BRIVARACETAM
Brand names: Briviact, brivaracetam, BRIVARACETAM, Brivaracetam, Brivaracetam Oral Solution
Warnings
5 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 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 ) Serious Dermatologic Reactions : Discontinue BRIVIACT unless an alternative etiology is established ( 5.5 ) Withdrawal of Antiepileptic Drugs : BRIVIACT should be gradually withdrawn. ( 5.6 ) 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. 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 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 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 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 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. Psychiatric adverse reactions were also observed in open-label pediatric trials and were generally similar to those observed in adults [see Adverse Reactions (6.1) and Use in Specific Populations (8.4) ]. 5.4 Hypersensitivity: Bronchospasm and Angioedema 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 Serious Dermatologic Reactions Serious dermatologic reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients treated with BRIVIACT. Time to onset of the serious dermatologic reaction ranged from 3 to 45 days after BRIVIACT initiation in reported cases. BRIVIACT 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 BRIVIACT should not be resumed and alternative therapy should be considered. 5.6 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.
Contraindications
4 CONTRAINDICATIONS Hypersensitivity to brivaracetam or any of the inactive ingredients in brivaracetam tablets (bronchospasm and angioedema have occurred) [see Warnings and Precautions (5.4) ] . Hypersensitivity to brivaracetam or any of the inactive ingredients in brivaracetam tablets. ( 4 )
Overdose
10 OVERDOSAGE There is limited clinical experience with brivaracetam 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 brivaracetam. The following adverse reactions were reported with brivaracetam overdose: vertigo, balance disorder, fatigue, nausea, diplopia, anxiety, and bradycardia. In general, the adverse reactions associated with brivaracetam overdose were consistent with the known adverse reactions. There is no specific antidote for overdose with brivaracetam. 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 brivaracetam. 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 brivaracetam clearance.
Drug interactions
7 DRUG INTERACTIONS Rifampin: Because of decreased concentrations, increasing brivaracetam 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. ( 7.2 ) Phenytoin: Because phenytoin concentrations can increase, phenytoin levels should be monitored in patients on concomitant brivaracetam. ( 7.3 ) Levetiracetam: Brivaracetam had no added therapeutic benefit when co-administered with levetiracetam. ( 7.4 ) 7.1 Rifampin Co-administration with rifampin decreases brivaracetam plasma concentrations likely because of CYP2C19 induction [see Clinical Pharmacology (12.3) ] . Prescribers should increase the brivaracetam 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 brivaracetam can increase plasma concentrations of phenytoin, phenytoin levels should be monitored in patients when concomitant brivaracetam is added to or discontinued from ongoing phenytoin therapy [see Clinical Pharmacology (12.3) ] . 7.4 Levetiracetam Brivaracetam provided no added therapeutic benefit to levetiracetam when the two drugs were co-administered [see Clinical Studies (14) ] .
Uses
1 INDICATIONS AND USAGE BRIVIACT is indicated for the treatment of partial-onset seizures in patients 1 month of age and older. BRIVIACT is indicated for the treatment of partial-onset seizures in patients 1 month of age and older. ( 1 )
Dosage forms & strengths
2 DOSAGE 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 ) 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) 2.2 Administration Instructions for Brivaracetam Tablets Brivaracetam tablets can be initiated with oral administration. Brivaracetam tablets may be taken with or without food. Brivaracetam tablets should be swallowed whole with liquid. Brivaracetam tablets should not be chewed or crushed. 2.4 Discontinuation of Brivaracetam Tablets Avoid abrupt withdrawal from brivaracetam tablets in order to minimize the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.6) and Clinical Studies (14) ] . 2.5 Patients with Hepatic Impairment The recommended dosage for patients with hepatic impairment is included in Table 2 [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . 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 brivaracetam tablets 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) ] .