Briviak (Tablets) Instructions for Use

ATC Code

N03AX23 (Brivaracetam)

Active Substance

Brivaracetam (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiepileptic drug

Pharmacotherapeutic Group

Antiepileptic agent

Pharmacological Action

Anticonvulsant. Brivaracetam has high and selective affinity for the synaptic vesicle protein 2A (SV2A) in the brain, a transmembrane glycoprotein found in neurons and endocrine cells at the presynaptic level.

Although the exact role of this protein is currently unknown, it has been shown to modulate neurotransmitter exocytosis. Binding to the synaptic vesicle glycoprotein 2A (SV2A) appears to be the primary mechanism of the anticonvulsant effect of brivaracetam.

Pharmacokinetics

Brivaracetam is characterized by linear and time-independent pharmacokinetics, low intra- and inter-individual variability, complete absorption, very low plasma protein binding, renal excretion after extensive biotransformation, and the presence of pharmacologically inactive metabolites.

Brivaracetam is rapidly and completely absorbed after oral administration, and its absolute bioavailability is approximately 100%. The median T_max for tablets taken on an empty stomach is 1 hour (range 0.25 to 3 hours).

Concomitant administration of brivaracetam with a high-fat meal slows the rate of absorption (median T_max 3 hours) and reduces plasma C_max by 37%, while the extent of absorption remains unchanged.

Plasma protein binding is low (≤20%). The V_d is 0.5 L/kg, which is close to the total body water volume. Due to its lipophilicity (LogP), Brivaracetam penetrates cell membranes well.

Brivaracetam is primarily metabolized by hydrolysis of the amide moiety to form the corresponding carboxylic acid (approximately 60% of the dose), and secondarily by hydroxylation of the propyl side chain (approximately 30% of the dose).

The hydrolysis of the amide moiety to form the carboxylic acid (34% of the renally excreted dose) is mediated by hepatic and extrahepatic amidase. In vitro, the hydroxylation of brivaracetam is mediated primarily by the CYP2C19 isoenzyme. Both metabolites are further converted to form a hydroxylated acid.

In vivo in humans with an inactive CYP2C19 isoenzyme due to mutation, the formation of the hydroxymetabolite is reduced by 10-fold, while the concentration of brivaracetam increases by 22% or 42% in subjects with one or both mutated alleles, respectively. These three metabolites have no pharmacological activity.

Brivaracetam is predominantly metabolized and excreted by the kidneys. More than 95% of the dose, including metabolites, is excreted in the urine within 72 hours after administration. Less than 1% of the dose is excreted via the intestine and less than 10% of the dose is excreted unchanged by the kidneys.

The terminal T_1/2 of brivaracetam is approximately 9 hours. The total plasma clearance of brivaracetam in patients is 3.6 L/h.

Pharmacokinetics are dose-proportional in the range from 10 to at least 600 mg.

Brivaracetam is eliminated via several pathways, including renal excretion, cytochrome P450 isoenzyme-independent hydrolysis, and cytochrome P450 isoenzyme-mediated oxidation.

In patients with severe renal impairment (CrCl<30 mL/min/1.73 m², not requiring hemodialysis), the plasma concentration of brivaracetam (as measured by AUC) was moderately increased (by 21%) compared to that in healthy volunteers. Meanwhile, the concentrations of the acid, hydroxyl, and hydroxyacid metabolites increased by 3, 4, and 21 times, respectively. The renal clearance of these inactive metabolites decreased by 10-fold.

A pharmacokinetic study in patients with liver cirrhosis (Child-Pugh A, B, C) revealed a comparable increase in brivaracetam exposure, regardless of the severity of the disease (50%, 57%, and 59%), compared to the control group of healthy volunteers.

Indications

As adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalization in adults and adolescents from 16 years of age with epilepsy.

ICD codes

Dosage Regimen

Tablets

For oral use. The recommended starting dose is 50 mg/day or 100 mg/day as decided by the treating physician, based on the required anticonvulsant effect and potential side effects.

The daily dose is divided equally into two doses, morning and evening. Depending on the individual patient response and tolerance, the dose can be adjusted within the range of 50 mg/day to 200 mg/day, within which Brivaracetam is effective as adjunctive therapy with antiepileptic drugs.

Adverse Reactions

Infections and infestations: Common – influenza.

Blood and lymphatic system disorders: Uncommon – neutropenia.

Metabolism and nutrition disorders: Common – decreased appetite.

Psychiatric disorders: Common – depression, anxiety, insomnia, irritability; Uncommon – suicidal thoughts, psychotic disorder, aggression, agitation.

Nervous system disorders: Very common – dizziness, somnolence; Common – convulsions, vertigo.

Respiratory, thoracic and mediastinal disorders: Common – upper respiratory tract infection, cough.

Gastrointestinal disorders: Common – nausea, vomiting, constipation.

General disorders and administration site conditions: Common – fatigue.

Contraindications

End-stage renal disease requiring hemodialysis (due to lack of clinical data), children under 16 years of age (due to lack of clinical data), hypersensitivity to the active substance.

Use in Pregnancy and Lactation

Data on the use of brivaracetam in pregnant women are limited. There are no data on the passage of brivaracetam through the human placental barrier. In rats, Brivaracetam readily crosses the placental barrier. The potential risk to humans is unknown.

Brivaracetam should not be used during pregnancy except in cases of clinical necessity where the benefit to the mother clearly outweighs the potential risk to the fetus. Discontinuation of brivaracetam may lead to exacerbation of the disease, which can be dangerous for both the mother and the fetus.

It is not known whether Brivaracetam is excreted in human breast milk. In lactating rats, Brivaracetam is excreted in milk. The decision to discontinue breastfeeding or brivaracetam therapy should be made based on an assessment of the mother’s need for therapy.

Before using brivaracetam, the physician should discuss family planning and contraceptive measures with women of childbearing potential. If a woman is planning a pregnancy, the issue of continuing brivaracetam should be reconsidered.

Use in Hepatic Impairment

Clinical data on the use of brivaracetam in patients with hepatic impairment are limited. Dose adjustment of the drug is recommended in patients with impaired liver function.

Use in Renal Impairment

Contraindicated in end-stage renal disease requiring hemodialysis.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

Use with caution in patients with a history of suicidal thoughts and suicide attempts; in patients with impaired liver function.

If it is necessary to discontinue treatment with brivaracetam, it is recommended to withdraw it gradually, reducing the dose by 50 mg per week. After one week of taking a dose of 50 mg/day, it is recommended to take Brivaracetam at a dose of 20 mg/day for the final week.

Suicidal ideation and suicide attempts have been observed in patients treated with antiepileptic drugs, including Brivaracetam, for various indications. A small increase in the risk of suicidal ideation and behavior has been shown. The mechanism for this risk is unknown, and the possibility of an increased risk with the use of brivaracetam cannot be excluded.

Patients should be monitored for signs of suicidal ideation and behavior, and appropriate treatment should be initiated promptly. Patients (and caregivers) should be informed of the need to seek immediate medical attention if suicidal thoughts or attempts occur.

Clinical data on the use of brivaracetam in patients with hepatic impairment are limited. Dose adjustment of the drug is recommended in patients with impaired liver function.

Effect on ability to drive and use machines

Brivaracetam has minor to moderate influence on the ability to drive and use machines. Due to differences in individual sensitivity to the drug, some patients may experience drowsiness, dizziness and other CNS effects.

Patients are advised not to drive a car or operate other potentially dangerous machinery until the effect of brivaracetam on their ability to perform such activities is established.

Drug Interactions

The effect of alcohol on psychomotor function, attention and memory was doubled when used concomitantly with brivaracetam. Alcohol consumption is not recommended during therapy with brivaracetam.

An increase in the concentration of brivaracetam is possible when combined with potent inhibitors of the CYP2C19 isoenzyme (fluconazole, fluvoxamine); however, the risk of clinically significant interaction mediated by the CYP2C19 isoenzyme is considered low.

Concomitant use in healthy volunteers with the potent enzyme inducer rifampicin (600 mg/day for 5 days) was accompanied by a 45% decrease in brivaracetam exposure. The dose of brivaracetam should be adjusted in patients starting or ending therapy with rifampicin.

The plasma concentration of brivaracetam decreases when used concomitantly with antiepileptic drugs that are potent enzyme inducers (carbamazepine, phenobarbital, phenytoin); however, no dose adjustment of the drugs is required in this situation.

Other potent enzyme inducers (such as St. John’s wort) may also reduce the systemic exposure of brivaracetam. Therefore, caution should be exercised when starting and ending the use of St. John’s wort during treatment with brivaracetam.

Brivaracetam at doses from 50 to 150 mg/day did not affect the AUC of midazolam (metabolized by the CYP3A4 isoenzyme).

In vitro studies have shown that Brivaracetam inhibits CYP450 isoenzymes to a minor extent or not at all. An exception is the CYP2C19 isoenzyme, which is involved in the metabolism of, for example, lansoprazole, omeprazole, diazepam; therefore, their plasma concentrations may increase when used concomitantly with brivaracetam.

Brivaracetam may reduce the plasma concentration of drugs metabolized by the CYP2B6 isoenzyme (e.g., efavirenz).

The concentration of brivaracetam in vitro that provides 50% of the maximum OAT3 inhibitory effect was 42 times higher than the C_max at the maximum therapeutic dose. Brivaracetam at a dose of 200 mg/day may increase the plasma concentration of drugs transported by OAT3.

Brivaracetam is a moderate reversible inhibitor of epoxide hydrolase, contributing to an increase in the blood concentration of carbamazepine epoxide (an active metabolite of carbamazepine). In controlled studies, plasma concentrations of carbamazepine epoxide increased on average by 37%, 62%, and 98% (with low variability) during concomitant use of brivaracetam at doses of 50 mg/day, 100 mg/day, or 200 mg/day, respectively. The safety profile was unchanged.

When brivaracetam was taken concomitantly at a dose of 400 mg/day (a dose twice the maximum recommended daily dose) with an oral contraceptive containing ethinylestradiol (30 mcg) and levonorgestrel (150 mcg), a decrease in the AUC values of the estrogen and progestin by 27% and 23%, respectively, was noted, which did not affect the degree of ovulation suppression.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.