Briviact (Page 4 of 8)

8.2 Lactation

Risk Summary

No data are available regarding the presence of brivaracetam in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Studies in lactating rats have shown excretion of brivaracetam or metabolites in milk [see Data].

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

Data

Animal Data

Following a single oral (5 mg/kg) dose of 14 C-brivaracetam to lactating rats, radioactivity was secreted in milk and rapidly reached levels similar to those in plasma.

8.4 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 [see Dosage and Administration (2.1), Warnings and Precautions (5.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

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 (0, 150, 300, or 600 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 (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, those in children and adolescents at the recommended maintenance dose.

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

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 C11 H20 N2 O2 and its molecular weight is 212.29. The chemical structure is:

Chemical Structure

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.

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 Alcohol

In a pharmacokinetic and pharmacodynamic interaction study in healthy subjects, co-administration of BRIVIACT (single dose 200 mg [2 times greater than the highest recommended single dose]) and ethanol (continuous intravenous infusion to achieve a blood alcohol concentration of 60 mg/100 mL during 5 hours) increased the effects of alcohol on psychomotor function, attention, and memory. Co-administration of BRIVIACT and ethanol caused a larger decrease from baseline in saccadic peak velocity, smooth pursuit, adaptive tracking performance, and Visual Analog Scale (VAS) alertness, and a larger increase from baseline in body sway and in saccadic reaction time compared with BRIVIACT alone or ethanol alone. The immediate word recall scores were generally lower for BRIVIACT when co-administered with ethanol.

Cardiac Electrophysiology

At a dose 4 times the maximum recommended dose, BRIVIACT did not prolong the QT interval to a clinically relevant extent.

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