse effects on embryofetal development in rabbit is approximately times that in humans at the MRHD.Oral administration of ubrogepant (0, 25, 60, or 160 mg/kg/day) to rats throughout gestation and lactation resulted in decreased body weight in offspring at birth and during the lactation period at the mid and high doses, which were associated with maternal toxicity. Plasma exposure (AUC) at the no-effect dose for adverse effects on pre- and postnatal development in rats (25 mg/kg/day) is approximately 15 times that in humans at the MRHD.

SPL PATIENT PACKAGE INSERT SECTION.


Patient InformationUBRELVY(R) (you- brel -vee) (ubrogepant)tablets, for oral useWhat is UBRELVYUBRELVY is prescription medicine used for the acute treatment of migraine attacks with or without aura in adults.UBRELVY is not used to prevent migraine headaches.It is not known if UBRELVY is safe and effective in children.Do not take UBRELVY if you are taking medicines known as strong CYP3A4 inhibitor, such as:ketoconazole clarithromycin itraconazoleAsk your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take UBRELVY with other medicines.Before you take UBRELVY tell your healthcare provider about all of your medical conditions, including if you:have liver problems have kidney problems are pregnant or plan to become pregnant. It is not known if UBRELVY will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if UBRELVY passes into your breast milk.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take any of the following, as your healthcare provider may need to change the dose of UBRELVY: verapamil cyclosporine ciprofloxacin fluconazole fluvoxamineo phenytoin barbiturates rifampin St. Johns Worto quinidine carvedilol eltrombopag curcumin These are not all of the medicines that could affect how UBRELVY works. Your healthcare provider can tell you if it is safe to take UBRELVY with other medicines. Keep list of medicines you take to show to your healthcare provider or pharmacist when you get new medicine.How should take UBRELVYTake UBRELVY exactly as your healthcare provider tells you to take it. Take UBRELVY with or without food. Most patients can take second tablet hours after the first tablet, as needed. You should not take second tablet within 24 hours if you consume grapefruit or grapefruit juice or are taking medications that may include: verapamil cyclosporine ciprofloxacin fluconazole fluvoxamineIt is not known if it is safe to take UBRELVY for more than migraine headaches in 30 days. You should write down when you have headaches and when you take UBRELVY so you can talk to your healthcare provider about how UBRELVY is working for you. If you take too much UBRELVY, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of UBRELVYThe most common side effects of UBRELVY are nausea and sleepiness. These are not all of the possible side effects of UBRELVY. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store UBRELVYStore UBRELVY at room temperature between 68oF to 77oF (20oC to 25oC).Keep UBRELVY and all medicines out of the reach of children.General information about the safe and effective use of UBRELVY.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use UBRELVY for condition for which it was not prescribed. Do not give UBRELVY to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about UBRELVY that is written for health professionals.What are the ingredients in UBRELVY Active ingredient: ubrogepant Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, mannitol, microcrystalline cellulose, polyvinylpyrrolidone vinyl acetate copolymer, sodium chloride, sodium stearyl fumarate, and vitamin polyethylene glycol succinate.Manufactured by: Forest Laboratories Ireland Ltd.,Dublin, IrelandDistributed by: Allergan USA, Inc.Madison, NJ 07940(C) 2021 Allergan. All rights reserved.UBRELVY(R) is registered trademark of Allergan Pharmaceuticals International Limited.Allergan(R) and its design are trademarks of Allergan, Inc.Patented. See www.allergan.com/patents This Patient Package Insert has been approved by the U.S. Food and Drug Administration Issued: 3/2021 v1.3PPI6498. ketoconazole clarithromycin itraconazole. have liver problems have kidney problems are pregnant or plan to become pregnant. It is not known if UBRELVY will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if UBRELVY passes into your breast milk.. Take UBRELVY exactly as your healthcare provider tells you to take it. Take UBRELVY with or without food. Most patients can take second tablet hours after the first tablet, as needed. You should not take second tablet within 24 hours if you consume grapefruit or grapefruit juice or are taking medications that may include:. It is not known if it is safe to take UBRELVY for more than migraine headaches in 30 days. You should write down when you have headaches and when you take UBRELVY so you can talk to your healthcare provider about how UBRELVY is working for you. If you take too much UBRELVY, call your healthcare provider or go to the nearest hospital emergency room right away. Store UBRELVY at room temperature between 68oF to 77oF (20oC to 25oC).. Allergan.

SPL UNCLASSIFIED SECTION.


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

STORAGE AND HANDLING SECTION.


16.2 Storage and Handling Store between 20C and 25C (68F and 77F): excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature ].

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm. (8.1) Avoid use in patients with end-stage renal disease. (8.7). Pregnancy: Based on animal data, may cause fetal harm. (8.1) Avoid use in patients with end-stage renal disease. (8.7). 8.1 Pregnancy. Risk SummaryThere are no adequate data on the developmental risk associated with the use of UBRELVY in pregnant women. In animal studies, adverse effects on embryofetal development were observed following administration of ubrogepant during pregnancy (increased embryofetal mortality in rabbits) or during pregnancy and lactation (decreased body weight in offspring in rats) at doses greater than those used clinically and which were associated with maternal toxicity 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 ConsiderationsDisease-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.DataAnimal DataOral administration of ubrogepant (0, 1.5, 5, 25, 125 mg/kg/day) to pregnant rats during the period of organogenesis resulted in no adverse effects on embryofetal development. Plasma exposure (AUC) at the highest dose tested is approximately 45 times that in humans at the maximum recommended human dose (MRHD) of 200 mg/day.In pregnant rabbits, ubrogepant (0, 15, 45, 75, or 250 mg/kg/day) was administered orally throughout organogenesis in two separate studies. In both studies, the highest dose tested (250 mg/kg/day) was associated with maternal toxicity. In the first study, ubrogepant produced abortion and increased embryofetal mortality in surviving litters at the high dose (250 mg/kg/day). In the second study, excessive maternal toxicity at the high dose (250 mg/kg/day) resulted in early termination and lack of fetal data for that dose group. Plasma exposure (AUC) at the highest no-effect dose (75 mg/kg/day) for adverse effects on embryofetal development in rabbit is approximately times that in humans at the MRHD.Oral administration of ubrogepant (0, 25, 60, or 160 mg/kg/day) to rats throughout gestation and lactation resulted in decreased body weight in offspring at birth and during the lactation period at the mid and high doses, which were associated with maternal toxicity. Plasma exposure (AUC) at the no-effect dose for adverse effects on pre- and postnatal development in rats (25 mg/kg/day) is approximately 15 times that in humans at the MRHD.. 8.2 Lactation There are no data on the presence of ubrogepant in human milk, the effects of ubrogepant on the breastfed infant, or the effects of ubrogepant on milk production. In lactating rats, oral dosing with ubrogepant resulted in levels of ubrogepant in milk comparable to peak plasma concentrations. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for UBRELVY and any potential adverse effects on the breastfed infant from UBRELVY or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use. In pharmacokinetic studies, no clinically significant pharmacokinetic differences were observed between elderly and younger subjects. Clinical studies of UBRELVY did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.. 8.6 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), ubrogepant exposure was increased by 7%, 50%, and 115%, respectively. No dose adjustment is recommended for patients with mild or moderate hepatic impairment. Dose adjustment for UBRELVY is recommended for patients with severe hepatic impairment s ee Dosage and Administration 2.2 ].. 8.7 Renal Impairment. The renal route of elimination plays minor role in the clearance of ubrogepant [see Clinical Pharmacology 12.3 )] No dose adjustment is recommended for patients with mild or moderate renal impairment. Dose adjustment is recommended for patients with severe renal impairment (CLcr 15-29 mL/min) [see Dosage and Administration 2.2 and Clinical Pharmacology 12.3 )]. Avoid use of UBRELVY in patients with end-stage renal disease (ESRD) (CLcr <15 mL/min).