BRIVATAM INJECTION

COMPOSITION

Each ml contains:

Brivaracetam                                        USP     10 mg

Water for Injections                               BP        q.s.                                                                                                                                                                                                                 DESCRIPTION

A clear, colourless to almost colorless sterile solution.

 PHARMACODYNAMIC

Pharmacotherapeutic group: antiepileptics, other antiepileptics.

ATC code: N03AX23

Mechanism of action

Brivaracetam displays a high and selective affinity for synaptic vesicle protein 2A (SV2A), a transmembrane glycoprotein found at presynaptic level in neurons and in endocrine cells. Although the exact role of this protein remains to be elucidated it has been shown to modulate exocytosis of neurotransmitters. Binding to SV2A is believed to be the primary mechanism for brivaracetam anticonvulsant activity.

PHARMACOKINETICS

Brivaracetam film-coated tablets, oral solution and solution for intravenous injection show the same AUC, while the maximum plasma concentration is slightly higher after intravenous administration. Brivaracetam exhibits linear and time-independent pharmacokinetics with low intra- and inter-subject variability, and features complete absorption, very low protein binding, renal excretion following extensive biotransformation, and pharmacologically inactive metabolites.Absorption

Brivaracetam is rapidly and completely absorbed after oral administration and the absolute bioavailability is approximately 100 %. The median t_max for tablets taken without food is 1 hour (t_max range is 0.25 to 3 h).

Coadministration with a high-fat meal slowed down the absorption rate (median t_max 3 h) and decreased the maximum plasma concentration (37 % lower) of brivaracetam, while the extent of absorption remained unchanged.

Distribution

Brivaracetam is weakly bound (≤ 20 %) to plasma proteins. The volume of distribution is 0.5 L/kg, a value close to that of the total body water.

Due to its lipophilicity (Log P) brivaracetam has high cell membrane permeability.

Biotransformation

Brivaracetam is primarily metabolized by hydrolysis of the amide moiety to form the corresponding carboxylic acid (approximately 60 % the elimination), and secondarily by hydroxylation on the propyl side chain (approximately 30 % the elimination). The hydrolysis of the amide moiety leading to the carboxylic acid metabolite (34 % of the dose in urine) is supported by hepatic and extra-hepatic amidase. In vitro, the hydroxylation of brivaracetam is mediated primarily by CYP2C19. Both metabolites, are further metabolised forming a common hydroxylated acid formed predominantly by hydroxylation of the propyl side chain on the carboxylic acid metabolite (mainly by CYP2C9). In vivo, in human subjects possessing ineffective mutations of CYP2C19, production of the hydroxy metabolite is decreased 10-fold while brivaracetam itself is increased by 22 % or 42 % in individuals with one or both mutated alleles. The three metabolites are not pharmacologically active.

Elimination

Brivaracetam is eliminated primarily by metabolism and by excretion in the urine. More than 95 % of the dose, including metabolites, is excreted in the urine within 72 hours after intake. Less than 1 % of the dose is excreted in faeces and less than 10 % of brivaracetam is excreted unchanged in urine. The terminal plasma half-life (t1/2) is approximately 9 hours. The total plasma clearance in patients was estimated to 3.6 L/h.

Linearity

Pharmacokinetics is dose-proportional from 10 to at least 600 mg.

Interactions with medicinal products

Brivaracetam is cleared by multiple pathways including renal excretion, non-CYP-mediated hydrolysis and CYP-mediated oxidations. In vitro, brivaracetam is not a substrate of human P-glycoprotein (P-gp), multidrug resistance proteins (MRP) 1 and 2, and likely not organic anion transporter polypeptide 1B1 (OATP1B1) and OATP1B3.

In vitro assays showed that brivaracetam disposition should not be significantly affected by CYP (e.g. CYP1A, CYP2C8, CYP2C9, CYP2D6 and CYP3A4) inhibitors.

In vitro, brivaracetam was not an inhibitor of the CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP3A4, or the transporters P-gp, BCRP, BSEP MRP2, MATE-K, MATE-1, OATP1B1, OATP1B3, OAT1 and OCT1 at clinically relevant concentrations. In vitro, brivaracetam did not induce CYP1A2.

Pharmacokinetics in special patient groups

Elderly (65 years of age and above)

In a study in elderly subjects (65 to79 years old; with creatinine clearance 53 to 98 ml/min/1.73 m²) receiving brivaracetam 400 mg/day in bid administration, the plasma half-life of brivaracetam was 7.9 hours and 9.3 hours in the 65 to 75 and >75 years groups, respectively. The steady-state plasma clearance of brivaracetam was similar (0.76 ml/min/kg) to young healthy male subjects (0.83 ml/min/kg).

Renal impairment

A study in subjects with severe renal impairment (creatinine clearance < 30 ml/min/1.73 m² and not requiring dialysis) revealed that the plasma AUC of brivaracetam was moderately increased (+21 %) relative to healthy controls, while the AUC of the acid, hydroxy and hydroxy acid metabolites were increased 3-, 4-, and 21-fold, respectively. The renal clearance of these non-active metabolites was decreased 10-fold. The hydroxy acid metabolite did not reveal any safety concerns in non-clinical studies. Brivaracetam has not been studied in patients undergoing hemodialysis.

Hepatic impairment

A pharmacokinetic study in subjects with hepatic cirrhosis (Child-Pugh classes A, B, and C) showed similar increases in exposure to brivaracetam irrespective of disease severity (50 %, 57 % and 59 %), relative to matched healthy controls.

Body weight

A 40 % decrease in steady-state plasma concentration has been estimated across a body weight range from 46 kg to 115 kg. However, this is not considered to be a clinically relevant difference.

Gender

There are no clinically relevant differences in the pharmacokinetics of brivaracetam by gender.

Race

The pharmacokinetics of brivaracetam was not significantly affected by race (Caucasian, Asian) in a population pharmacokinetic modeling from epilepsy patients. The number of patients with other ethnic background was limited.

Pharmacokinetic/pharmacodynamics relationship

The EC50 (brivaracetam plasma concentration corresponding to 50 % of the maximum effect) was estimated to be 0.57 mg/L. This plasma concentration is slightly above the median exposure obtained after brivaracetam doses of 50 mg/day. Further seizure frequency reduction is obtained by increasing the dose to 100 mg/day and reaches a plateau at 200 mg/day.

Paediatric population

In a pharmacokinetic study with a 3-week evaluation period and weekly fixed 3-step up-titration using the brivaracetam oral solution, 99 subjects aged 1 month to < 16 years were evaluated. Brivaracetam was administered at weekly increasing doses of approximately 1 mg/kg/day, 2 mg/kg/day, and 4 mg/kg/day. All doses were adjusted by body weight, and did not exceed a maximum of 50 mg/day, 100 mg/day, and 200 mg/day. At the end of the evaluation period, subjects may have been eligible for entry into a long-term follow-up study continuing on their last received dose. Plasma concentrations were shown to be dose-proportional in all age groups. Population pharmacokinetics modeling was performed based on sparse plasma concentration data collected in the 3-week PK study and the ongoing long-term follow-up study. 232 paediatric patients with epilepsy, aged 2 months to 17 years, were included in the analysis. The analysis indicated that doses of 5.0 (body weights 10-20 kg) and 4.0 mg/kg/day (body weights 20-50 kg) provide the same steady-state average plasma concentration as in adults receiving 200 mg/day. The estimated plasma clearance was 0.96 L/h, 1.61 L/h, 2.18 L/h and 3.19 L/h for children weighing 10 kg, 20 kg, 30 kg and 50 kg, respectively. In comparison, plasma clearance was estimated at 3.58 L/h in adult patients (70 kg body weight).

Currently, no clinical data are available in neonates.

THERAPEUTIC INDICATION

Brivaracetam is indicated as adjunctive therapy in the treatment of partial onset seizures with or without secondary generalization in adults, adolescents and children from 2 years of age with epilepsy.

DOSAGE AND ADMINISTRATION

Posology

Brivaracetam solution for injection/infusion is an alternative route of administration for patients when oral administration is temporarily not feasible. There is no experience with twice daily intravenous administration of brivaracetam for a period longer than 4 days.

The recommended posology for adults, adolescents and children from 2 years of age is summarized in the following table. The dose should be administered in two equally divided doses, approximately 12 hours apart.

* Based on individual patient response, the dose may be adjusted between this effective dose range.

** Based on physician’s assessment of need for seizure control.

Adults

Brivaracetam may be initiated with either intravenous or oral administration. When converting from oral to intravenous administration or vice versa, the total daily dose and frequency of administration should be maintained.

The recommended starting dose is either 50 mg/day or 100 mg/day based on physician’s assessment of required seizure reduction versus potential side effects. Based on individual patient response and tolerability, the dose may be adjusted in the effective dose range of 50 mg/day to 200 mg/day.

Adolescents and children weighing 50 kg or more

The recommended starting dose is 50 mg/day. Brivaracetam may also be initiated at 100 mg/day based on physician’s assessment of need for seizure control. The recommended maintenance dose is 100 mg/day. Based on individual patient response, the dose may be adjusted in the effective dose range of 50 mg/day to 200 mg/day.

Adolescents and children weighing from 20 kg to less than 50 kg

The recommended starting dose is 1 mg/kg/day. Brivaracetam may also be initiated at doses up to 2 mg/kg/day based on physician’s assessment of need for seizure control. The recommended maintenance dose is 2 mg/kg/day. Based on individual patient response, the dose may be adjusted in the effective dose range of 1 mg/kg/day to 4 mg/kg/day.

Children weighing from 10 kg to less than 20 kg

The recommended starting dose is 1 mg/kg/day. Brivaracetam may also be initiated at doses up to 2.5 mg/kg/day based on physician’s assessment of need for seizure control. The recommended maintenance dose is 2.5 mg/kg/day. Based on individual patient response, the dose may be adjusted in the effective dose range of 1 mg/kg/day to 5 mg/kg/day.

Missed doses

If patients missed one dose or more, it is recommended that they take a single dose as soon as they remember and take the following dose at the usual morning or evening time. This may avoid the brivaracetam plasma concentration falling below the efficacy level and prevent breakthrough seizures from occurring.

Discontinuation

For patients from 16 years of age, if brivaracetam has to be discontinued, it is recommended that the dose is reduced gradually by 50 mg/day on a weekly basis.

For patients below the age of 16 years, if brivaracetam has to be discontinued, it is recommended that the dose is reduced by a maximum of half the dose every week until a dose of 1 mg/kg/day (for patients with a body weight less than 50 kg) or 50 mg/day (for patients with body weight of 50 kg or more) is reached.

After 1 week of treatment at 50 mg/day, a final week of treatment at the dose of 20 mg/day is recommended.

Special populations

Elderly (65 years of age and above)

No dose adjustment is needed in elderly patients.

The clinical experience in patients ≥ 65 years is limited.

Renal impairment

No dose adjustment is needed in patients with impaired renal function. Brivaracetam is not recommended in end-stage renal disease patients undergoing dialysis due to lack of data.

Based on data in adults, no dose adjustment is necessary in paediatric patients with impaired renal function. No clinical data are available in paediatric patients with renal impairment.

Hepatic impairment

Exposure to brivaracetam was increased in adult patients with chronic liver disease.

In patients with hepatic impairment, the following adjusted doses, administered in 2 divided doses, approximately 12 hours apart, are recommended for all stages of hepatic impairment. No clinical data are available in paediatric patients with hepatic impairment.

 Paediatric patients less than 2 years of age

The efficacy of brivaracetam in paediatric patients aged less than 2 years has not yet been established.

Method of administration

• Intravenous bolus: brivaracetam may be administered as an intravenous bolus without dilution.
• Intravenous infusion: brivaracetam may be diluted in a compatible diluent and administered as a 15-minute intravenous infusion. This medicinal product must not be mixed with other medicinal products.

Brivaracetam bolus injection or intravenous infusion has not been studied in acute conditions; e.g. status epilepticus and is therefore not recommended for such conditions.

 Diluents:

• Sodium chloride 9 mg/ml (0.9%) solution for injection
• Ringer’s lactate solution for injection
• Glucose 50 mg/ml (5%) solution for injection

Medicinal product with particulate matter or discoloration should not be used. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

OVERDOSE

Symptoms

There is limited clinical experience with brivaracetam overdose in humans. Somnolence and dizziness have been reported in a healthy subject taking a single dose of 1,400 mg of brivaracetam.

The following adverse reactions were reported with brivaracetam overdose: nausea, vertigo, balance disorder, anxiety, fatigue, irritability, aggression, insomnia, depression, and suicidal ideation in the post-marketing experience. In general, the adverse reactions associated with brivaracetam overdose were consistent with the known adverse reactions.

Management of overdose

There is no specific antidote for overdose with brivaracetam. Treatment of an overdose should include general supportive measures. Since less than 10 % of brivaracetam is excreted in urine, haemodialysis is not expected to significantly enhance brivaracetam clearance.

CONTRAINDICATION

Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients.

 WARNING AND PRECAUTIONS

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic drugs (AEDs), including brivaracetam, in several indications. A meta-analysis of randomized placebo-controlled clinical studies of AEDs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for brivaracetam.

Patients should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should any signs of suicidal ideation or behaviour emerge. See also section 4.8, paediatric data.

Hepatic impairment

There are limited clinical data on the use of brivaracetam in patients with pre-existing hepatic impairment. Dose adjustments are recommended for patients with hepatic impairment.

Excipients

This medicinal product contains 17.72 mg sodium per vial, which is equivalent to less than 1 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

PREGNANCY, LACTATION AND ABILITY TO DRIVE

Women of childbearing potential

Physicians should discuss family planning and contraception with women of childbearing potential taking brivaracetam.

If a woman decides to become pregnant, the use of brivaracetam should be carefully re-evaluated.

Pregnancy

Risk related to epilepsy and antiepileptic medicinal products in general

For all anti-epileptic drugs, it has been shown that in the offspring of treated women with epilepsy, the prevalence of malformations is two to three times greater than the rate of approximately 3 % in the general population. In the treated population, an increase in malformations has been noted with polytherapy; however, the extent to which the treatment and/or the underlying condition is responsible has not been elucidated. Discontinuation of anti-epileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus.

Risk related to brivaracetam

There is a limited amount of data from the use of brivaracetam in pregnant women. There is no data on placental transfer in humans, but brivaracetam was shown to readily cross the placenta in rats. The potential risk for humans is unknown. Animal studies did not detect any teratogenic potential of brivaracetam.

In clinical studies, brivaracetam was used as adjunctive therapy and when it was used with carbamazepine, it induced a dose-related increase in the concentration of the active metabolite, carbamazepine-epoxide. There is insufficient data to determine the clinical significance of this effect in pregnancy.

As a precautionary measure, brivaracetam should not be used during pregnancy unless clinically necessary i.e. (if the benefit to the mother clearly outweighs the potential risk to the foetus).

Breast-feeding

Brivaracetam is excreted in human breast milk. A decision should be made whether to discontinue breastfeeding or to discontinue brivaracetam, taking into account the benefit of the medicinal product to the mother. In case of co-administration of brivaracetam and carbamazepine, the amount of carbamazepine-epoxide excreted in breast milk could increase. There is insufficient data to determine the clinical significance.

Fertility

No human data on the effect of brivaracetam on fertility are available. In rats, there was no effect on fertility with brivaracetam.

DRUG INTERACTION

Formal interaction studies have only been performed in adults.

Pharmacodynamic interactions

Concomitant treatment with levetiracetam

 In the clinical studies, although the numbers were limited, there was no observed benefit of brivaracetam versus placebo in patients taking levetiracetam concurrently. No additional safety or tolerability concern was observed.

Interaction with alcohol

In a pharmacokinetic and pharmacodynamic interaction study between brivaracetam 200 mg single dose and ethanol 0.6 g/L continuous infusion in healthy subjects, there was no pharmacokinetic interaction, but brivaracetam approximately doubled the effect of alcohol on psychomotor function, attention and memory. Intake of brivaracetam with alcohol is not recommended.

Pharmacokinetic interactions

 Effects of other medicinal products on the pharmacokinetics of brivaracetam

In vitro data suggest that brivaracetam has a low interaction potential. The main disposition pathway of brivaracetam is by CYP-independent hydrolysis. A second disposition pathway involves hydroxylation mediated by CYP2C19.

Brivaracetam plasma concentrations may increase when coadministered with CYP2C19 strong inhibitors (e.g. fluconazole, fluvoxamine), but the risk of a clinically relevant CYP2C19-mediated interaction is considered to be low. Limited clinical data are available implying that coadministration of cannabidiol may increase the plasma exposure of brivaracetam, possibly through CYP2C19 inhibition, but the clinical relevance is uncertain.

Rifampicin

In healthy subjects, coadministration with the strong enzyme inducer rifampicin (600 mg/day for 5 days), decreased brivaracetam area under the plasma concentration curve (AUC) by 45 %. Prescribers should consider adjusting the brivaracetam dose in patients starting or ending treatment with rifampicin.

Strong enzyme inducing AEDs

Brivaracetam plasma concentrations are decreased when coadministered with strong enzyme inducing AEDs (carbamazepine, phenobarbital, phenytoin) but no dose adjustment is required.

 Other enzyme inducers

Other strong enzyme inducers (such as St John´ s wort (Hypericum perforatum)) may also decrease the systemic exposure of brivaracetam. Therefore, starting or ending treatment with St John’s wort should be done with caution.

Effects of brivaracetam on other medicinal products

Brivaracetam given 50 or 150 mg/day did not affect the AUC of midazolam (metabolised by CYP3A4). The risk of clinically relevant CYP3A4 interactions is considered to be low.

In vitro studies have shown that brivaracetam exhibits little or no inhibition of CYP450 isoforms except for CYP2C19. Brivaracetam may increase plasma concentrations of medicinal products metabolised by CYP2C19 (e.g. lanzoprazole, omeprazole, diazepam). When tested in vitro brivaracetam did not induce CYP1A1/2 but induced CYP3A4 and CYP2B6. No CYP3A4 induction was found in vivo (see midazolam above). CYP2B6 induction has not been investigated in vivo and brivaracetam may decrease plasma concentrations of medicinal products metabolised by CYP2B6 (e.g. efavirenz). In vitro, interaction studies to determine the potential inhibitory effects on transporters concluded that there were no clinically relevant effects, except for OAT3. In vitro, brivaracetam inhibits OAT3 with a half maximal inhibitory concentration 42-fold higher than the C_max at the highest clinical dose. Brivaracetam 200mg/day may increase plasma concentrations of medicinal products transported by OAT3.

Antiepileptic drugs

Potential interactions between brivaracetam (50 mg/day to 200 mg/day) and other AEDs were investigated in a pooled analysis of plasma drug concentrations from all phase 2-3 studies in a population pharmacokinetic analysis of placebo-controlled phase 2-3 clinical studies, and in dedicated drug-drug interaction studies (for the following AEDs: carbamazepine, lamotrigine, phenytoin and topiramate). The effect of the interactions on the plasma concentration is summarized in table bellow (increase is indicated as “↑” and decrease as “↓”, area under the plasma concentration versus time curve as “AUC”, maximum observed concentration as C_max).

Pharmacokinetic interactions between brivaracetam and other AEDs

^a based on a study involving the administration of a supratherapeutic dose of 400 mg/day brivaracetam

Carbamazepine

Brivaracetam is a moderate reversible inhibitor of epoxide hydrolase resulting in an increased concentration of carbamazepine epoxide, an active metabolite of carbamazepine. In controlled clinical studies, the carbamazepine epoxide plasma concentration increased by a mean of 37 %, 62 % and 98 % with little variability at brivaracetam doses of 50 mg/day, 100 mg/day and 200 mg/day respectively. No safety risks were observed. There was no additive effect of brivaracetam and valproate on the AUC of carbamazepine epoxide.

Oral contraceptives

Co-administration of brivaracetam (100 mg/day) with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg) did not influence the pharmacokinetics of either substance. When brivaracetam was coadministered at a dose of 400 mg/day (twice the recommended maximum daily dose) with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg), a reduction in oestrogen and progestin AUCs of 27 % and 23 %, respectively, was observed without impact on suppression of ovulation. There was generally no change in the concentration-time profiles of the endogenous markers estradiol, progesterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), and sex hormone binding globulin (SHBG).

 ADVERSE EFFECTS

 Summary of the safety profile

The most frequently reported adverse reactions (>10%) with brivaracetam treatment were: somnolence (14.3 %) and dizziness (11.0 %). They were usually mild to moderate in intensity. Somnolence and fatigue were reported at a higher incidence with increasing dose.

The discontinuation rate due to adverse reactions was 3.5 %, 3.4 % and 4.0 % for patients randomized to brivaracetam at respectively the dose of 50 mg/day, 100 mg/day and 200 mg/day and 1.7 % for patients randomized to placebo. The adverse reactions most frequently resulting in discontinuation of brivaracetam therapy were dizziness (0.8 %) and convulsion (0.8 %).

 Tabulated list of adverse reactions

In the table below, adverse reactions, which were identified based on review of the three placebo-controlled, fixed-dose studies safety database in subjects ≥ 16 years of age, are listed by System Organ Class and frequency.

The frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Description of selected adverse reactions

Neutropenia has been reported in 0.5 % (6/1,099) brivaracetam patients and 0 % (0/459) placebo patients. Four of these subjects had decreased neutrophil counts at baseline, and experienced additional decrease in neutrophil counts after initiation of brivaracetam treatment. None of the 6 cases of neutropenia were severe, required any specific treatment or led to discontinuation of brivaracetam and none had associated infections.

Suicidal ideation has been reported in 0.3 % (3/1,099) brivaracetam patients and 0.7 % (3/459) placebo patients. In the short-term clinical studies of brivaracetam in epilepsy patients, there were no cases of completed suicide and suicide attempt, however both have been reported in open-label extension studies.

\Reactions suggestive of immediate (Type I) hypersensitivity have been reported in a small number of brivaracetam patients (9/3022) during clinical development.

Adverse reactions with intravenous administration generally appeared to be similar to those observed with oral administration. Intravenous administration was associated with infusion site pain in 2.8 % of the patients.

Paediatric population

The safety profile of brivaracetam observed in children from 1 month of age was consistent with the safety profile observed in adults. In the open label, uncontrolled, long-term studies suicidal ideation was reported in 4.7 % of paediatric patients (assessed from 6 years onwards, more common in adolescents) compared with 2.4 % of adults and behavioral disorders were reported in 24.8 % of paediatric patients compared with 15.1 % of adults. The majority of events were mild or moderate in intensity, were non-serious, and did not lead to discontinuation of study drug. An additional adverse reaction reported in children was psychomotor hyperactivity (4.7 %).

No specific pattern of adverse event (AE) was identified in children from 1 month to < 4 years of age when compared to older paediatric age groups. No significant safety information was identified indicating the increasing incidence of a particular AE in this age group. As data available in children younger than 2 years of age is limited, brivaracetam is not indicated in this age range. Limited clinical data are available in neonates.

Elderly

Of the 130 elderly subjects enrolled in the brivaracetam phase 2/3 development program (44 with epilepsy), 100 were 65-74 years of age and 30 were 75-84 years of age. The safety profile in elderly patients appears to be similar to that observed in younger adult patients.

PRESENTATION

BRIVATM Injections are supplied in 5 ml flint, Type I USP, Tubular vial.

STORAGE AND OTHER INFORMATION

Store in a cool and dry place. Protect from light.

Store at below 30°C temperature.

Caution: Not to be used if container is found leaking or solution is hazy or contain any visible solid particles. Keep this medicine out of the sight and reach of children.