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Brivaracetam

Class: Anticonvulsants, Miscellaneous
Chemical Name: (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide
Molecular Formula: C11H20N2O2
CAS Number: 357336-20-0
Brands: Briviact

Introduction

Brivaracetam is an anticonvulsant.

Uses for Brivaracetam

Brivaracetam has the following uses:

Brivaracetam is indicated as adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy.1

Brivaracetam Dosage and Administration

General

Brivaracetam is available in the following dosage form(s) and strength(s):

  • Tablets: 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg.1

  • Oral solution: 10 mg/mL.1

  • Injection: 50 mg/5 mL single-dose vial.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • 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).1

  • Brivaracetam injection may be used when oral administration is temporarily not feasible.1

  • Hepatic impairment: For all stages of hepatic impairment, the recommended starting dosage is 25 mg twice daily; maximum dosage is 75 mg twice daily.1

Cautions for Brivaracetam

Contraindications

Hypersensitivity to brivaracetam or any of the inactive ingredients in brivaracetam.1

Warnings/Precautions

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.1

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.1

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.1

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.1

Table 1: 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.1

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.1

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.1

Brivaracetam causes dose-dependent increases in somnolence and fatigue-related adverse reactions (fatigue, asthenia, malaise, hypersomnia, sedation, and lethargy). 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.1

Brivaracetam causes adverse reactions related to dizziness and disturbance in gait and coordination (dizziness, vertigo, balance disorder, ataxia, nystagmus, gait disturbance, and abnormal coordination). 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.1

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.1

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 is contraindicated in patients with a prior hypersensitivity reaction to brivaracetam or any of the inactive ingredients.1

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. But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.1

Specific Populations

Pregnancy

Pregnancy category C.1

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. Brivaracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.1

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 (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.1

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.1

Physicians are advised to recommend that pregnant patients taking brivaracetam 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 .1

Labor and Delivery

The effect of brivaracetam on labor and delivery in humans is unknown.1

Nursing Mothers

It is not known whether brivaracetam 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 brivaracetam, taking into account the importance of the drug to the mother.1

Pediatric Use

Safety and effectiveness of brivaracetam in adolescents 16 years of age have been established.1

Safety and effectiveness of brivaracetam in patients less than 16 years of age have not been established.1

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.1

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 brivaracetam 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.1

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 brivaracetam is not recommended in this patient population.1

Hepatic Impairment

Because of increases in brivaracetam exposure, dosage adjustment is recommended for all stages of hepatic impairment.1

Common Adverse Effects

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.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Rifampin: Because of decreased brivaracetam concentrations, increasing brivaracetam dosage in patients on concomitant rifampin is recommended.1

  • Carbamazepine: Because of increased exposure to carbamazepine metabolite, if tolerability issues arise, consider reducing carbamazepine dosage in patients on concomitant brivaracetam.1

  • Phenytoin: Because phenytoin concentrations can increase, phenytoin levels should be monitored in patients on concomitant brivaracetam.1

  • Levetiracetam: Brivaracetam had no added therapeutic benefit when co-administered with levetiracetam.1

Actions

Mechanism of Action

The precise mechanism by which brivaracetam 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.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).1

Suicidal Behavior and Ideation

Counsel patients, their caregivers, and/or families that antiepileptic drugs, including brivaracetam, may increase the risk of suicidal thoughts and behavior, and advise patients to be alert for the emergence or worsening of symptoms of depression; unusual changes in mood or behavior; or suicidal thoughts, behavior, or thoughts about self-harm. Advise patients, their caregivers, and/or families to report behaviors of concern immediately to a healthcare provider.1

Neurological Adverse Reactions

Counsel patients that brivaracetam causes somnolence, fatigue, dizziness, and gait disturbance. These adverse reactions, if observed, are more likely to occur early in treatment but can occur at any time. Advise patients 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.1

Psychiatric Adverse Reactions

Advise patients that brivaracetam causes changes in behavior (e.g., aggression, agitation, anger, anxiety, and irritability) and psychotic symptoms. Instruct patients to report these symptoms immediately to their healthcare provider.1

Hypersensitivity: Bronchospasm and Angioedema

Advise patients that symptoms of hypersensitivity including bronchospasm and angioedema can occur with brivaracetam. Instruct them to seek immediate medical care should they experience signs and symptoms of hypersensitivity.1

Withdrawal of Antiepileptic Drugs

Advise patients not to discontinue use of brivaracetam without consulting with their healthcare provider. Brivaracetam should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus.1

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during brivaracetam therapy. Encourage patients to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy.1

Dosing Instructions

Counsel patients that brivaracetam may be taken with or without food. Instruct patients that brivaracetam tablets should be swallowed whole with liquid and not chewed or crushed.1

Advise patients that the dosage of brivaracetam oral solution should be measured using a calibrated measuring device and not a household teaspoon. Instruct patients to discard any unused brivaracetam oral solution after 5 months of first opening the bottle.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Brivaracetam

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

10 mg

Briviact

UCB Inc.

25 mg

Briviact

UCB Inc.

50 mg

Briviact

UCB Inc.

75 mg

Briviact

UCB Inc.

100 mg

Briviact

UCB Inc.

Solution

10 mg/mL

Briviact

UCB Inc.

Parenteral

Injection

50 mg/5 mL

Briviact

UCB Inc.

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: September 14, 2016
Last reviewed: September 14, 2016
Date modified: October 12, 2016

References

1. UCB, Inc. Briviact (brivaracetam) ORAL prescribing information. 2016 March.

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