advise patients not to drive or operate machinery until they have gained
`sufficient experience on BRIVIACT. (5.2)
`
`
`
` Psychiatric Adverse Reactions: Behavioral reactions including psychotic
`symptoms, irritability, depression, aggressive behavior, and anxiety;
`
`monitor patients for symptoms. (5.3)
` Hypersensitivity: Bronchospasm and Angioedema: Advise patients to seek
`immediate medical care. Discontinue and do not restart BRIVIACT if
`hypersensitivity occurs. (5.4)
` Withdrawal of Antiepileptic Drugs: BRIVIACT should be gradually
`withdrawn. (5.5)
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`Most common adverse reactions (at least 5% for BRIVIACT and at least 2%
`more frequently than placebo) are somnolence/sedation, dizziness, fatigue,
`and nausea/vomiting. (6.1)
`
`
`
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at
`1-844-599-2273 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS------------------------------­
`
`
` Rifampin: Because of decreased BRIVIACT concentrations, increasing
`BRIVIACT dosage in patients on concomitant rifampin is recommended.
`
`(2.6, 7.1)
`
`
` Carbamazepine: Because of
`to carbamazepine
`increased exposure
`
`metabolite, if tolerability issues arise, consider reducing carbamazepine
`dosage in patients on concomitant BRIVIACT. (7.2)
`
`
` Phenytoin: Because phenytoin concentrations can increase, phenytoin
`
`
`levels should be monitored in patients on concomitant BRIVIACT. (7.3)
`
`
`
` Levetiracetam: BRIVIACT had no added therapeutic benefit when co­
`administered with levetiracetam. (7.4)
`
`
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------­
`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`
`
`
`Revised: 06/2016
`
`8
`
`9
`
`13
`
`
`USE IN SPECIFIC POPULATIONS
`8.1
` Pregnancy
`8.2 Labor and Delivery
`8.3
` Nursing Mothers
`8.4
` Pediatric Use
`8.5
` Geriatric Use
`8.6
` Renal Impairment
`8.7
` Hepatic Impairment
`DRUG ABUSE AND DEPENDENCE
`9.1
` Controlled Substance
`9.2
` Abuse
`9.3
` Dependence
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`
` NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage and Handling
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`listed.
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`BRIVIACT® safely and effectively. See full prescribing information for
`BRIVIACT.
`
`BRIVIACT® (brivaracetam) tablets, for oral use, CV
`
`
`BRIVIACT® (brivaracetam) oral solution, CV
`
`
`BRIVIACT® (brivaracetam) injection, for intravenous use, CV
`
`
`Initial U.S. Approval: 2016
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
`BRIVIACT is indicated as adjunctive therapy in the treatment of partial-onset
`seizures in patients 16 years of age and older with epilepsy. (1)
`
`
`
`
`
`
`
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`
` The recommended starting dosage is 50 mg twice daily. Based on
`
`individual patient tolerability and therapeutic response, the dosage may be
`
`adjusted down to 25 mg twice daily (50 mg per day) or up to 100 mg twice
`daily (200 mg per day). (2.1)
`
` BRIVIACT injection may be used when oral administration is temporarily
`not feasible.
`Impairment: For all stages of hepatic
` Hepatic
`the
`impairment,
`recommended starting dosage is 25 mg twice daily; maximum dosage is 75
`
`mg twice daily. (2.5, 8.7, 12.3)
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
` Tablets: 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg (3)
`
` Oral solution: 10 mg/mL (3)
`
` Injection: 50 mg/5 mL single-dose vial (3)
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`
`Hypersensitivity to brivaracetam or any of the inactive ingredients in
`
`
`BRIVIACT. (4)
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
` Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and
`
`ideation. (5.1)
`
` Neurological Adverse Reactions: Monitor for somnolence and fatigue, and
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
`2
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`
` Dosage Information
`2.1
`2.2 Administration Instructions for BRIVIACT Tablets and
`
`BRIVIACT Oral Solution
`2.3 Preparation and Administration Instructions for BRIVIACT
`
`Injection
`2.4 Discontinuation of BRIVIACT
`2.5 Patients with Hepatic Impairment
`
` Co-administration with Rifampin
`2.6
`
`3
`DOSAGE FORMS AND STRENGTHS
`
`4
`CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Suicidal Behavior and Ideation
`5.2 Neurological Adverse Reactions
`
`5.3 Psychiatric Adverse Reactions
` Hypersensitivity: Bronchospasm and Angioedema
`5.4
`
`
`5.5 Withdrawal of Antiepileptic Drugs
` ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
` DRUG INTERACTIONS
`
`
` Rifampin
`7.1
`
` Carbamazepine
`7.2
`7.3
` Phenytoin
`7.4
` Levetiracetam
`
`
`
`
`6
`
`7
`
`
`
`Reference ID: 3940707
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2138 - 1/18
`
`

`
`
`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`
`
`
`1
`
`BRIVIACT is indicated as adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with
`
`
`
`
`epilepsy.
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`
`2.1 Dosage Information
`
`
`When initiating treatment, gradual dose escalation is not required. The recommended starting dosage is 50 mg twice daily (100
`mg per day). Based on individual patient tolerability and therapeutic response, the dosage may be adjusted down to 25 mg twice
`
`
`daily (50 mg per day) or up to 100 mg twice daily (200 mg per day) [see Clinical Studies (14)].
`
`
`
`
`
`BRIVIACT injection may be used when oral administration is temporarily not feasible. BRIVIACT injection should be
`
`
`administered at the same dosage and same frequency as BRIVIACT tablets and oral solution.
`
`
`
`The clinical study experience with BRIVIACT injection is limited to 4 consecutive days of treatment.
`
`
`2.2 Administration Instructions for BRIVIACT Tablets and BRIVIACT Oral Solution
`
`
`BRIVIACT can be initiated with either intravenous or oral administration.
`
`
`
`
`
`BRIVIACT tablets and oral solution may be taken with or without food.
`
`
`
`BRIVIACT Tablets
`
`BRIVIACT tablets should be swallowed whole with liquid. BRIVIACT tablets should not be chewed or crushed.
`
`
`
`
`
`
`
`BRIVIACT Oral Solution
`
`
`A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or
`tablespoon is not an adequate measuring device.
`
`
`
`When using BRIVIACT oral solution, no dilution is necessary. BRIVIACT oral solution may also be administered using a
`
`
`
`nasogastric tube or gastrostomy tube.
`
`
`
`
`Discard any unused BRIVIACT oral solution remaining after 5 months of first opening the bottle.
`
`
`
`
`
`2.3 Preparation and Administration Instructions for BRIVIACT Injection
`
`
`
`
`
`BRIVIACT injection is for intravenous use only.
`
`Preparation
`
`BRIVIACT injection can be administered intravenously without further dilution or may be mixed with diluents listed below.
`
`
`
`
`
`
`
`
`Diluents
`0.9% Sodium Chloride injection, USP
`
`
`Lactated Ringer’s injection
`
`
`5% Dextrose injection, USP
`
`
`
`Administration
`
`BRIVIACT injection should be administered intravenously over 2 to 15 minutes.
`
`
`
`
`
`Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever
`solution and container permit. Product with particulate matter or discoloration should not be used. BRIVIACT injection is for
`
`
`
`
`single dose only.
`
`
`Storage and Stability
`
`
`
`
`Reference ID: 3940707
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2138 - 2/18
`
`

`
`The diluted solution should not be stored for more than 4 hours at room temperature and may be stored in polyvinyl chloride
`
`
`(PVC) bags. Discard any unused portion of the BRIVIACT injection vial contents.
`
`
`
`
`
`
`
`
`2.4 Discontinuation of BRIVIACT
`
`
`
`
`Avoid abrupt withdrawal from BRIVIACT in order to minimize the risk of increased seizure frequency and status epilepticus [see
`
`Warnings and Precautions (5.5) and Clinical Studies (14)].
`
`
`
`
`2.5 Patients with Hepatic Impairment
`
`
`
`For all stages of hepatic impairment, the recommended starting dosage is 25 mg twice daily (50 mg per day) and the
`recommended maximum dosage is 75 mg twice daily (150 mg per day) [see Use in Specific Populations (8.7) and Clinical
`
`
`
`Pharmacology (12.3)].
`
`
`
`2.6 Co-administration with Rifampin
`
`
`
`Increase the BRIVIACT dosage in patients on concomitant rifampin by up to 100% (i.e., double the dosage) [see Drug
`
`
`
`
`
`
`Interactions (7.1) and Clinical Pharmacology (12.3)].
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`Tablets
`
`
`
`
`
`
`
`
`
`
`
`
`10 mg: white to off white, round, film-coated, and debossed with "u10" on one side.
`
`
`
`
`
`
`
`
`25 mg: grey, oval, film-coated, and debossed with "u25" on one side.
`
`
`
`
`
`
`50 mg: yellow, oval, film-coated, and debossed with "u50" on one side.
`
`
`75 mg: purple, oval, film-coated, and debossed with “u75” on one side.
`
`
`
`100 mg: green-grey, oval, film-coated, and debossed with “u100” on one side.
`
`
`
`
`
`
`Oral Solution
`
`
`10 mg/mL: slightly viscous, clear, colorless to yellowish, raspberry-flavored liquid.
`
`
`
`
`Injection
`
`
`50 mg in 5 mL in one single-dose vial. It is a clear, colorless, sterile solution.
`
`
`
`
`
`
`4 CONTRAINDICATIONS
`
`
`
`Hypersensitivity to brivaracetam or any of the inactive ingredients in BRIVIACT (bronchospasm and angioedema have occurred)
`[see Warnings and Precautions (5.4)].
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Suicidal Behavior and Ideation
`
`
`
`
`Antiepileptic drugs (AEDs), including BRIVIACT, increase the risk of suicidal thoughts or behavior in patients taking these drugs
`
`
`
`for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of
`depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
`
`Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that
`
`
`
`
`
`patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal
`thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12
`weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to
`
`
`0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior
`for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients,
`
`
`but the number is too small to allow any conclusion about drug effect on suicide.
`
`
`The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment
`
`
`
`
`
`with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend
`beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3940707
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2138 - 3/18
`
`

`
`The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk
`
`with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for
`
`
`any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and
`
`
`relative risk by indication for all evaluated AEDs.
`
`
`
`Table 1: Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis
`
`
`
`Relative Risk:
`Incidence of Events
`
`in Drug
`
`Patients/Incidence
`
`in Placebo Patients
`
`3.5
`
`1.5
`
`1.9
`
`1.8
`
`Risk Difference:
`
`Additional Drug
`Patients with
`
`
`Events Per 1000
`Patients
`
`2.4
`
`2.9
`
`0.9
`
`1.9
`
`Drug
`Patients with
`Events Per
`1000
`Patients
`
`3.4
`
`8.5
`
`1.8
`
`4.3
`
`
`
`Indication
`
`Placebo
`Patients with
`Events Per
`1000
`
`Patients
`
`Epilepsy
`1.0
`
`Psychiatric 5.7
`
`1.0
`Other
`
`2.4
`Total
`
`
`
`
`
`
`
`
`
`The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in
`
`patients with psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric
`
`indications.
`
`
`Anyone considering prescribing BRIVIACT or any other AED must balance the risk of suicidal thoughts or behaviors with the
`
`
`
`
`risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with
`morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
`
`
`
`during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being
`treated.
`
`
`5.2 Neurological Adverse Reactions
`
`
`
`BRIVIACT causes somnolence, fatigue, dizziness, and disturbance in coordination. Patients should be monitored for these signs
`
`and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on BRIVIACT to gauge
`whether it adversely affects their ability to drive or operate machinery.
`
`
`
`
`Somnolence and Fatigue
`
`
`
`BRIVIACT causes dose-dependent increases in somnolence and fatigue-related adverse reactions (fatigue, asthenia, malaise,
`hypersomnia, sedation, and lethargy) [see Adverse Reactions (6.1)]. In the Phase 3 controlled adjunctive epilepsy trials, these
`events were reported in 25% of patients randomized to receive BRIVIACT at least 50 mg/day (20% at 50 mg/day, 26% at 100
`
`
`mg/day, and 27% at 200 mg/day) compared to 14% of patients who received placebo. The risk is greatest early in treatment but
`
`can occur at any time.
`
`
`
`Dizziness and Disturbance in Gait and Coordination
`
`
`
`
`BRIVIACT causes adverse reactions related to dizziness and disturbance in gait and coordination (dizziness, vertigo, balance
`disorder, ataxia, nystagmus, gait disturbance, and abnormal coordination) [see Adverse Reactions (6.1)]. In the Phase 3 controlled
`
`
`adjunctive epilepsy trials, these events were reported in 16% of patients randomized to receive BRIVIACT at least 50 mg/day
`
`compared to 10% of patients who received placebo. The risk is greatest early in treatment but can occur at any time.
`
`
`5.3 Psychiatric Adverse Reactions
`
`BRIVIACT causes psychiatric adverse reactions. In the Phase 3 controlled adjunctive epilepsy trials, psychiatric adverse reactions
`
`were reported in approximately 13% of patients who received BRIVIACT (at least 50 mg/day) compared to 8% of patients who
`received placebo. Psychiatric events included both non-psychotic symptoms (irritability, anxiety, nervousness, aggression,
`belligerence, anger, agitation, restlessness, depression, depressed mood, tearfulness, apathy, altered mood, mood swings, affect
`lability, psychomotor hyperactivity, abnormal behavior, and adjustment disorder) and psychotic symptoms (psychotic disorder
`
`
`
`
`along with hallucination, paranoia, acute psychosis, and psychotic behavior). A total of 1.7% of adult patients treated with
`BRIVIACT discontinued treatment because of psychiatric reactions compared to 1.3% of patients who received placebo.
`
`
`
`5.4 Hypersensitivity: Bronchospasm and Angioedema
`
`
`
`
`Reference ID: 3940707
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2138 - 4/18
`
`

`
`
`
`BRIVIACT can cause hypersensitivity reactions. Bronchospasm and angioedema have been reported in patients taking
`
`
`BRIVIACT. If a patient develops hypersensitivity reactions after treatment with BRIVIACT, the drug should be discontinued.
`BRIVIACT is contraindicated in patients with a prior hypersensitivity reaction to brivaracetam or any of the inactive ingredients
`[see Contraindications (4)].
`
`5.5 Withdrawal of Antiepileptic Drugs
`
`
`
`
`As with most antiepileptic drugs, BRIVIACT should generally be withdrawn gradually because of the risk of increased seizure
`frequency and status epilepticus [see Dosage and Administration (2.4) and Clinical Studies (14)]. But if withdrawal is needed
`
`because of a serious adverse event, rapid discontinuation can be considered.
`
`6
` ADVERSE REACTIONS
`
`
`The following serious adverse reactions are described elsewhere in labeling:
`
`
`
`
`
` Suicidal Behavior and Ideation [see Warnings and Precautions (5.1)]
`
`
`
`
`
` Neurological Adverse Reactions [see Warnings and Precautions (5.2)]
`
`
`
`
` Psychiatric Adverse Reactions [see Warnings and Precautions (5.3)]
`
`
`
` Hypersensitivity: Bronchospasm and Angioedema [see Warnings and Precautions (5.4)]
`
`
`
`
` Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.5)]
`
`
`
`
`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.
`
`
`
`
`
`
`In all controlled and uncontrolled trials performed in adult epilepsy patients, BRIVIACT was administered as adjunctive therapy
`to 2437 patients. Of these patients, 1929 were treated for at least 6 months, 1500 for at least 12 months, 1056 for at least 24
`months, and 758 for at least 36 months. A total of 1558 patients (1099 patients treated with BRIVIACT and 459 patients treated
`with placebo) constituted the safety population in the pooled analysis of Phase 3 placebo-controlled studies in patients with
`partial-onset seizures (Studies 1, 2, and 3) [see Clinical Studies (14)]. The adverse reactions presented in Table 2 are based on this
`
`safety population; the median length of treatment in these studies was 12 weeks. Of the patients in those studies, approximately
`
`51% were male, 74% were Caucasian, and the mean age was 38 years.
`
`In the Phase 3 controlled epilepsy studies, adverse events occurred in 68% of patients treated with BRIVIACT and 62% treated
`
`with placebo. The most common adverse reactions occurring at a frequency of at least 5% in patients treated with BRIVIACT
`doses of at least 50 mg/day and greater than placebo were somnolence and sedation (16%), dizziness (12%), fatigue (9%), and
`nausea and vomiting symptoms (5%).
`
`The discontinuation rates due to adverse events were 5%, 8%, and 7% for patients randomized to receive BRIVIACT at the
`
`recommended doses of 50 mg, 100 mg, and 200 mg/day, respectively, compared to 4% in patients randomized to receive placebo.
`
`
`
`
`
`Table 2 lists adverse reactions for BRIVIACT that occurred at least 2% more frequently for BRIVIACT doses of at least 50
`mg/day than placebo.
`
`Table 2: Adverse Reactions in Pooled Placebo-Controlled Adjunctive Therapy Studies in Patients with Partial-Onset
`
`Seizures (BRIVIACT 50 mg/day, 100 mg/day, and 200 mg/day)
`
`
`BRIVIACT
`(N=803)
`%
`
`
`5
`2
`
`
`16
`
`12
`9
`
`3
`
`Adverse Reactions
`
`
`Gastrointestinal disorders
`
`Nausea/vomiting symptoms
`Constipation
`Nervous system disorders
`
`
`Somnolence and sedation
`Dizziness
`Fatigue
`
`Cerebellar coordination and balance disturbances*
`
`
`
`Reference ID: 3940707
`
`Placebo
`(N=459)
`%
`
`
`3
`0
`
`
`8
`
`7
`4
`
`1
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2138 - 5/18
`
`

`
` Psychiatric disorders
`
`
`
`1
`3
`Irritability
`* Cerebellar coordination and balance disturbances includes ataxia, balance disorder, coordination abnormal, and nystagmus.
`
`
`
`
`
`
`There was no apparent dose-dependent increase in adverse reactions listed in Table 2 with the exception of somnolence and
`
`sedation.
`
`
`Hematologic Abnormalities
`
`BRIVIACT can cause hematologic abnormalities. In the Phase 3 controlled adjunctive epilepsy studies, a total of 1.8% of
`
`
`BRIVIACT-treated patients and 1.1% of placebo-treated patients had at least one clinically significant decreased white blood cell
`count (<3.0 x 109/L), and 0.3% of BRIVIACT-treated patients and 0% of placebo-treated patients had at least one clinically
`
`significant decreased neutrophil count (<1.0 x 109/L).
`
`
`
`
`Adverse Reactions with BRIVIACT Injection
`
`Adverse reactions with BRIVIACT injection were generally similar to those observed with BRIVIACT tablets. Other adverse
`events that occurred in at least 3% of patients who received BRIVIACT injection included dysgeusia, euphoric mood, feeling
`drunk, and infusion site pain.
`
`Comparison by Sex
`There were no significant differences by sex in the incidence of adverse reactions.
`
`
`
`7 DRUG INTERACTIONS
`
`7.1 Rifampin
`
`
`
`Co-administration with rifampin decreases BRIVIACT plasma concentrations likely because of CYP2C19 induction [see Clinical
`
`
`Pharmacology (12.3)]. Prescribers should increase the BRIVIACT dose by up to 100% (i.e., double the dosage) in patients while
`
`
`receiving concomitant treatment with rifampin [see Dosage and Administration (2.6)].
`
`7.2 Carbamazepine
`
`
`
`Co-administration with carbamazepine may increase exposure to carbamazepine-epoxide, the active metabolite of carbamazepine.
`Though available data did not reveal any safety concerns, if tolerability issues arise when co-administered, carbamazepine dose
`
`reduction should be considered [see Clinical Pharmacology (12.3)].
`
`
`
`7.3 Phenytoin
`
`
`
`Because BRIVIACT can increase plasma concentrations of phenytoin, phenytoin levels should be monitored in patients when
`concomitant BRIVIACT is added to or discontinued from ongoing phenytoin therapy [see Clinical Pharmacology (12.3)].
`
`
`
`
`7.4 Levetiracetam
`
`
`
`BRIVIACT provided no added therapeutic benefit to levetiracetam when the two drugs were co-administered [see Clinical
`
`Studies (14)].
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`Pregnancy Category C
`
`
`There are no adequate and well-controlled studies in pregnant women. In animal studies, brivaracetam produced evidence of
`
`
`developmental toxicity at plasma exposures greater than clinical exposures. BRIVIACT should be used during pregnancy only if
`
`
`
`the potential benefit justifies the potential risk to the fetus.
`
`Oral administration of brivaracetam (0, 150, 300, or 600 mg/kg/day) to pregnant rats during the period of organogenesis did not
`
`produce any significant maternal or embryofetal toxicity. The highest dose tested was associated with maternal plasma exposures
`
`
`
`
`Reference ID: 3940707
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2138 - 6/18
`
`

`
`
`
`(area under the brivaracetam plasma concentration versus time curve, an exposure metric, AUC) approximately 30 times
`
`exposures in humans at the maximum recommended dose (MRD) of 200 mg/day. Oral administration of brivaracetam (0, 30, 60,
`
`
`120, or 240 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in embryofetal mortality and decreased
`
`
`
`fetal body weights at the highest dose tested, which was also maternally toxic. The highest no-effect dose (120 mg/kg/day) was
`
`
`
`
`associated with maternal plasma exposures approximately 4 times human exposures at the MRD.
`
`
`
`When brivaracetam (0, 150, 300, or 600 mg/kg/day) was orally administered to rats throughout pregnancy and lactation,
`
`
`
`
`decreased growth, delayed sexual maturation (female), and long-term neurobehavioral changes were observed in the offspring at
`
`
`
`
`the highest dose. The highest no-effect dose (300 mg/kg/day) was associated with maternal plasma exposures approximately 7
`
`
`
`
`times human exposures at the MRD.
`
`
`Pregnancy Registry
`
`
`
`
`
`Physicians are advised to recommend that pregnant patients taking BRIVIACT enroll in the North American Antiepileptic Drug
`
`
`
`
`Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves.
`
`
`Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
`
`
`
`8.2 Labor and Delivery
`
`
`The effect of BRIVIACT on labor and delivery in humans is unknown.
`
`
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`8.3 Nursing Mothers
`
`
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`It is not known whether BRIVIACT is excreted in human milk. Studies in rats have shown excretion of brivaracetam in milk.
`
`
`
`
`
`Because many drugs are excreted into human milk, a decision should be made whether to discontinue nursing or to discontinue
`
`BRIVIACT, taking into account the importance of the drug to the mother.
`
`8.4 Pediatric Use
`
`
`
`Safety and effectiveness of BRIVIACT in adolescents 16 years of age have been established [see Clinical Studies (14)].
`
`
`
`
`Safety and effectiveness of BRIVIACT in patients less than 16 years of age have not been established.
`
`
`
`
`
`
`The potential adverse effects of brivaracetam on postnatal growth and development were investigated in juvenile rats and dogs.
`
`
`Oral administration (0, 150, 300, or 600 mg/kg/day) to rats during the neonatal and juvenile periods of development resulted in
`
`
`
`
`increased mortality, decreased body weight gain, delayed male sexual maturation, and adverse neurobehavioral effects at the
`
`
`highest dose tested and decreased brain size and weight at all doses. Therefore, a no-effect dose was not established; the lowest
`
`
`dose tested in juvenile rats was associated with plasma exposures (AUC) approximately 2 times those in adult humans at the
`
`
`
`
`
`maximum recommended dose (MRD) of 200 mg/day. In dogs, oral administration (0, 15, 30, or 100 mg/kg/day) throughout the
`
`neonatal and juvenile periods of development induced liver changes similar to those observed in adult animals at the highest dose
`
`but produced no adverse effects on growth, bone density or strength, neurological testing, or neuropathology evaluation. The
`
`
`
`
`overall no-effect dose (30 mg/kg/day) and the no-effect dose for adverse effects on developmental parameters (100 mg/kg/day)
`
`
`
`were associated with plasma exposures approximately equal to and 4 times, respectively, adult human exposures at the MRD.
`
`
`8.5 Geriatric Use
`
`
`
`There were insufficient numbers of patients 65 years of age and older in the double-blind, placebo-controlled epilepsy trials
`
`(n=38) to allow adequate assessment of the effectiveness of BRIVIACT in this population. In general, dose selection for an
`
`
`elderly patient should be judicious, usually starting at the low end of the dosing range, reflecting the greater frequency of
`
`
`
`
`
`decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology
`
`
`
`
`(12.3)].
`
`
`8.6 Renal Impairment
`
`
`Dose adjustments are not required for patients with impaired renal function. There are no data in patients with end-stage renal
`
`
`
`
`disease undergoing dialysis, and use of BRIVIACT is not recommended in this patient population [see Clinical Pharmacology
`
`
`
`
`
`(12.3)].
`
`
`
`8.7 Hepatic Impairment
`
`
`
`Reference ID: 3940707
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2138 - 7/18
`
`

`
`
`
`Because of increases in BRIVIACT exposure, dosage adjustment is recommended for all stages of hepatic impairment [see
`Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].
`
`9 DRUG ABUSE AND DEPENDENCE
`
`
`9.1 Controlled Substance
`
`
`
`
`BRIVIACT contains brivaracetam and is listed as a Schedule V controlled substance.
`
`
`9.2 Abuse
`
`
`
`In a human abuse potential study, single doses of BRIVIACT at therapeutic and supratherapeutic doses were compared to
`
`
`alprazolam (C-IV) (1.5 mg and 3 mg). BRIVIACT at the recommended single dose (50 mg) caused fewer sedative and euphoric
`
`effects than alprazolam; however, BRIVIACT at supratherapeutic single doses (200 mg and 1000 mg) was similar to alprazolam
`
`on other measures of abuse.
`
`
`9.3 Dependence
`
`
`There was no evidence of physical dependence potential or a withdrawal syndrome with BRIVIACT in a pooled review of
`
`
`
`
`
`placebo-controlled adjunctive therapy studies [see Warnings and Precautions (5.5)].
`
`10 OVERDOSAGE
`
`
`There is limited clinical experience with BRIVIACT overdose in humans. Somnolence and dizziness were reported in a patient
`
`
`
`taking a single dose of 1400 mg (14 times the highest recommended single dose) of BRIVIACT. The following adverse reactions
`
`were reported with BRIVIACT overdose: vertigo, balance disorder, fatigue, nausea, diplopia, anxiety, and bradycardia. In
`
`
`
`
`general, the adverse reactions associated with BRIVIACT overdose were consistent with the known adverse reactions.
`
`
`
`There is no specific antidote for overdose with BRIVIACT. In the event of overdose, standard medical practice for the
`management of any overdose should be used. An adequate airway, oxygenation, and ventilation should be ensured; monitoring of
`
`
`
`cardiac rate and rhythm and vital signs is recommended. A certified poison control center should be contacted for updated
`
`
`information on the management of overdose with BRIVIACT. There are no data on the removal of brivaracetam using
`hemodialysis, but because less than 10% of brivaracetam is excreted in urine, hemodialysis is not expected to enhance
`
`BRIVIACT clearance.
`
`
`
`11 DESCRIPTION
`
`
`
`The chemical name of BRIVIACT (brivaracetam) is (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl] butanamide. Its
`molecular formula is C11H20N2O2 and its molecular weight is 212.29. The chemical structure is:
`
`
`
`
`
`
`Brivaracetam is a white to off-white crystalline powder. It is very soluble in water, buffer (pH 1.2, 4.5, and 7.4), ethanol,
`methanol, and glacial acetic acid. It is freely soluble in acetonitrile and acetone and soluble in toluene. It is very slightly soluble in
`
`n-hexane.
`
`
`Tablets
`BRIVIACT tablets are for oral administration and contain the following inactive ingredients: croscarmellose sodium, lactose
`monohydrate, betadex (β-cyclodextrin), anhydrous lactose, magnesium stearate, and film coating agents specified below:
`
`
`
`10 mg tablets: polyvinyl alcohol, talc, polyethylene glycol 3350, titanium dioxide
`
`
`25 mg and 100 mg tablets: polyvinyl alcohol, talc, polyethylene glycol 3350, titanium dioxide, yellow iron oxide, black iron oxide
`
`
`
`
`
`Reference ID: 3940707
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2138 - 8/18
`
`

`
`50 mg tablets: polyvinyl alcohol, talc, polyethylene glycol 3350, titanium dioxide, yellow iron oxide, red iron oxide
`
`
`
`
`
`75 mg tablets: polyvinyl alcohol, talc, polyethylene glycol 3350, titanium dioxide, yellow iron oxide, red iron oxide, black iron
`
`
`
`
`
`oxide
`
`
`Oral Solution
`BRIVIACT oral solution contains 10 mg of brivaracetam per mL. The inactive ingredients are sodium citrate, anhydrous citric
`
`
`acid, methylparaben, sodium carboxymethylcellulose, sucralose, sorbitol solution, glycerin, raspberry flavor, and purified water.
`
`Injection
`
`
`
`
`BRIVIACT injection is a clear, colorless liquid provided as a sterile, preservative-free solution. BRIVIACT injection contains 10
`
`mg brivaracetam per mL for intravenous administration. One vial contains 50 mg of brivaracetam drug substance. It contains the
`
`following inactive ingredients: sodium acetate (trihydrate), glacial acetic acid (for pH adjustment to 5.5), sodium chloride, and
`
`water for injection.
`
`
`
`
`
`
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`
`
`The precise mechanism by which BRIVIACT exerts its anticonvulsant activity is not known. Brivaracetam displays a high and
`selective affinity for synaptic vesicle protein 2A (SV2A) in the brain, which may contribute to the anticonvulsant effect.
`
`
`
`12.2 Pharmacodynamics
`
`
`
`Interactions with Alcoh