Ubrelvy Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................... 2

Table of Contents ................................................................................................................... 2

Part 1: Healthcare Professional Information ........................................................................... 4

1. 1.

   Indications ....................................................................................................................... 4

   1.1. Pediatrics .................................................................................................................. 4

   1.2. Geriatrics .................................................................................................................. 4

2. 2. Contraindications ............................................................................................................ 4
3. 4.

   Dosage and Administration ............................................................................................. 4

   4.1. Dosing Considerations .............................................................................................. 4

   4.2. Recommended Dose and Dosage Adjustment ......................................................... 5

   4.3. Reconstitution .......................................................................................................... 5

   4.4. Administration .......................................................................................................... 5

4. 5. Overdose ......................................................................................................................... 5
5. 6. Dosage Forms, Strengths, Composition, and Packaging ................................................... 6
6. 7.

   Warnings and Precautions ............................................................................................... 6

   Driving and Operating Machinery ......................................................................................... 6

   Immune ................................................................................................................................ 6

   Reproductive Health ............................................................................................................. 6

   7.1. Special Populations .................................................................................................. 7

   7.1.1. Pregnancy ........................................................................................................ 7

   7.1.2. Breastfeeding .................................................................................................. 7

   7.1.3. Pediatrics ......................................................................................................... 7

   7.1.4. Geriatrics ......................................................................................................... 7

7. 8.

   Adverse Reactions ........................................................................................................... 8

   8.1. Adverse Reaction Overview ...................................................................................... 8

   8.2. Clinical Trial Adverse Reactions ................................................................................ 8

   8.2.1. Clinical Trial Adverse Reactions – Pediatrics .................................................... 9

   8.3. Less Common Clinical Trial Adverse Reactions ......................................................... 9

   8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data ................................................................................................................. 9

   8.5. Post-Market Adverse Reactions ............................................................................... 9

8. 9.

   Drug Interactions ............................................................................................................. 9

   9.2. Drug Interactions Overview ...................................................................................... 9

   9.3. Drug-Behaviour Interactions .................................................................................. 10

   9.4. Drug-Drug Interactions ........................................................................................... 10

   9.5. Drug-Food Interactions........................................................................................... 12

   9.6. Drug-Herb Interactions ........................................................................................... 12

   9.7. Drug-Laboratory Test Interactions ......................................................................... 12

9. 10.

   Clinical Pharmacology ................................................................................................... 12

   10.1. Mechanism of Action .............................................................................................. 12

   10.2. Pharmacodynamics ................................................................................................ 13

   10.3. Pharmacokinetics ................................................................................................... 13

10. 11. Storage, Stability, and Disposal ...................................................................................... 14

Part 2: Scientific Information ................................................................................................ 15

1. 13. Pharmaceutical Information .......................................................................................... 15
2. 14.

   Clinical Trials .................................................................................................................. 16

   14.1. Clinical Trials by Indication ..................................................................................... 16

   Acute Treatment of Migraine, With or Without Aura ................................................... 16

3. 16. Non-Clinical Toxicology .................................................................................................. 18

Patient Medication Information ........................................................................................... 20

Part 1: Healthcare Professional Information

1. Indications

UBRELVY® (ubrogepant tablets) is indicated for:

• acute treatment of migraine, with or without aura, in adults.

1.1. Pediatrics

Pediatrics (< 18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2. Geriatrics

Clinical studies of UBRELVY did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Caution should be exercised in dose selection for an elderly patient, recognizing the more frequent hepatic and renal dysfunctions in this population (see 4.2 Recommended Dose and Dosage Adjustment and 10.3 Pharmacokinetics).

2. Contraindications

UBRELVY is contraindicated:

• In patients with hypersensitivity to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition and Packaging.
• With concomitant use of strong CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) (see 9.4 Drug-Drug Interactions).

4. Dosage and Administration

4.1. Dosing Considerations

• The maximum daily dose of UBRELVY should not exceed 200 mg.
• Dose adjustments are recommended in patients with severe hepatic (Child-Pugh Class C) or renal (CrCl 15-29 mL/min) impairment (see 10.3 Pharmacokinetics and 4.2 Recommended Dose and Dosage Adjustment).
• UBRELVY is contraindicated in patients taking strong CYP3A4 inhibitors (see 2 Contraindications).
• Dose adjustments are recommended in patients who are taking mild or moderate CYP3A4 inhibitors or inducers as well as BCRP and/or P-gp only Inhibitors (see 9.4 Drug-Drug Interactions).
• Consumption of a high-fat meal delays ubrogepant peak plasma concentrations (see 10.3 Pharmacokinetics).

4.2. Recommended Dose and Dosage Adjustment

• Adults (≥ 18 years of age): The recommended dose of UBRELVY is 50 mg or 100 mg taken orally, with or without food. If needed, an optional second dose may be taken, at least 2 hours after the initial dose. The maximum daily dose is 200 mg. The safety of taking more than 16 doses in a 30 day period has not been established.
• Pediatrics (< 18 years of age): Health Canada has not authorized an indication for pediatric use.
• Geriatrics: There is limited data available involving the use of UBRELVY in patients aged 65 and over. Caution should be exercised when using UBRELVY in elderly patients. The recommended dose for elderly patients is 50 mg. The optional second dose should also be limited to 50 mg, for a maximum daily dose of 100 mg.
• Patients with Hepatic Insufficiency: UBRELVY is metabolized primarily in the liver. Ubrogepant exposure is increased in patients with hepatic impairment. In patients with severe hepatic impairment (Child-Pugh Class C), doses should be limited to 50 mg for both the initial dose and the optional second dose, for a maximum daily dose of 100 mg (see 10.3 Pharmacokinetics).
• Patients with Renal Insufficiency: There is limited experience with the use of UBRELVY in patients with renal insufficiency. While renal clearance is not a significant route of elimination for ubrogepant, dose adjustments are recommended for patients with severe renal impairment (CrCl 15-29 mL/min). In these patients, it is recommended that doses be limited to 50 mg for both the initial dose and the optional second dose, for a maximum daily dose of 100 mg. The use of UBRELVY in patients with end-stage renal disease (ESRD) (CrCl <15 mL/min) is not recommended (see 10.3 Pharmacokinetics).

4.3. Reconstitution

Not applicable

4.4. Administration

UBRELVY should be taken orally, with or without food (see 10.3 Pharmacokinetics).

5. Overdose

A supratherapeutic dose of 400 mg (2 times maximum recommended human dose (MRHD)) once daily for 10 days was safe and well tolerated by healthy volunteers. The elimination half-life of ubrogepant is approximately 5 to 7 hours, therefore monitoring of patients after overdose with UBRELVY should continue for at least 24 hours or while symptoms or signs persist.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 1 – Dosage Forms, Strengths, and Composition

Description

UBRELVY 50 mg tablets are formulated for oral use as white to off-white, capsule-shaped, biconvex tablets debossed with “U50” on one side.

UBRELVY 100 mg tablets are formulated for oral use as white to off-white, capsule-shaped, biconvex tablets debossed with “U100” on one side.

Tablets are packaged in unit-dose packets and supplied in cartons of:

• 1 packet (physician sample only)
• 10 packets

7. Warnings and Precautions

Driving and Operating Machinery

Somnolence is a common adverse event associated with the use of UBRELVY. Patients should be advised to exercise caution when driving or operating a vehicle or potentially dangerous machinery (see 8.2 Clinical Trial Adverse Reactions).

Immune

Hypersensitivity reactions, including rash, urticaria, facial edema, and dyspnea, have been reported with use of UBRELVY. Most reactions occurred within hours after dosing and were not serious. Some hypersensitivity reactions led to discontinuation. If a serious hypersensitivity reaction occurs, discontinue UBRELVY and institute appropriate therapy.

Reproductive Health

The use of UBRELVY may reduce the effectiveness of oral contraceptives. This should be taken into consideration when choosing the dose of oral contraceptives. Supplemental methods of birth control should also be considered (see 9.4 Drug-Drug Interactions).

7.1. Special Populations

7.1.1. Pregnancy

The use of UBRELVY in pregnant women is not recommended.

The use of UBRELVY in pregnancy during clinical trials was very limited. Data on pregnancy exposure during clinical trials are insufficient to inform the risk of maternal,

fetal, and infant outcomes associated with the use of ubrogepant. UBRELVY should not be used by pregnant women unless the expected benefit to the mother outweighs the potential risk to the fetus.

CGRP may play an important role in supporting a normal healthy pregnancy.

In animal studies, adverse effects on embryofetal development were observed following administration of ubrogepant during pregnancy, including abortion and increased embryofetal mortality in rabbits and decreased body weight in offspring in rats, at doses greater than those used clinically and which were associated with maternal toxicity (see 16 Non-Clinical Toxicology).

In embryofetal toxicity studies in rats and rabbits, there were no treatment-related external visceral, coronal, or skeletal malformations or variations. Therefore, no evidence of teratogenicity has been observed in rats or rabbits with UBRELVY (see 16 Non-Clinical Toxicology).

Several studies have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy.

Pregnancy registry

Patients who become pregnant while taking UBRELVY should be encouraged to enroll in the EMPRESS Pregnancy Registry at https://www.empresspregnancyregistry.ca, or call 1-844-467-0844 to speak to a registry representative. This registry is collecting information about the effect of UBRELVY exposure during pregnancy.

7.1.2. Breastfeeding

Data from a human lactation study shows minimal transfer of ubrogepant into breast milk following a single dose (see 10.3 Pharmacokinetics).

There are no data on the effects of ubrogepant on the breastfed infant or on milk production.

The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for UBRELVY and any potential adverse effects on the breastfed infant from UBRELVY or from the underlying maternal condition.

7.1.3. Pediatrics

Pediatrics (< 18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4. Geriatrics

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, elderly patients are more likely to have reduced hepatic and renal function, which may affect ubrogepant exposure. Dose selection for an elderly patient should be cautious, limiting doses to 50 mg for the initial and optional second dose (see 4.2 Recommended Dose and Dosage Adjustment).

8. Adverse Reactions

8.1. Adverse Reaction Overview

Ubrogepant is generally safe and well-tolerated. Most adverse reactions were mild or moderate and the frequencies were low and comparable between ubrogepant and placebo-treated patients. The most commonly reported adverse reactions are nausea, somnolence, and dry mouth (see Error! Reference source not found.).

In an open-label 52 week study 2.5% of patients discontinued due to an adverse event, however, no single event led to discontinuation in more than 2 patients. Incidence of serious adverse events with ubrogepant in this study was low and comparable to usual care, defined as the medications a patient routinely used to relieve a migraine attack (4.1% - usual care; 2.2% ubrogepant 50 mg; 2.9% ubrogepant 100 mg).

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

The safety of UBRELVY was evaluated in 3664 subjects who received at least one dose of UBRELVY. In the two randomized, double-blind, placebo-controlled, Phase 3 trials in adult patients with migraine (ACHIEVE I and ACHIEVE II), a total of 1439 patients received UBRELVY 50 mg or 100 mg (see 14 Clinical Trials). Of the UBRELVY-treated patients in these 2 studies, approximately 89% were female, 82% were Caucasian, 15% were Black, 1% were Asian and 17% were of Hispanic or Latino ethnicity. The mean age at study entry was 41 years (range of 18-75).

Adverse reactions in the placebo-controlled studies are shown in Error! Reference source not found..

Table 2 – Adverse Reactions Occurring with an Incidence of at Least 2% for Either Dose of UBRELVY and at a Frequency at Least Twice the Rate of Placebo in Studies 1 and 2 (ACHIEVE I and II)

The incidence of adverse reactions in controlled clinical trials was not affected by gender, race, age or cardiovascular risk.

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. A total of 421 patients were exposed to 50 mg or 100 mg of UBRELVY for at least 6 months, and 364 patients were exposed to these doses for at least 1 year, all of whom treated at least 2 migraine attacks per month, on average. In this study 21,454 migraines were treated with UBRELVY. The overall safety profile in the open-label, long-term, 52-week safety study was consistent with the placebo-controlled Studies (ACHIEVE I and II) (see 14 Clinical Trials).

8.2.1. Clinical Trial Adverse Reactions – Pediatrics

The safety and efficacy of UBRELVY have not been studied in pediatric patients.

8.3. Less Common Clinical Trial Adverse Reactions

No less common adverse reactions (<2%), related to UBRELVY, were identified in Clinical Trials.

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data

Clinical Trial Findings

No abnormal laboratory findings were identified during clinical trials.

8.5. Post-Market Adverse Reactions

In addition to the adverse reactions reported during clinical studies, the adverse reaction, hypersensitivity (e.g. rash, urticaria, facial edema, dyspnea), has been identified during post-marketing experience.

9. Drug Interactions

9.2. Drug Interactions Overview

Ubrogepant is metabolized primarily by cytochrome P450 3A4 (CYP3A4). Drug interactions with medications that are inducers or inhibitors of CYP3A4 have been demonstrated. UBRELVY is contraindicated with concomitant use of strong CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) (see 2 Contraindications).

Ubrogepant is a 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 inhibitor of CYP1A2, 2B6, or 3A4. Ubrogepant is not an inducer of CYP1A2, 2B6 or 3A4 at clinically relevant concentrations.

Ubrogepant is a substrate of BCRP and P-gp efflux transporters in vitro; therefore, concomitant use of inhibitors of BCRP and/or P-gp (e.g., quinidine, carvedilol, eltrombopag, curcumin) may increase the exposure of ubrogepant.

Ubrogepant is a weak substrate of OATP1B1, OATP1B3, and OAT1, but not a substrate of OAT3. It is a weak inhibitor of OATP1B1, OATP1B3 and OCT2 transporters. It is not an inhibitor of P-gp, BCRP, BSEP, MRP3, MRP4, OAT1, OAT3, or NTCP transporters.

There are no clinically significant pharmacokinetic interactions with atogepant. Potential pharmacodynamic interactions may increase the risk of adverse reactions. Ubrogepant should be used with care when other gepants, such as atogepant, are used concurrently.

9.3. Drug-Behaviour Interactions

Drug-behavioural interactions have not been studied.

9.4. Drug-Drug Interactions

The drugs listed in Error! Reference source not found. are based on either drug interaction case reports or studies, or potential interactions due to expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 3 – Established or Potential Drug-Drug Interactions

Legend: CT = Clinical Trial; T = Theoretical

No clinically significant pharmacokinetic interactions were observed when UBRELVY was co-administered with acetaminophen, naproxen, sumatriptan, proton pump inhibitors (e.g., esomeprazole), erenumab, galcanezumab or atogepant.

9.5. Drug-Food Interactions

UBRELVY may be taken with or without food. When UBRELVY is taken with a high-fat meal, peak plasma concentrations are delayed (see 10.3 Pharmacokinetics). The effect of this delay on the efficacy of UBRELVY remains unknown.

Consumption of grapefruit and grapefruit juice may increase exposure of ubrogepant and should be avoided.

9.6. Drug-Herb Interactions

Interactions of UBRELVY with herbal products have not been studied.

St-John's Wort (Hypericum perforatum) is a strong inducer of CYP3A4 and has the potential to significantly reduce ubrogepant exposure. Concomitant use of UBRELVY with St-John’s Wort should be avoided.

Curcumin is an inhibitor of P-gp efflux transporters and CYP3A4 enzymes and has the potential to increase ubrogepant exposure. Patients taking curcumin should be advised to limit dosing to UBRELVY 50 mg for the initial dose and optional second dose.

Green tea extracts are inhibitors of intestinal P-gp and CYP3A4 enzymes. The ingestion of green tea extract or its associated catechins is not expected to result in clinically significant influences on ubrogepant exposure. However, some caution is advised in the consumption of significant amounts of green tea beverages or green tea extract in patients prescribed UBRELVY.

Feverfew (Tanacetum parthenium) may inhibit CYP3A4 enzyme activity, potentially increasing ubrogepant exposure.

9.7. Drug-Laboratory Test Interactions

Interference of UBRELVY with laboratory and/or diagnostic tests has not been studied.

10. Clinical Pharmacology

10.1. Mechanism of Action

Calcitonin gene-related peptide (CGRP) is a neuropeptide present in the peripheral and central nervous system. CGRP is released from sensory nerve endings during a migraine attack, particularly the nerve endings of sensory trigeminal ganglion neurons. Ubrogepant is a small molecule, high affinity (K_i = 0.07nM) CGRP receptor antagonist (gepant) that blocks the binding of CGRP to its receptor and antagonizes CGRP receptor function.

Ubrogepant may relieve migraine by blocking CGRP-induced neurogenic vasodilation, halting the cascade of CGRP-induced neurogenic inflammation, and/or inhibiting the central relay of pain signals from the trigeminal nerve to the caudal trigeminal nucleus.

In vitro studies in coronary, meningeal and cerebral artery strips indicate that ubrogepant lacks vasoconstrictive effects in cranial and coronary arteries.

10.2. Pharmacodynamics

For pain freedom, pain relief, sustained pain relief, and sustained pain freedom, ubrogepant demonstrates a significant exposure-response relationship. Differences between the 50 mg and 100 mg doses were minimal (see 14 Clinical Trials).

Abuse liability has not been studied in humans. Animal studies showed no indications of significant abuse potential, drug dependence or withdrawal.

In a double-blind, randomized, placebo- and positive-controlled, 4-period crossover ECG assessment study in healthy subjects (N=72), ubrogepant at single doses of 100 mg (therapeutic) and 400 mg (supratherapeutic) was not observed to have any pharmacodynamic effect on the QTcF interval.

10.3. Pharmacokinetics

Table 4 – Summary of Mean (±SD) Ubrogepant Pharmacokinetic Parameters in Migraine Patients and Healthy Subjects

Absorption

Ubrogepant is rapidly absorbed following oral administration of UBRELVY, with peak plasma concentrations observed around 1.5 hours post-dose.

Ubrogepant displays dose-proportional pharmacokinetics within the range 40 to 400 mg.

When UBRELVY was administered with a high-fat meal, the time to maximum ubrogepant plasma concentration was delayed by 2 hours and resulted in a 20% reduction in C_max with no change in AUC. The impact on UBRELVY efficacy of delayed exposure, associated with consumption of a high-fat meal, is unknown. UBRELVY may be taken with or without food.

Distribution

Plasma 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.

Metabolism

Ubrogepant is eliminated mainly through metabolism, primarily by CYP3A4. The parent compound (ubrogepant), and 2 glucuronide conjugate metabolites (M15 and M20) were the most prevalent circulating components in human plasma. The glucuronide metabolites are not expected to contribute to the pharmacological activity of ubrogepant, as M15 was approximately 6000-fold less potent in a CGRP receptor binding assay, while M20 is present at extremely low levels.

Elimination

The 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 a 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.

Special populations and conditions

• Pediatrics: The pharmacokinetics of ubrogepant in pediatric patients has not been studied. Health Canada has not authorized an indication for pediatric use.
• Geriatrics: Assessment of UBRELVY pharmacokinetics in patients 65 years of age and older is limited. The greater frequency of decreased hepatic, renal, or cardiac function, characteristic of the elderly, as well as concomitant disease and use of other medications may impact the pharmacokinetics of UBRELVY in this population. Caution should be exercised when dosing in the elderly (see 4.2 Recommended Dose and Dosage Adjustment).
• Sex: Based on population PK analysis, no clinically significant differences in the pharmacokinetics of ubrogepant were noted between men and women.

• Pregnancy and breastfeeding: It is not known whether ubrogepant crosses the placenta in humans (see 16 Non-Clinical Toxicology).

  In a study of 12 breastfeeding women, administered a single oral dose of ubrogepant 100 mg, transfer of ubrogepant into breast milk was minimal. The relative infant dose was approximately 0.15% of the maternal weight-adjusted dose with a milk to plasma ratio of 0.23. The cumulative amount of ubrogepant excreted in breast milk over 24 hours was minimal, at less than 0.02 mg. There are no data on the effects of ubrogepant on the breastfed infant or on milk production (see 7.1.2 Breastfeeding, 16 Non-Clinical Toxicology).

• Ethnic origin: As assessed by population PK analysis, no clinically significant differences in the pharmacokinetics of ubrogepant based on ethnic origin were observed.
• Hepatic Insufficiency: 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 required for patients that have mild or moderate hepatic impairment. Patients with severe hepatic impairment should be advised to use UBRELVY 50 mg (see 4.2 Recommended Dose and Dosage Adjustment).
• Renal Insufficiency: Population pharmacokinetic analysis based on pooled data from clinical studies was used to evaluate the effect of renal impairment characterized based on estimated creatine clearance (CLcr) using the Cockcroft-Gault (C-G) equation. No significant difference in the pharmacokinetics of ubrogepant was predicted in patients with mild to 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 (see 4.2 Recommended Dose and Dosage Adjustment).
• Storage, Stability, and Disposal

Store between 15˚C and 30˚C.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance(s): ubrogepant

Chemical name: (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

Molecular formula and molecular mass: Molecular formula is C₂₉H₂₆F₃N₅O₃ /Molecular weight is 549.6

Structural formula:

Physicochemical properties: Ubrogepant (as ubrogepant trihydrate) is a white to off-white powder. It is freely soluble in ethanol, methanol, acetone, acetonitrile and practically insoluble in water.

14. Clinical Trials

14.1. Clinical Trials by Indication

Acute Treatment of Migraine, With or Without Aura

Table 5 – Summary of Patient Demographics for Clinical Trials in Acute Treatment of Migraine

The efficacy of UBRELVY for the acute treatment of migraine was demonstrated in two multicenter, randomized, double-blind, placebo-controlled, single migraine attack studies.

These studies enrolled patients with a history of migraine with and without aura, according to the ICHD-3 beta diagnostic criteria, and who experienced 2 to 8 migraine attacks per month with moderate to severe headache pain. In Study 1 (ACHIEVE I), patients were randomized to receive UBRELVY 50 mg or 100 mg or placebo; and in Study 2 (ACHIEVE II), patients were randomized to receive UBRELVY 50 mg or placebo. Patients were permitted to use standard migraine preventive medications during the study. At baseline, 23% percent of patients were taking preventive medications for migraine. The most commonly used preventive medications were topiramate, onabotulinumtoxinA, propranolol, and amitriptyline.

These studies included patients with moderate to high risk for cardiovascular disease (11%) and excluded patients with any clinically significant cardiovascular or cerebrovascular disease.

In all studies, patients were instructed to treat a migraine with moderate to severe headache pain intensity within the first 4 hours of pain onset. An optional second dose of study medication (UBRELVY or placebo) or the patient’s usual acute treatment for migraine was allowed 2 to 48 hours after the initial treatment for a non-responding or recurrent migraine headache.

The co-primary endpoints were the percentage of patients with:

• Migraine headache pain-freedom, defined as reduction in headache severity from moderate or severe pain to no pain, assessed at 2 hours after initial dosing.
• Most bothersome symptom (MBS) freedom, defined as the absence of the self-identified MBS, other than headache pain (i.e., photophobia, phonophobia, or nausea), assessed at 2 hours after initial dosing.

Among patients who selected a MBS, the most commonly selected was photophobia (56%), followed by phonophobia (24%), and nausea (19%).

Migraine headache pain relief (defined as reduction in headache severity from moderate or severe pain to mild or no pain) and absence of individual symptoms of photophobia, phonophobia, and nausea were assessed at 2 hours after initial dosing, as secondary endpoints.

Sustained pain relief (defined as mild to no pain at 2 hours and continued pain relief without the use of study medication or other acute treatment) and sustained pain freedom (defined as no pain at 2 hours and continued pain freedom without the use of study medication or other acute treatment) were assessed at 24 and 48 hours after dosing.

In both studies, the percentage of patients achieving migraine headache pain freedom and MBS freedom at 2 hours after initial dosing was significantly greater among patients receiving UBRELVY compared to those who received placebo. The results for primary and secondary endpoints are shown in Error! Reference source not found..

Table 6 – Results of Key Endpoints in Subjects with Acute Migraine in Studies ACHIEVE I and ACHIEVE II (modified ITT population^a)

16. Non-Clinical Toxicology

General toxicology: At high doses in rats, a decrease in body weight gain and a reversible epithelial vacuolation of the small intestine was observed at exposures 8.5-fold the anticipated clinical exposure (AUC) after a 200 mg dose. No adverse effects were observed in monkeys up to the highest dose level tested which represents an 81-fold margin above the anticipated clinical exposure after a 200 mg dose.

Genotoxicity: Ubrogepant was negative in the Ames test, chromosomal aberration test in Chinese Hamster Ovary cells, and in the in vivo rat bone marrow micronucleus test.

Carcinogenicity Two-year carcinogenicity studies have been conducted with ubrogepant in CD-1 mice at doses up to 50 mg/kg/day and in Wistar-Han rats at doses up to 100 mg/kg/day in males and 150 mg/kg/day in females. Oral administration of ubrogepant for 104 weeks did not produce tumors in rats or mice. The highest dose tested in mice is similar to the maximum recommended human dose (200 mg/day) on a 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 MRHD of 200 mg/day.

Reproductive and developmental toxicology: Oral administration of ubrogepant (1.5, 5, 25, 125 mg/kg/day) to pregnant rats during the period of organogenesis resulted in no embryo-fetal toxicity. Plasma exposure (AUC) at high dose in animals is approximately 45 times that in humans at the MRHD of 200 mg/day.

In a similar study in rabbits at oral doses of 15, 45, 75, or 250 mg/kg/day, maternal toxicity consisting of blood in the cage pan, abortions, body weight loss and decreased food consumption was observed at 250 mg/kg/day and led to early termination of the dose group prior to litter assessment. Maternal toxicity was observed at 75 mg/kg/day however there was no embryo-fetal toxicity at this dose level. Plasma exposure (AUC) at the highest no-effect dose (75 mg/kg/day) for adverse effects on embryofetal development in rabbit is approximately 8 times that in humans at the MRHD.

In the embryo-fetal toxicity studies in rats and rabbits, there were no treatment-related external, visceral, coronal, or skeletal malformations or variations. Ubrogepant was not teratogenic in these studies.

In a prenatal-postnatal development study where rats received oral administration of ubrogepant at doses of 25, 60 and 160 mg/kg/day throughout gestation and lactation, reduced maternal body weights and food consumption at doses ≥ 60 mg/kg/day resulted in reduced body weights in the pups at the same doses. There were no developmental effects on sexual maturation, memory and learning, or fertility. Ubrogepant was excreted into breast milk, with concentrations that were comparable to peak plasma concentrations. Plasma exposure (AUC) at the no-effect dose (25 mg/kg/day) is approximately 15 times that in humans at the MRHD.

Impairment of fertility: Ubrogepant, at oral doses up to 160 mg/kg/day, was found to have no adverse effect on fertility and reproductive performance of male and female rats.

Juvenile toxicity: Administration of ubrogepant, at oral doses up to 160 mg/kg/day, to juvenile rats from postnatal day 28 through postnatal day 70 was associated with reductions in body weights and body weight gains and effects on acoustic startle habituation in males at 160 mg/kg/day and learning and memory in the females at ≥ 20 mg/kg/day during the dose period, however, these showed full recovery during the off-dose period and were not considered adverse. There were no other drug related effects observed. The no-observed-adverse-effect level (NOAEL) for the males and females was 160 mg/kg/day. Plasma exposures (AUC) at the NOAEL are approximately 90 times the estimated pediatric exposures.