Briviact Drug Information

BRIVIACT is indicated for the treatment of partial-onset seizures in patients 1 month of age and older.

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 BRIVIACT Injection Dosage BRIVIACT injection may be used when oral administration is temporarily not feasible. 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.

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.

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. 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.

Discontinuation of BRIVIACT

Avoid abrupt withdrawal from BRIVIACT in order to minimize the risk of increased seizure frequency and status epilepticus.

Patients with Hepatic Impairment

The recommended dosage for patients with hepatic impairment is included in Table 2.

Co-administration with Rifampin Increase the BRIVIACT dosage in patients on concomitant rifampin by up to 100% (i.e., double the dosage).

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. 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 BRIVIACT and 62% treated with placebo. Table 4 lists adverse reactions for BRIVIACT that occurred at least 2% more frequently for BRIVIACT doses of at least 50 mg/day than placebo.

Pediatric Patients Safety of BRIVIACT 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 BRIVIACT oral solution or tablet, of whom 123 received BRIVIACT 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 BRIVIACT can cause hematologic abnormalities. Adverse Reactions with BRIVIACT Injection Adverse reactions with BRIVIACT injection administered to adults and pediatric patients 2 months to 16 years of age were generally similar to those observed with BRIVIACT tablets.

Other adverse events that occurred in at least 3% of adult 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.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of BRIVIACT. 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)

Rifampin Co-administration with rifampin decreases

BRIVIACT plasma concentrations likely because of CYP2C19 induction. Prescribers should increase the BRIVIACT dose by up to 100% (i.e., double the dosage) in patients while receiving concomitant treatment with rifampin.

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.

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.

Levetiracetam

BRIVIACT provided no added therapeutic benefit to levetiracetam when the two drugs were co-administered.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as BRIVIACT, during pregnancy. Encourage patients who are taking BRIVIACT during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary Available data from the North American Antiepileptic Drug (NAAED) pregnancy registry, a prospective cohort study, case reports, and a case series are insufficient to identify a risk of major birth defects, miscarriage or other maternal or fetal outcomes associated with BRIVIACT use during pregnancy.

In animal studies, brivaracetam produced evidence of developmental toxicity (increased embryofetal mortality and decreased fetal body weights in rabbits; decreased growth, delayed sexual maturation, and long-term neurobehavioral changes in rat offspring) at maternal plasma exposures greater than clinical exposures. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Oral administration of brivaracetam 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 (AUC) approximately 30 times exposures in humans at the maximum recommended dose (MRD) of 200 mg/day.

Oral administration of brivaracetam 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 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.

Brivaracetam was shown to readily cross the placenta in pregnant rats after a single oral (5 mg/kg) dose of 14 C-brivaracetam. From 1 hour post dose, radioactivity levels in fetuses, amniotic fluid, and placenta were similar to those measured in maternal blood.

Pediatric Use Safety and effectiveness of BRIVIACT have been established in pediatric patients 1 month to less than 16 years of age. Use of BRIVIACT in these age groups is supported by evidence from adequate and well-controlled studies of BRIVIACT in adults with partial-onset seizures, pharmacokinetic data from adult and pediatric patients, and safety data in pediatric patients 2 months to less than 16 years of age. Safety and effectiveness in pediatric patients below the age of 1 month have not been established.

Juvenile Animal Toxicity Data The potential adverse effects of brivaracetam on postnatal growth and development were investigated in juvenile rats and dogs. Oral administration mg/kg/day to rats during the neonatal and juvenile periods of development (approximately equivalent to neonatal through adolescent development in humans) 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 children and adolescents at the recommended maintenance dose.

In dogs, oral administration 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, those in children and adolescents at the recommended maintenance dose.

Hypersensitivity to brivaracetam or any of the inactive ingredients in BRIVIACT (bronchospasm and angioedema have occurred).

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.