BRIVEPSY Tablets (Brivaracetam 50mg and 100mg)

Table of Content

For the use of Specialist or a Hospital or a Laboratory only

Qualitative and Quantitative Composition

Each film coated tablet contains Brivaracetam 50mg

Excipients     q.s.

Colours: Yellow oxide of Iron, Red oxide of iron and Titanium Dioxide I.P.

Each film coated tablet contains Brivaracetam 100mg

Excipients     q.s.

Colours: Yellow oxide of Iron, Black oxide of iron and Titanium Dioxide I.P.

Dosage Form(S) And Strength(S)

Film coated tablets containing 50mg and 100mg of Brivaracetam.

Clinical Particulars

Therapeutic Indication

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

Posology and Method of Administration

Posology

The physician should prescribe the most appropriate formulation and strength according to weight and dose.

Adults

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. The dose should be administered in two equally divided doses, once in the morning and once in the evening. Based on individual patient response and tolerability, the dose may be adjusted in the dose range of 50 mg/day to 200 mg/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 of Brivaracetam

If brivaracetam has to be discontinued, it is recommended to withdraw it gradually by 50 mg/day on a weekly basis. 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.

Hepatic impairment

Exposure to brivaracetam was increased in adult patients with chronic liver disease. In adults, a 50 mg/day starting dose should be considered. No clinical data are available in paediatric patients with hepatic impairment.

Method of administration

Brivaracetam film-coated tablets must be taken orally swallowed in whole with liquid and may be taken with or without food.

Contraindications

Hypersensitivity to brivaracetam or any of the inactive ingredients in Brivaracetam  (bronchospasm and angioedema have occurred) .

Special Warnings and Precautions for Use

Suicidal ideation and behavior

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.

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.

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.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analysed. 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 analysed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table1: 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.

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.

Excipients

Lactose intolerance

Brivaracetam tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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.

Somnolence and Fatigue

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.

Dizziness and Disturbance in Gait and Coordination

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.

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 behaviour, and adjustment disorder) and psychotic symptoms (psychotic disorder along with hallucination, paranoia, acute psychosis, and psychotic behaviour). 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.

Psychiatric adverse reactions were also observed in open label paediatric trials and were generally similar to those observed in adults.

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.

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.

Drugs interactions

Rifampin

Co-administration with rifampin decreases brivaracetam plasma concentrations likely because of CYP2C19 induction. Prescribers should increase the brivaracetam dose by up to 100% (i.e., double the dosage) in patients while receiving concomitant treatment with rifampin.

Carbamazepine

Co-administration with carbamazepine may increase exposure to carbamazepine-epoxide, the active metabolite of carbamazepine. Though available data did not reveal any safety concerns, if tolerability issues arise when co-administered, carbamazepine dose reduction should be considered.

Phenytoin

Because Brivaracetam can increase plasma concentrations of phenytoin, phenytoin levels should be monitored in patients when concomitant brivaracetam is added to or discontinued from ongoing phenytoin therapy.

Levetiracetam

Brivaracetam provided no added therapeutic benefit to levetiracetam when the two drugs were co-administered.

Use in Special Populations

Patients with 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.

Patients with Hepatic Impairment

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

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.

Pregnant Women

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 antiepileptic 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).

 Lactating Women

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

Data

Animal Data

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

Fertility

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

.Geriatric Patients

There were insufficient numbers of patients 65 years of age and older in the double-blind, placebo-controlled epilepsy trials (n=38) to allowed 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

Effects on Ability to Drive and Use Machines

Brivaracetam has minor or moderate influence on the ability to drive and use machines.

Due to possible differences in individual sensitivity some patients might experience somnolence, dizziness, and other central nervous system (CNS) related symptoms. Patients should be advised not to drive a car or to operate other potentially hazardous machines until they are familiar with the effects of brivaracetam on their ability to perform such activities.

Undesirable 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 (8.2 %) 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 %).

list of adverse reactions

Adverse reactions, which were identified based on review of the three placebo-controlled, fixed dose studies safety databases 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.

Infections and infestations

Common: Influenza

Blood and lymphatic system disorders

Uncommon: Neutropenia

Immune system disorders

Uncommon: Type I hypersensitivity

Metabolism and nutrition disorders

Common: Decreased appetite

Psychiatric disorders

Common: Depression, anxiety, insomnia, irritability

Uncommon: Suicidal ideation, psychotic disorder, aggression, agitation

Nervous system disorders

Very common: Dizziness, somnolence

Common: Convulsion, vertigo

Respiratory, thoracic and mediastinal disorders

Common: Upper respiratory tract infections, cough

Gastrointestinal disorders

Common: Nausea, vomiting, constipation

General disorders and administration site conditions

Common: Fatigue

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. If your patient experiences any side-effects, write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side-effects, you can help provide more information on the safety of this product.

Drug Abuse And Dependence

Controlled Substance

brivaracetam contains brivaracetam and is listed as a Schedule V controlled substance.

Abuse

In a human abuse potential study, single doses of brivaracetam at therapeutic and supra therapeutic doses were compared to alprazolam (C-IV) (1.5 mg and 3 mg). Brivaracetam at the recommended single dose (50 mg) caused fewer sedative and euphoric effects than alprazolam; however, brivaracetam at supra therapeutic single doses (200mg and 1000 mg) was similar to alprazolam on other measures of abuse.

Dependence

There was no evidence of physical dependence potential or a withdrawal syndrome with brivaracetam in a pooled review of placebo-controlled adjunctive therapy studies.

Overdosage

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 (14 times highest recommended single dose) of brivaracetam. The following adverse reactions were reported with brivaracetam overdose: vertigo, balance disorder, fatigue, nausea, diplopia, anxiety, and bradycardia. 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. 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 centre should be contacted for updated information on the management of overdose with brivaracetam. There are no data on the removal of brivaracetam using haemodialysis, but because less than 10 % of brivaracetam is excreted in urine, haemodialysis is not expected to enhance brivaracetam clearance.

Pharmacological Properties

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 protein2A (SV2A) in the brain, which may contribute to the anticonvulsant effect.

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.

Pharmacodynamic Properties

Interactions with Alcohol

In a pharmacokinetic and pharmacodynamics interaction study in healthy subjects, co-administration of brivaracetam (single dose 200 mg ) 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 brivaracetam 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 brivaracetam alone or ethanol alone. The immediate word recall scores were generally lower for brivaracetam when co-administered with ethanol.

Cardiac Electrophysiology

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

Pharmacokinetic Properties

Brivaracetam exhibits linear and time-independent pharmacokinetics at approved doses.  

The pharmacokinetics of brivaracetam are similar when used as monotherapy or as adjunctive therapy for the treatment of partial onset seizures.

Absorption

Brivaracetam is highly permeable and is rapidly and almost completely absorbed after oral administration. Pharmacokinetics is dose-proportional from 100 to 600 mg (a range that extends beyond the minimum and maximum single administration dose levels described in Dosage and Administration and the absolute bioavailability is approximately 100 %. The median tmax for tablets taken without food is 1 hour (range is 0.25 to 3 h).

Coadministration with a high-fat meal slowed absorption, but the extent of absorption remained unchanged. Specially, when a 50-mg tablet was administered with high-fat meal, Cmax (maximum brivaracetam plasma concentration during a dose interval, an exposure metric) was decreased by 37% and Tmax was delayed by 3 hours, but AUC (area under the brivaracetam plasma concentration versus time curve, an exposure metric) was essentially unchanged (decreased by 5%).

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.

 Elimination

Metabolism

Brivaracetam is primarily metabolized by hydrolysis of the amide moiety to form the corresponding carboxylic acid metabolite, and secondarily by hydroxylation on the propyl side chain to form the hydroxy metabolite. The hydrolysis reaction is mediated by hepatic and extra-hepatic amidase. The hydroxylation pathway is mediated primarily by CYP2C19. In human subjects possessing genetic variations in CYP2C19, production of the hydroxy metabolite is decreased 2-fold or 10-fold, while the blood level of brivaracetam itself is increased by 22% or 42%, respectively, in individuals with one or both mutated alleles. CYP2C19 poor metabolizers and patients using inhibitors of CYP2C19 may require dose reduction. An additional hydroxy acid metabolite is created by hydrolysis of the amide moiety on the hydroxyl metabolite or hydroxylation of the propyl side chain on the carboxylic acid metabolite (mainly by CYP2C9). None of the 3 metabolites are pharmacologically active.

Excretion

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. Fecal excretion accounts for less than 1 % of the dose. Less than 10 % of brivaracetam is excreted unchanged in urine. Thirty-four percent of the dose is excreted as the carboxylic acid metabolite 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 (eg. CYP1A, 2B6, 2C8, 2C9, 2D6, 2C19 and 3A4 and epoxide hydrolase) inhibitors.

In vitro, brivaracetam was not an inhibitor of the CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 3A4, or the transporters P-gp, BCRP, BSEP MRP2, MATE-K, MATE-1, OATP1B1, OATP1B3, OAT1, P-gp and OCT1 at clinically relevant concentrations. In vitro, brivaracetam did not induce CYP1A2. brivaracetam weakly inhibited CYP2C19 and would not be expected to cause significant inhibition of CYP2C19 in humans. brivaracetam was an inhibitor of epoxide hydrolase, (IC50 = 8.2 μM), suggesting that brivaracetam can inhibit the enzyme in vivo.

In Vivo Assessment of Drug Interactions

Drug Interaction Studies with Antiepileptic Drugs (AEDs)

Potential interactions between brivaracetam (25 mg twice daily to 100 mg twice daily) and other AEDs were investigated in a pooled analysis of plasma drug concentrations from all Phase 2 and 3 studies and in a population exposure-response analysis of placebo-controlled, Phase 3 studies in adjunctive therapy in the treatment of partial-onset seizures. None of the interactions require changes in the dose of brivaracetam. Interactions with carbamazepine and phenytoin can be clinically important. The interactions are summarized in Table 3.

Table2: Drug Interactions between Brivaracetam and Concomitant Anti-epileptic Drugs

Concomitant AED

Influence of AED on Brivaracetam

Influence of Brivaracetam on AED

Carbamazepine

26% decrease in plasma concentration

None for carbamazepine Increase of carbamazepine-epoxide metabolite*

Lacosamide

No data

None

Lamotrigine

None

None

Levetiracetam

None

None

Oxcarbazepine

None

None on the active monohydroxy metabolite derivative (MHD)

Phenobarbital

19% decrease in plasma concentration

None

Phenytoin

21% decrease in plasma concentration

Up to 20% increase in plasma concentration**

Pregabalin

No data

None

Topiramate

None

None

Valproic acid

None

None

Zonisamide

No data

None

* Brivaracetam is a reversible inhibitor of epoxide hydrolase resulting in an increased concentration of carbamazepine epoxide, an active metabolite of carbamazepine. The carbamazepine epoxide plasma concentration increased up to 198% at a brivaracetam dose of 100 mg twice daily.

** At a supratherapeutic dose of 400 mg/day brivaracetam, there was a 20% increase in phenytoin plasma concentration.

Drug Interaction Studies with Other Drugs

Effect of Other Drugs on Brivaracetam

Co-administration with CYP inhibitors or transporter inhibitors is unlikely to significantly affect brivaracetam exposure.

Co-administration with rifampin decreases brivaracetam plasma concentrations by 45%, an effect that is probably the result of CYP2C19 induction.

Oral Contraceptives

Co-administration of brivaracetam 200 mg twice daily (twice the recommended maximum daily dosage) with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg) reduced estrogen and progestin AUCs by 27% and 23%, respectively, without impact on suppression of ovulation. However, co-administration of brivaracetam 50 mg twice daily with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg) did not significantly influence the pharmacokinetics of either substance. The interaction is not expected to be of clinical significance.

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 200 mg twice daily (2 times the highest recommended dosage), 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 slightly lower (0.76 mL/min/kg) than in young healthy Controls  (0.83mL/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 hydroxyacid metabolites were increased 3-fold,4-fold, and 21-fold, respectively. The renal clearance of these inactive metabolites was decreased 10-fold. The hydroxyacid metabolite did not reveal any safety concerns in nonclinical studies. brivaracetam has not been studied in patients undergoing haemodialysis.

Hepatic impairment

A pharmacokinetic study in subjects with hepatic cirrhosis, Child-Pugh grades A, B, and C showed 50 %, 57 % and 59 % increases in brivaracetam exposure, respectively, compared  to matched healthy controls. The effect of hepatic impairment on brivaracetam pharmacokinetics in paediatric patients is expected to be comparable to the effect observed in adults.

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.

Sex

There were no differences observed in the pharmacokinetics of brivaracetam between male and female subjects.

Race

A population pharmacokinetic analysis comparing Caucasian and non-Caucasian patients showed no significant pharmacokinetic difference.

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.

Nonclinical Properties

Decreased spontaneous locomotor activity) seen at multiples (greater than 50-fold) of the pharmacologically active dose of brivaracetam, 2 mg/kg. Learning and memory function were not affected. Findings not observed in clinical studies but seen in the repeated-dose toxicology dog studies at exposure similar to the clinical plasma AUC, were hepatotoxic effects (mainly porphyria). However, toxicological data accumulated on brivaracetam and on a structurally related compound indicate that the dog liver changes have developed through mechanisms not relevant for humans. No adverse liver changes were seen in rats and monkeys following chronic administration of brivaracetam at 5- and 42-fold the clinical AUC exposure. In monkeys, CNS signs (prostrate, loss of balance, clumsy movements) occurred at 64-fold the clinical Cmax, these effects being less apparent over time.

Genotoxicity studies have not detected any mutagenic or clastogenic activity. Carcinogenicity studies did not indicate any oncogenic potential in rats, whereas increased incidences of hepatocellular tumors in male mice are considered to result of a non-genotoxic, mode of action linked to a phenobarbitone -like liver enzyme induction, which is a known rodent specific phenomenon.

Brivaracetam did not affect male or female fertility and has demonstrated no teratogenic potential in either rat or rabbit. Embryo toxicity was observed in rabbits at a maternal toxic dose of brivaracetam with an exposure level 8-fold the clinical AUC exposure at the maximum recommended dose. In rats, brivaracetam was shown to readily cross the placenta and to be excreted in milk of lactating rats with concentrations similar to maternal plasma levels. brivaracetam did not show any dependence potential in rats.

.Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a carcinogenicity study in mice, oral administration of brivaracetam (0, 400, 550, or 700 mg/kg/day) for 104 weeks increased the incidence of liver tumors (hepatocellular adenoma and carcinoma) in male mice at the two highest doses tested. At the dose (400 mg/kg) not associated with an increase in liver tumors, plasma exposures (AUC) were approximately equal to those in humans at the maximum recommended dose (MRD) of 200 mg/day. Oral administration (0, 150, 230, 450, or 700 mg/kg/day) to rats for 104 weeks resulted in an increased incidence of thymus tumors (benign thymoma) in female rats at the highest dose tested. At the highest dose not associated with an increase in thymus tumors, plasma exposures were approximately 9 times those in humans at the MRD.

Mutagenesis

Brivaracetam was negative for genotoxicity in in vitro (Ames, mouse lymphoma, and CHO chromosomal aberration) and in vivo (rat bone marrow micronucleus) assays.

Impairment of Fertility

Oral administration of brivaracetam (0, 100, 200, or 400 mg/kg/day) to male and female rats prior to and throughout mating and early gestation produced no adverse effects on fertility. The highest dose tested was associated with plasma exposures approximately 6 (males) and 13 (females) times those in humans at the MRD.

Description

The chemical name of brivaracetam is (2S)-2- butanamide. Its molecular formula is C11H20N2O2 and its molecular weight is 212.29. The chemical structure is:

Pharmaceutical Particulars

Incompatibilities

None

Shelf life

24 months

Packaging information

Blister pack of 14 tablets

Storage and handing instructions

Store at a temperature not exceeding 300C, protected from light and moisture. Keep out of reach of children.

Patient Counseling Information

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.

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.

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.

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.

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.

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during brivaracetam therapy.

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.

What is the most important information I should know about Brivaracetam?

Brivaracetam is a federally controlled substance (CV) because it can be abused or lead to dependence. Keep brivaracetam in a safe place to prevent misuse and abuse. Selling or giving away brivaracetam may harm others and is against the law.

Like other antiepileptic drugs, brivaracetam may cause suicidal thoughts or actions in a very small number of people, about 1 in 500 people taking it.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

  • thoughts about suicide or dying
  • new or worse depression
  • feeling agitated or restless
  • trouble sleeping (insomnia)
  • acting aggressive, feeling angry, or being violent
  • an extreme increase in activity and talking (mania)
  • attempts to commit suicide
  • new or worse anxiety
  • panic attacks
  • new or worse irritability
  • acting on dangerous impulses
  • other unusual changes in behavior or mood

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

  • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
  • Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Do not stop brivaracetam without first talking to a healthcare provider.

  • Stopping brivaracetam suddenly can cause serious problems.
  • Stopping a seizure medicine suddenly can cause seizures that will not stop (status epilepticus).

What is Brivaracetam?

Brivaracetam is a prescription medicine used to treat partial-onset seizures in patients 16 years of age and older with epilepsy.

Who should not take Brivaracetam?

Do not take brivaracetam if you are allergic to brivaracetam or any of the inactive ingredients in brivaracetam. See the end of this Medication Guide for a complete list of ingredients in brivaracetam.

What should I tell my healthcare provider before starting Brivaracetam?

Before taking brivaracetam, tell your healthcare provider about all of your medical conditions, including if you:

  • have or had depression, mood problems, or suicidal thoughts or behaviour.

have liver problems.

  • have abused or been dependent on prescription medicines, street drugs, or alcohol.
  • are pregnant or plan to become pregnant. It is not known if Brivaracetam will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking brivaracetam. You and your healthcare provider will have to decide if you should take Brivaracetam while you are pregnant. If you become pregnant while taking Brivaracetam, talk to your healthcare provider. 
  • are breastfeeding or plan to breastfeed. It is not known if Brivaracetam passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take brivaracetam.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. brivaracetam may affect the way other medicines work, and other medicines may affect how brivaracetam works. Do not start a new medicine without first talking with your healthcare provider. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine.

How should I take Brivaracetam?

  • Take brivaracetam exactly as your healthcare provider tells you.
  • Your healthcare provider will tell you how much brivaracetam to take and when to take it.
  • Your healthcare provider may change your dose if needed. Do not change your dose without talking to your healthcare provider.
  • Take brivaracetam with or without food.
  • Swallow brivaracetam tablets whole with a liquid. Do not chew or crush brivaracetam tablets before swallowing.
  • If you take too much brivaracetam, call your Poison Control Center or go to the nearest emergency room right away.

What should I avoid while taking Brivaracetam?

Do not drive or operate machinery until you know how brivaracetam affects you. Brivaracetam may cause drowsiness, tiredness, dizziness, and problems with your balance and coordination.

What are the possible side effects of Brivaracetam?

Brivaracetam may cause serious side effects, including:

  • See “What is the most important information I should know about brivaracetam?”
  • Nervous system problems. Drowsiness, tiredness, and dizziness are common with brivaracetam, but can be severe. See “What should I avoid while taking brivaracetam?” brivaracetam can also cause problems with balance and coordination.
  • Mental (psychiatric) symptoms. Brivaracetam can cause mood and behaviour changes such as aggression, agitation, anger, anxiety, apathy, mood swings, depression, hostility, and irritability. Irritability and anxiety are common with brivaracetam and can be severe. People who take brivaracetam can also get psychotic symptoms such as hallucinations (seeing or hearing things that are really not there), delusions (false or strange thoughts or beliefs), and unusual behavior.

The most common side effects of brivaracetam in adults include:

  • sleepiness
  • dizziness
  • feeling tired
  • nausea and vomiting

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. If your patient experiences any side-effects, write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side-effects, you can help provide more information on the safety of this product.

How should I store Brivaracetam?

  • Store brivaracetam at a temperature not exceeding 30°C. Protected from light & moisture.

General information about the safe and effective use of Brivaracetam.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use brivaracetam for a condition for which it was not prescribed. Do not give brivaracetam to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about brivaracetam. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about brivaracetam that is written for health professionals.

What are the ingredients in Brivepsy?

Active ingredient: brivaracetam

Tablet inactive ingredients: Lactose Monohydrate, Lactose anhydrous, Crosscarmellose sodium, Mangnesium stearate, Opadry II 85F270000 Tan, Opadry II 85f2000021 purple, Opadry II 85F38197 Yellow and Opadry II 85f275014 Grey.

Details of Manufacturer

Manufactured by:

Optimus Pharma Private Limited,

Plot No.73/B,73/B/2, EPIP, Pashamylaram (V),

Patancheru (M), Sangareddy (Dist.) – 502307,

Hyderabad, Telangana State, India.

Marketed by:

Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai,Maharashtra, INDIA

Details of Permission or Licence Number with Date

22/SRD/TS/2017/F/G, 29.01.2021

Date

01/Feb/2021