BRIVARACETAM: 6,098 Adverse Event Reports & Safety Profile

The chemical name of BRIVIACT (brivaracetam) is (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1 H -pyrrol-1-yl] butanamide. Its molecular formula is C 11 H 20 N 2 O 2 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 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 (1.64 mg/mL), glacial acetic acid (for pH adjustment to 5.5), sodium chloride (9.00 mg/mL), and water for injection.

Chemical

Structure

AND USAGE Brivaracetam oral solution is indicated for the treatment of partial-onset seizures in patients 1 month of age and older. Brivaracetam oral solution is indicated for the treatment of partial-onset seizures in patients 1 month of age and older. ( 1 )

AND ADMINISTRATION Adults (16 Years and Older): The recommended starting dosage for monotherapy or adjunctive therapy 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). ( 2.1 )

Pediatric

Patients (1 Month to less than 16 Years): The recommended dosage is based on body weight and is administered orally twice daily ( 2.1 ) Injection: for intravenous use only when oral administration is temporarily not feasible; dosing is the same as oral regimen. ( 2.1 , 2.3 )

Hepatic

Impairment: Dose adjustment is recommended for all stages of hepatic impairment. ( 2.5 )

2.1 Dosage Information Monotherapy or Adjunctive Therapy The recommended dosage for patients 1 month of age and older is included in Table 1. In pediatric patients weighing less than 50 kg, the recommended dosing regimen is dependent upon body weight. When initiating treatment, gradual dose escalation is not required. Dosage should be adjusted based on clinical response and tolerability.

Table

1: Recommended Dosage for Patients 1 Month of Age and Older Age and Body Weight Initial Dosage Minimum and Maximum Maintenance Dosage Adults (16 years and older) 50 mg twice daily (100 mg per day) 25 mg to 100 mg twice daily (50 mg to 200 mg per day) Pediatric patients weighing 50 kg or more 25 mg to 50 mg twice daily (50 mg to 100 mg per day) 25 mg to 100 mg twice daily (50 mg to 200 mg per day) Pediatric patients weighing 20 kg to less than 50 kg 0.5 mg/kg to 1 mg/kg twice daily (1 mg/kg to 2 mg/kg per day) 0.5 mg/kg to 2 mg/kg twice daily (1 mg/kg to 4 mg/kg per day) Pediatric patients weighing 11 kg to less than 20 kg 0.5 mg/kg to 1.25 mg/kg twice daily (1 mg/kg to 2.5 mg/kg per day) 0.5 mg/kg to 2.5 mg/kg twice daily (1 mg/kg to 5 mg/kg per day) Pediatric patients weighing less than 11 kg 0.75 mg/kg to 1.5 mg/kg twice daily (1.5 mg/kg to 3 mg/kg per day) 0.75 mg/kg to 3 mg/kg twice daily (1.5 mg/kg to 6 mg/kg per day)

Briviact

Injection Dosage BRIVIACT injection may be used when oral administration is temporarily not feasible [see Dosage and Administration (2.3) ]. BRIVIACT injection should be administered intravenously at the same dosage and same frequency as BRIVIACT tablets and oral solution. The clinical study experience with BRIVIACT injection is up 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 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6) and Clinical Studies (14) ]</span>.

2.5 Patients with Hepatic Impairment The recommended dosage for patients with hepatic impairment is included in Table 2 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]</span> .

Table

2: Recommended Dosage for Patients with Hepatic Impairment Age and Body Weight Initial Dosage Maximum Maintenance Dosage Adults (16 years and older) 25 mg twice daily (50 mg per day) 75 mg twice daily (150 mg per day) Pediatric patients weighing 50 kg or more Pediatric patients weighing 20 kg to less than 50 kg 0.5 mg/kg twice daily (1 mg/kg per day) 1.5 mg/kg twice daily (3 mg/kg per day) Pediatric patients weighing 11 kg to less than 20 kg 0.5 mg/kg twice daily (1 mg/kg per day) 2 mg/kg twice daily (4 mg/kg per day) Pediatric patients weighing less than 11 kg 0.75 mg/kg twice daily (1.5 mg/kg per day) 2.25 mg/kg twice daily (4.5 mg/kg per day)

2.6 Co-administration with Rifampin Increase the BRIVIACT dosage in patients on concomitant rifampin by up to 100% (i.e., double the dosage) <span class="opacity-50 text-xs">[see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]</span> .

Hypersensitivity to brivaracetam or any of the inactive ingredients in brivaracetam oral solution (bronchospasm and angioedema have occurred) [see Warnings and Precautions (5.4) ] . Hypersensitivity to brivaracetam or any of the inactive ingredients in brivaracetam oral solution. ( 4 )

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) ]

Serious Dermatologic

Reactions [see Warnings and Precautions (5.5) ] Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.6) ] Adults: Most common adverse reactions (at least 5% for Brivaracetam and at least 2% more frequently than placebo) are somnolence/sedation, dizziness, fatigue, and nausea/vomiting. ( 6.1 )

Pediatric

Patients: Most common adverse reactions are similar to those seen in adult patients. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact PAI Pharma at 1-800-845-8210 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In all controlled and uncontrolled trials performed in adult epilepsy patients, brivaracetam 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 brivaracetam 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) <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> . The adverse reactions presented in Table 4 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 brivaracetam and 62% treated with placebo. The most common adverse reactions occurring at a frequency of at least 5% in patients treated with brivaracetam 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 brivaracetam at the recommended doses of 50 mg, 100 mg, and 200 mg/day, respectively, compared to 4% in patients randomized to receive placebo.

Table

4 lists adverse reactions for brivaracetam that occurred at least 2% more frequently for brivaracetam doses of at least 50 mg/day than placebo.

Table

4: Adverse Reactions in Pooled Placebo-Controlled Adjunctive Therapy Studies in Adult Patients with Partial-Onset Seizures (Brivaracetam 50 mg/day, 100 mg/day, and 200 mg/day)

Adverse Reactions

Brivaracetam (N=803) % Placebo (N=459) % Gastrointestinal disorders Nausea/vomiting symptoms 5 3 Constipation 2 0 Nervous system disorders Somnolence and sedation 16 8 Dizziness 12 7 Fatigue 9 4 Cerebellar coordination and balance disturbances Cerebellar coordination and balance disturbances includes ataxia, balance disorder, coordination abnormal, and nystagmus. 3 1 Psychiatric disorders Irritability 3 1 There was no apparent dose-dependent increase in adverse reactions listed in Table 4 with the exception of somnolence and sedation.

Pediatric Patients

Safety of brivaracetam was evaluated in two open-label, safety and pharmacokinetic trials in pediatric patients 2 months to less than 16 years of age. Across studies of pediatric patients with partial onset seizures, 186 patients received brivaracetam oral solution or tablet, of whom 123 received brivaracetam for at least 12 months. Adverse reactions reported in clinical studies of pediatric patients were generally similar to those seen in adult patients. Decreased appetite was also observed in these pediatric trials.

Hematologic Abnormalities

Brivaracetam can cause hematologic abnormalities. In the Phase 3 controlled adjunctive epilepsy studies, a total of 1.8% of brivaracetam -treated patients and 1.1% of placebo-treated patients had at least one clinically significant decreased white blood cell count (<3.0 × 10 9 /L), and 0.3% of brivaracetam -treated patients and 0% of placebo-treated patients had at least one clinically significant decreased neutrophil count (<1.0 × 10 9 /L).

Adverse

Reactions with brivaracetam Injection Adverse reactions with brivaracetam injection administered to adults and pediatric patients 2 months to 16 years of age were generally similar to those observed with brivaracetam tablets. Other adverse events that occurred in at least 3% of adult patients who received brivaracetam 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.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of brivaracetam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: Serious dermatologic reactions (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5) ]</span>

AND PRECAUTIONS Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and ideation. ( 5.1 )

Neurological Adverse

Reactions: Monitor for somnolence and fatigue and advise patients not to drive or operate machinery until they have gained sufficient experience on brivaracetam. ( 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 brivaracetam if hypersensitivity occurs. ( 5.4 )

Serious Dermatologic

Reactions: Discontinue brivaracetam unless an alternative etiology is established ( 5.5 ) Withdrawal of Antiepileptic Drugs: Brivaracetam should be gradually withdrawn. ( 5.6 )

5.1 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including brivaracetam, 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. 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 years to 100 years) in the clinical trials analyzed.

Table

3 shows absolute and relative risk by indication for all evaluated AEDs.

Table

3 Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1 3.4 3.5

2.4 Psychiatric 5.7 8.5 1.5

2.9 Other 1 1.8 1.9

0.9 Total 2.4 4.3 1.8

1.9 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 brivaracetam 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 Brivaracetam 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 brivaracetam to gauge whether it adversely affects their ability to drive or operate machinery. Somnolence and Fatigue Brivaracetam causes dose-dependent increases in somnolence and fatigue-related adverse reactions (fatigue, asthenia, malaise, hypersomnia, sedation and lethargy) <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . In the Phase 3 controlled adjunctive epilepsy trials, these events were reported in 25% of patients randomized to receive brivaracetam 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 Brivaracetam causes adverse reactions related to dizziness and disturbance in gait and coordination (dizziness, vertigo, balance disorder, ataxia, nystagmus, gait disturbance and abnormal coordination) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . In the Phase 3 controlled adjunctive epilepsy trials, these events were reported in 16% of patients randomized to receive brivaracetam 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 Brivaracetam causes psychiatric adverse reactions. In the Phase 3 controlled adjunctive epilepsy trials, psychiatric adverse reactions were reported in approximately 13% of patients who received brivaracetam (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 brivaracetam discontinued treatment because of psychiatric reactions compared to 1.3% of patients who received placebo. Psychiatric adverse reactions were also observed in open-label pediatric trials and were generally similar to those observed in adults <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ) and Use in Specific Populations ( 8.4 )]</span> .

5.4 Hypersensitivity: Bronchospasm and Angioedema Brivaracetam can cause hypersensitivity reactions. Bronchospasm and angioedema have been reported in patients taking brivaracetam. If a patient develops hypersensitivity reactions after treatment with brivaracetam, the drug should be discontinued. Brivaracetam tablets are contraindicated in patients with a prior hypersensitivity reaction to brivaracetam or any of the inactive ingredients <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

5.5 Serious Dermatologic Reactions Serious dermatologic reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients treated with brivaracetam. Time to onset of the serious dermatologic reaction ranged from 3 days to 45 days after brivaracetam initiation in reported cases. Brivaracetam should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest a serious dermatologic reaction, use of brivaracetam should not be resumed and alternative therapy should be considered.

5.6 Withdrawal of Antiepileptic Drugs As with most antiepileptic drugs, brivaracetam should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ) and Clinical Studies ( 14 )]</span> . But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.

5.7 Risk of Allergic Reactions Due to Tartrazine Brivaracetam tablets, 100 mg contain FD&amp;C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&amp;C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

INTERACTIONS Rifampin: Because of decreased concentrations, increasing brivaracetam oral solution dosage in patients on concomitant rifampin is recommended. ( 2.6 , 7.1 ) Carbamazepine: Because of increased exposure to carbamazepine metabolite, if tolerability issues arise, consider reducing carbamazepine dosage in patients on concomitant brivaracetam oral solution. ( 7.2 ) Phenytoin: Because phenytoin concentrations can increase, phenytoin levels should be monitored in patients on concomitant brivaracetam oral solution. ( 7.3 ) Levetiracetam:B rivaracetam oral solution had no added therapeutic benefit when co-administered with levetiracetam. ( 7.4 )

7.1 Rifampin Co-administration with rifampin decreases brivatacetum plasma concentrations likely because of CYP2C19 induction <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Prescribers should increase the brivatacetum dose by up to 100% (i.e., double the dosage) in patients while receiving concomitant treatment with rifampin <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.3 Phenytoin Because brivatacetum can increase plasma concentrations of phenytoin, phenytoin levels should be monitored in patients when concomitant brivatacetum is added to or discontinued from ongoing phenytoin therapy <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.4 Levetiracetam Brivatacetum provided no added therapeutic benefit to levetiracetam when the two drugs were co-administered <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span>.