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Brivaracetam

Pronunciation

(briv a RA se tam)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Briviact: 50 mg/5 mL (5 mL)

Solution, Oral:

Briviact: 10 mg/mL (300 mL) [contains methylparaben; raspberry flavor]

Tablet, Oral:

Briviact: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg

Brand Names: U.S.

  • Briviact

Pharmacologic Category

  • Anticonvulsant, Miscellaneous

Pharmacology

The precise mechanism by which brivaracetam exerts its antiepileptic activity is unknown. Brivaracetam displays a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain, which may contribute to the antiepileptic effect.

Absorption

Oral: Rapidly and almost completely absorbed; delayed by 3 hours with a high-fat meal.

Distribution

0.5 L/kg

Metabolism

Hepatic and extrahepatic amidase mediated hydrolysis of the amide moiety to form carboxylic acid metabolite (primary route) and hydroxylation primarily by CYP2C19 to form the hydroxy metabolite (secondary route). Metabolites are inactive, including an additional hydroxy acid metabolite.

Excretion

Urine (>95%; <10% unchanged); feces (<1%).

Time to Peak

Oral: 1 hour (fasting, range: 0.25 to 3 hours).

Half-Life Elimination

~9 hours

Protein Binding

≤20% to plasma proteins

Special Populations: Renal Function Impairment

In patients with creatinine clearance <30 mL/minute/1.73 m2 not requiring dialysis, plasma AUC of brivaracetam was moderately increased (21%), while the AUCs of the acid, hydroxy, and hydroxyacid metabolites were increased 3-fold, 4-fold, and 21-fold, respectively. Renal clearance of these inactive metabolites was decreased 10-fold.

Special Populations: Hepatic Function Impairment

In patients with hepatic cirrhosis, Child-Pugh classes A, B, and C, showed 50%, 57%, and 59% increases in brivaracetam exposure, respectively.

Special Populations: Elderly

Plasma half-life was 7.9 hours and 9.3 hours in the 65 to 75 and >75 years of age groups, respectively. Steady-state plasma clearance was slightly lower than in younger patients.

Special Populations Note

CYP2C19 poor metabolizers: In patients possessing genetic variations in CYP2C19, production of the hydroxy metabolite is decreased 2-fold or 10-fold, and the blood level of brivaracetam itself is increased by 22% or 42%, respectively, in individuals with one or both mutated alleles.

Use: Labeled Indications

Partial-onset seizures: Adjunctive therapy in the treatment of partial-onset seizures in adults and adolescents 16 years of age and older with epilepsy.

Contraindications

Hypersensitivity to brivaracetam or any component of the formulation

Dosing: Adult

Partial onset seizures: Oral, IV: Initial: 50 mg twice daily; may decrease to 25 mg twice daily or increase up to 100 mg twice daily based on individual patient response and tolerability (maximum: 200 mg/day). Note: Use injection when oral administration is temporarily not feasible; clinical study experience with brivaracetam injection is limited to 4 consecutive days of treatment.

Dosage adjustment for concomitant therapy with rifampin: Increase brivaracetam dosage by up to 100% (ie, double the brivaracetam dose).

Discontinuation of therapy: Reduce gradually; Canadian labeling recommends reducing the dose by 50 mg/day on a weekly basis with the final week of treatment at the dose of 20 mg/day.

Dosing: Geriatric

Refer to adult dosing. Consider starting at the low end of the dosage range.

Dosing: Pediatric

Partial onset seizures: Adolescents ≥16 years (US labeling): Oral, IV: Refer to adult dosing.

Dosing: Renal Impairment

Mild to severe impairment: No dosage adjustment necessary.

End-stage renal disease requiring dialysis: Use is not recommended (has not been studied).

Dosing: Hepatic Impairment

Mild to severe impairment (Child Pugh classes A, B, and C): Initial: 25 mg twice daily, up to a maximum of 75 mg twice daily.

Administration

Injection: Administer IV over 2 to 15 minutes; may administer undiluted or diluted with NS, LR, or D5W.

Oral solution: Administer with or without food. Use a calibrated measuring device to measure (household teaspoon or tablespoon is not an adequate measuring device). May also be administered using a nasogastric tube or gastronomy tube.

Tablets: Administer with or without food. Swallow tablets whole with liquid; do not chew or crush.

Compatibility

Stable in NS, LR, D5W.

Storage

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Oral solution: Do not freeze. Discard any oral solution remaining after 5 months of first opening the bottle.

Injection: Do not freeze. May store solution diluted in NS, LR, or D5W for ≤4 hours at room temperature in polyvinyl chloride (PVC) bags. Discard any unused portion.

Drug Interactions

Alcohol (Ethyl): May enhance the CNS depressant effect of Brivaracetam. Monitor therapy

Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CarBAMazepine: Brivaracetam may increase serum concentrations of the active metabolite(s) of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Brivaracetam. Monitor therapy

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C19 Substrates. Management: Seek alternatives to the CYP2C19 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dimethindene (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C19 Substrates. Conversely, concentrations of active metabolites may be increased for those drugs activated by CYP2C19. Management: Concurrent use of enzalutamide with CYP2C19 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C19 substrate should be performed with caution and close monitoring. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

LevETIRAcetam: May diminish the therapeutic effect of Brivaracetam. Specifically, the therapeutic effect of brivaracetam may be diminished and/or negligible when given to patients already receiving levetiracetam. Consider therapy modification

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Lumacaftor: May decrease the serum concentration of CYP2C19 Substrates. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Mianserin: May diminish the therapeutic effect of Anticonvulsants. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Orlistat: May decrease the serum concentration of Anticonvulsants. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Phenytoin: May decrease the serum concentration of Brivaracetam. Brivaracetam may increase the serum concentration of Phenytoin. Monitor therapy

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

RifAMPin: May decrease the serum concentration of Brivaracetam. Management: Increase the brivaracetam dose by up to 100% (ie, double the dose) if used together with rifampin. Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

Frequency not always defined.

Central nervous system: Fatigue (≤20% to ≤27%; dose-dependent), hypersomnia (≤20% to ≤27%; dose-dependent), lethargy (≤20% to ≤27%), malaise (≤20% to ≤27%; dose-dependent), drowsiness (≤16% to ≤27%; dose-dependent), sedation (≤16% to ≤27%; dose-dependent), dizziness (12% to ≤16%), equilibrium disturbance (≤3% to ≤16%), abnormal gait (≤16%), ataxia (≤16%), vertigo (≤16%), psychiatric disturbance (13%; includes psychotic and nonpsychotic), euphoria (IV: ≥3%), feeling drunk (IV: ≥3%), infusion-site pain (IV: ≥3%), irritability (3%), suicidal ideation

Gastrointestinal: Nausea and vomiting (5%), dysgeusia (IV:≥3%), constipation (2%)

Hematologic & oncologic: Decreased white blood cell count (2%)

Hypersensitivity: Hypersensitivity reaction

Neuromuscular & skeletal: Weakness (≤20% to ≤27%)

Ophthalmic: Nystagmus (≤16%)

<1% (Limited to important or life-threatening): Angioedema, bronchospasm, decreased neutrophils

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression (impaired coordination, ataxia, abnormal gait, fatigue, dizziness, and somnolence), which may impair physical or mental abilities. Risk is greatest early in treatment, but may occur at any time. Patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

• Hematologic effects: May cause hematologic abnormalities; significant decreased white blood cell count (<3.0 x 109/L) and decreased neutrophil count (<1.0 x 109/L) have been reported.

• Hypersensitivity: Bronchospasm and angioedema have been reported. Discontinue therapy if a hypersensitivity reaction develops. Multiorgan hypersensitivity syndrome (also known as Drug Rash Eosinophilia and Systemic Symptoms or DRESS), is a serious condition sometimes induced by antiepileptic drugs. DRESS initially presents with fever and rash, then with other organ system involvement that may include eosinophilia, lymphadenopathy, hepatitis, nephritis, and/or myocarditis. If any of these hypersensitivity reactions are suspected and an alternative cause cannot be established, discontinue brivaracetam.

• Psychiatric symptoms: Psychosis, paranoia, hallucinations, and behavioral symptoms (including abnormal behavior, adjustment disorder, affect liability, aggression, agitation, altered mood, anger, anxiety, apathy, belligerence, depression, irritability, mood swings, nervousness, psychomotor hyperactivity, restlessness, and tearfulness) may occur; clinical trials reported events in 13% of patients receiving brivaracetam compared with 8% receiving placebo.

• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared with 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify the health care provider immediately if symptoms occur.

Disease-related concerns:

• Hepatic impairment: Use caution in patients with hepatic impairment; dosage adjustment recommended.

• Renal impairment: Use caution in patients with renal impairment; not recommended in patients with end-stage renal disease (ESRD) undergoing dialysis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• CYP2C19 poor metabolizers: Poor metabolizers of CYP2C19 may require dose reduction.

Other warnings/precautions:

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

Monitoring Parameters

CBC with differential, liver and renal function, and symptoms of depression and suicidality (as clinically indicated)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies.

Females exposed to brivaracetam during pregnancy are encouraged to enroll themselves into the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334. Additional information is available at http://www.aedpregnancyregistry.org.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea or vomiting. Have patient report immediately to prescriber seizures, hallucinations, mood changes, agitation, irritability, panic attacks, behavioral changes, change in balance, abnormal gait, clumsiness, involuntary eye movements, severe fatigue, severe loss of strength and energy, severe dizziness, or signs of depression (suicidal ideation, anxiety, emotional instability, or confusion) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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