Consumer medicine information

Briviact Tablets & Oral solution

Brivaracetam

BRAND INFORMATION

Brand name

Briviact

Active ingredient

Brivaracetam

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Briviact Tablets & Oral solution.

What is in this leaflet

This leaflet answers some common questions about Briviact.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Briviact against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Briviact is used for

Briviact tablets and oral solution are used in combination with other medicines to control epilepsy. Epilepsy is a condition where you have repeated seizures. There are many different types of seizures, ranging from mild to severe.

This medicine belongs to a group of medicines called antiepileptics. These medicines are thought to work by controlling brain chemicals which send signals to nerves so that seizures do not happen.

Your doctor may have prescribed this medicine for another reason.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

There is no evidence that Briviact is addictive.

This medicine is available only with a doctor’s prescription.

Briviact is not recommended for use in children under the age of 4 years as its safety and effectiveness has not been established in this age group.

Before you take Briviact

When you must not take it

Do not take Briviact if you have an allergy to:

  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

If you are not sure whether any of the above conditions apply to you, ask your doctor.

Do not take this medicine after the expiry date printed on the pack.

Do not take this medicine if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor or pharmacist.

Before you start to take it

Tell your doctor or pharmacist if you have allergies to:

  • any other medicines, especially barbiturates (such as phenobarbitone) or any other antiepileptic medicines (such as carbamazepine, lamotrigine or levetiracetam)
  • any other substances, such as foods, preservatives or dyes.

Tell your doctor if you have, or have had, any medical conditions, especially the following:

  • kidney problems
  • liver problems.

Tell your doctor if you are pregnant or intend to become pregnant. Briviact may affect your developing baby if you take it during pregnancy. However, it is very important to control your seizures while you are pregnant. Your doctor will outline and weigh up all the risks and benefits of taking Briviact during pregnancy to help decide whether or not you should take it.

Tell your doctor if you are breastfeeding or plan to breastfeed. Your doctor will discuss the risks and benefits of using Briviact if you are breastfeeding.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking Briviact.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Briviact may interfere with each other. These include:

  • rifampicin, a medicine used to treat tuberculosis

Briviact does not interact with the oral contraceptive pill.

However, you may be given Briviact together with other antiepileptic medicines that do interact and may affect the effectiveness of your contraceptive. Your doctor may advise you to use an additional method of contraception if you take Briviact with other antiepileptic medicines.

How to take Briviact

How much to take

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

Your doctor will tell you how much Briviact you will need to take each day. This may depend on your condition and whether or not you are taking any other medicines.

If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

How to take it

Tablets
Swallow Briviact tablets whole with a glass of water.

Oral Solution

  1. Press the cap and turn it anticlockwise to open the bottle.

  1. Separate the adaptor from the syringe.

  1. Insert the adaptor into the bottle neck. Ensure it is well fixed.

  1. Take the syringe and put it in the adaptor opening.

  1. Turn the bottle upside down.

Fill the syringe with a small amount of solution by pulling the piston down (5A), then push the piston upward in order to remove any possible bubble (5B). Pull the piston down to the graduation mark corresponding to the quantity in milliliters (mL) prescribed by your doctor (5C)

  1. Turn the bottle the right way up (6A). Remove the syringe from the adaptor (6B).

  1. Empty the contents of the syringe in a glass of water by pushing the piston to the bottom of the syringe. Drink the whole contents of the glass. Close the bottle with the plastic screw cap.

  1. Wash the syringe with water only

When to take it

Take Briviact twice a day, once in the morning and once at night. Take it at about the same time each day. Taking your medicine at the same time each day will have the best effect. It will also help you remember when to take it.

It does not matter if you take this medicine before or after food.

If you forget to take it

Contact your doctor if you have missed one or more doses.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

How long to take it

Most antiepileptic medicines take time to work, so do not be discouraged if you do not feel better straight away.

Continue taking your medicine for as long as your doctor tells you to. This medicine helps control your condition, but does not cure it. Therefore you must take your medicine every day, even if you feel well.

Do not stop taking Briviact, or change the dosage, without checking with your doctor. Do not let yourself run out of medicine over the weekend or on holidays. Stopping Briviact suddenly may cause unwanted side effects or make your condition worse. Your doctor will slowly reduce your dose before you can stop taking it completely.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone in Australia 13 11 26), or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much Briviact. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of overdose may include feeling dizzy or drowsy.

While you are using Briviact

Things you must do

Tell your doctor immediately if you notice an increase in seizures or a change in the type of seizures you usually have.

Tell your doctor immediately if you have symptoms of depression or thoughts of harming yourself.

Tell any other doctors, dentists, and pharmacists who are treating you that you are taking this medicine.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking Briviact.

Before you have any surgery or emergency treatment, tell your doctor or dentist that you are taking Briviact.

Tell your doctor if you feel Briviact is not helping your condition. Your doctor may need to change your medicine.

Tell your doctor if, for any reason, you have not taken this medicine exactly as prescribed. Otherwise, your doctor may change your treatment unnecessarily.

If you become pregnant while taking this medicine, tell your doctor.

Be sure to keep all of your doctor’s appointments so that your progress can be checked. Your doctor will check your progress and may want to take some tests from time to time. This helps to prevent unwanted side effects.

Things you must not do

Do not give Briviact to anyone else, even if their symptoms seem similar to yours or they have the same condition as you.

Do not take Briviact to treat any other complaints unless your doctor tells you to.

Do not stop taking Briviact or change the dosage unless your doctor tells you to. Stopping Briviact suddenly may cause unwanted side effects or make your condition worse.

Things to be careful of

Be careful driving or operating machinery until you know how Briviact affects you.

As with other antiepileptic medicines Briviact may cause dizziness or drowsiness.

If you are feeling dizzy or drowsy, do not drive a car, operate machinery, or do anything else that could be dangerous.

Combining this medicine with alcohol is not recommended. If you drink alcohol while taking Briviact the negative effects of alcohol may be increased.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Briviact.

This medicine helps most people with epilepsy but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by this list of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

If you get any side effects, do not stop taking Briviact without first talking to your doctor or pharmacist.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • flu and upper respiratory tract infections
  • cough
  • dizziness
  • nausea (feeling sick) or vomiting
  • constipation
  • feeling tired, drowsy or sleepy

The above list includes the more common side effects of your medicine. They are mostly mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • feelings of depression, anxiety or nervousness
  • feeling aggressive
  • spinning sensations
  • recurrent infections

The above list includes serious side effects that may require medical attention.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • thoughts of harming yourself
  • more frequent or more severe seizures
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

The above list includes more serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may happen in some people.

After using Briviact

Storage

Keep your medicine in the pack until it is time to take them. If you take the tablets out of the pack they will not keep well.

Keep your tablets & oral solution in a cool dry place where the temperature stays below 30°C.

Do not store Briviact or any other medicine in the bathroom or near a sink.

Do not leave your medicine on a window sill or in the car on hot days. Heat and dampness can destroy some medicines.

Keep Briviact where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Dispose of any unused oral solution within 5 months of opening the bottle.

Product description

What it looks like

Tablets
Briviact tablets are available in five strengths:

  • 10 mg – White to off white, round, film-coated, and debossed with "u10" on one side.
  • 25 mg – Grey, oval, film-coated, and debossed with "u25" on one side.
  • 50 mg – Yellow, oval, film-coated, and debossed with "u50" on one side.
  • 75 mg – Purple, oval, film-coated, and debossed with “u75” on one side.
  • 100 mg - Green-grey, oval, film-coated, and debossed with “u100” on one side.

Oral Solution
Briviact oral solution is packed in a 300 mL glass bottle and is available as 10 mg/mL strength. The pack also contains a 10 mL oral syringe and an adaptor for the syringe.

Ingredients

Tablets
Each Briviact tablet contains either 10 mg, 25 mg, 50 mg, 75 mg, 100 mg of brivaracetam as the active ingredient.

Other ingredients in Briviact tablets include:

  • croscarmellose sodium
  • lactose monohydrate
  • betadex
  • lactose
  • magnesium stearate
  • polyvinyl alcohol
  • purified talc
  • macrogol 3350
  • titanium dioxide

The following strengths also contain:

  • 25 mg - iron oxide yellow, iron oxide black
  • 50 mg - iron oxide yellow, iron oxide red
  • 75 mg - iron oxide yellow, iron oxide red, iron oxide black
  • 100 mg - iron oxide yellow, iron oxide black

Briviact tablets do not contain sucrose, gluten, tartrazine or any other azo dyes.

Briviact tablets contain lactose.

Oral Solution
Briviact oral solution contains the following ingredients: sodium citrate, citric acid anhydrous, methyl hydroxybenzoate, carmellose sodium, sucralose, sorbitol solution (70 percent)(crystallising), glycerol, raspberry flavour 7557-A and purified water.

Australian Sponsor:

UCB Pharma
A division of UCB Australia Pty Ltd
Level 1, 1155 Malvern Road
Malvern Vic 3144
Australia

Briviact 10 mg tablets
- AUST R 243794

Briviact 25 mg tablets
- AUST R 243796

Briviact 50 mg tablets
- AUST R 243797

Briviact 75 mg tablets
- AUST R 243798

Briviact 100 mg tablets
- AUST R 243792

Briviact 10 mg/mL oral solution
- AUST R 243793

Date of preparation:

April 2019

BRIVIACT is a registered trademark of UCB Biopharma SPRL

Published by MIMS July 2019

BRAND INFORMATION

Brand name

Briviact

Active ingredient

Brivaracetam

Schedule

S4

 

1 Name of Medicine

Brivaracetam.

6.7 Physicochemical Properties

Chemical name: (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide.
Molecular formula: C11H20N2O2.
MW: 212.29.

Chemical structure.


CAS number.

357336-20-0.

2 Qualitative and Quantitative Composition

The active ingredient brivaracetam is a white to off-white crystalline powder. It is very soluble in water, buffer (pH 1.2, 4.5 and 7.4), ethanol, methanol, and glacial acetic acid. It is freely soluble in acetonitrile and acetone and soluble in toluene. It is very slightly soluble in n-hexane.
Briviact film-coated tablets are available in strengths of 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg brivaracetam.

Briviact film-coated tablets contain the following excipients.

Lactose, lactose anhydrous.
Briviact oral solution is available as 10 mg/mL strength.

Briviact oral solution contains the following excipients with known effect.

Methyl hydroxybenzoate, sucralose, sorbitol solution (70%) (crystallising).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Briviact film coated tablets.

10 mg.

White to off white, round, film-coated, and debossed with "u10" on one side.

25 mg.

Grey, oval, film-coated, and debossed with "u25" on one side.

50 mg.

Yellow, oval, film-coated, and debossed with "u50" on one side.

75 mg.

Purple, oval, film-coated, and debossed with "u75" on one side.

100 mg.

Green-grey, oval, film-coated, and debossed with "u100" on one side.

Briviact oral solution.

Raspberry flavor.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Brivaracetam displays a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain. Binding to SV2A is considered to be the primary mechanism for brivaracetam anticonvulsant activity, however, the precise mechanism by which brivaracetam exerts its anticonvulsant activity has not been fully elucidated.

Effects on QT interval.

The effect of brivaracetam on QTc prolongation was evaluated in a randomized, double blind, positive controlled (moxifloxacin 400 mg) and placebo controlled parallel group study of brivaracetam (150 mg/day and 800 mg/day in two daily intakes) in 184 healthy subjects. There was no evidence that brivaracetam prolongs the QT interval.

Seizure frequency.

A statistically significant correlation has been demonstrated between brivaracetam plasma concentration and seizure frequency reduction from baseline in confirmatory clinical studies in adjunctive treatment of partial onset seizures. 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.

Clinical trials.

The efficacy of Briviact as adjunctive therapy in partial-onset seizures with or without secondary generalization was established in 3 fixed-dose, randomized, double blind, placebo controlled, multicenter studies (Studies 1, 2 and 3) which included 1558 patients. Patients enrolled had partial onset seizures and were not adequately controlled with 1 to 2 concomitant AEDs. In Studies 1 and 2, approximately 80% of patients were taking 2 concomitant AEDs, and in Study 3, 71% were taking 2 concomitant AEDs with or without vagal nerve stimulation. The most commonly used AEDs across the three studies were carbamazepine (41%), lamotrigine (25%), valproate (21%), oxcarbazepine (16%), topiramate (14%), phenytoin (10%) and levetiracetam (10%). Patients on levetiracetam were excluded from Study 3. In Study 3, approximately 19% of the patients had a history of 0-1 previous AEDs, 34% with a history of 2-4 AEDs, and 47% with a history of 5 or more AEDs. The median baseline seizure frequency across the 3 studies was 9 seizures per 28 days. Patients had a mean duration of epilepsy of approximately 23 years.
All trials had an 8 week baseline period, during which patients were required to have at least 8 partial onset seizures. The baseline period was followed by a 12 week treatment period. There was no titration period in these studies. Study N01252 compared doses of Briviact 50 mg/day and 100 mg/day with placebo. Study N01253 compared a dose of Briviact 50 mg/day with placebo. Study N01358 compared doses of Briviact 100 mg/day and 200 mg/day with placebo.
The primary efficacy outcome for Study N01252 and Study N01253 was the percent reduction in 7-day partial onset seizure frequency over placebo. For Study N01358, the primary efficacy outcome was the percent reduction in 28-day partial onset seizure frequency over placebo and the 50% responder rate. The criteria for statistical significance for all 3 studies was p < 0.05. For Study N01252 and N01253, a post-hoc analysis was conducted to evaluate the percent reduction in 28-day partial onset seizure frequency over placebo. The results of the post hoc analysis for Study N01252 and N01253 were comparable to the 7-day prospective analysis.
In Study N01252, a sequential testing procedure, which required statistical significance at the 0.050 level for Briviact 50 mg/day versus placebo, was required prior to testing Briviact 100 mg/day. A statistically significant treatment effect was not observed for the 50 mg/day dose. The 100 mg/day dose was nominally significant. In Study N01253, the 50 mg/day dose showed a statistically significant treatment effect. In Study N01358, the 100 mg/day and 200 mg/day doses showed a statistically significant treatment effect.
The primary and secondary efficacy outcomes of all 3 studies are summarized in Table 4.
Figure 1 shows the percentage of patients (excluding patients with concomitant levetiracetam) by category of reduction from baseline in partial onset seizure frequency per 28 days across all 3 studies. Patients with more than a 25% increase in partial onset seizure are shown at left as "worse". Patients with an improvement in percent reduction from baseline in partial onset seizure frequency are shown in the 4 right-most categories. The percentages of patients with at least a 50% reduction in seizure frequency were 20.3%, 34.2%, 39.5%, and 37.8% for placebo, 50 mg/day, 100 mg/day, and 200 mg/day, respectively.

Treatment with levetiracetam.

In Studies N01252 and N01253, approximately 20% of the patients were on concomitant levetiracetam. Although the number of subjects is limited, there was no observed benefit versus placebo when brivaracetam was added to levetiracetam. No additional safety or tolerability concerns were observed.
In Study N01358, a pre-specified analysis of median percent reduction in partial onset seizure frequency by levetiracetam status demonstrated efficacy over placebo in patients with prior exposure to levetiracetam.

Paediatric population.

In children aged 4 years and older, partial-onset seizures have a similar clinical expression to those in adolescents and adults. Experience with epilepsy medicines suggests that the results of efficacy studies performed in adults can be extrapolated to children down to the age of 4 years provided the dose is established (see Section 5.2 Pharmacokinetic Properties). The results of efficacy have also been extrapolated to the IV route of administration on the basis of comparison with oral bioavailability. Doses in patients from 4 years of age were defined by dose adaptations which have been established to achieve plasma concentrations in the range observed in adults taking efficacious doses (see Section 5.2 Pharmacokinetic Properties).

Open label extension studies.

Across all studies, 81.7% of the patients who completed randomized studies were enrolled in the long-term open-label extension studies. From entry into the randomized studies, 5.3% of the subjects exposed to brivaracetam for 6 months (n=1500) were seizure free compared to 4.6% and 3.7% for subjects exposed for 12 months (n=1188) and 24 months (n=847), respectively.

5.2 Pharmacokinetic Properties

Absorption.

Brivaracetam is rapidly and completely absorbed after oral administration. Pharmacokinetics is dose proportional from 10 to 600 mg.
The median tmax for tablets taken without food is 1 hour (tmax range is 0.25 to 3 h).
Coadministration with a high fat meal slowed down the absorption rate of brivaracetam while the extent of absorption remained unchanged.
The extent of absorption of brivaracetam is unchanged by food.

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 favourable lipophilicity (log P) resulting in high cell membrane permeability, brivaracetam penetrates rapidly into the brain. Brivaracetam is rapidly and evenly distributed in most tissues. In rodents, the brain to plasma concentration ratio equilibrates rapidly, indicating fast brain penetration, and is close to 1, indicating absence of active transport.

Metabolism.

Brivaracetam is primarily metabolised by hydrolysis of the amide moiety to form the corresponding carboxylic acid, and secondarily by hydroxylation on the propyl side chain. The hydrolysis of the amide moiety leading to the carboxylic acid metabolite (34% of the dose in urine) is supported by hepatic and extrahepatic amidase (E.C.3.5.1.4). In vitro, the hydroxylation of brivaracetam is mediated primarily by CYP2C19. 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. Therefore, inhibitors of CYP2C19 are unlikely to have a significant effect on brivaracetam. The 3 metabolites are not 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. 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.

Pharmacokinetics in special patient groups.

Gender.

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

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, 4, and 21-fold, respectively. The renal clearance of these nonactive metabolites was decreased 10-fold. Human exposure of the 3 metabolites, hydroxy, acid and hydroxyacid, at the maximum therapeutic dose of brivaracetam was sufficiently covered by levels achieved at the no observed adverse effect level (NOAEL) in repeated dose toxicity studies in animals, including for patients with severe renal impairment. The hydroxyacid metabolite did not reveal any safety concerns in nonclinical studies. Brivaracetam has not been studied in patients undergoing hemodialysis (see Section 4.2 Dose and Method of Administration).

Hepatic impairment.

A pharmacokinetic study in subjects with hepatic cirrhosis (Child-Pugh grades A, B, and C) showed similar increases in exposure to brivaracetam irrespective of disease severity (50%, 57% and 59%), relative to matched healthy controls. Dose adjustments are recommended for patients with hepatic impairment (see Section 4.2 Dose and Method of Administration).
No clinical data are available in paediatric patients with hepatic impairment.

Elderly (over 65 years of age).

In a study in elderly subjects (65 to 79 years old; with creatinine clearance 53 to 98 mL/min/1.73 m2) receiving Briviact 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 slightly lower (0.76 mL/min/kg) than in young healthy male subjects (0.83 mL/min/kg). No dose adjustment is required (see Section 4.2 Dose and Method of Administration).

Paediatric population (1 month to 16 years of age).

In a pharmacokinetic study with 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 1.0 mg/kg/day, 2.0 mg/kg/day, and 4.0 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 (see Section 4.8 Adverse Effects (Undesirable Effects)). Plasma concentrations were shown to be dose proportional in all age groups. Population pharmacokinetics modeling indicated that the dose of 2.0 mg/kg twice a day provides the same steady-state average plasma concentration as in adults receiving 100 mg twice daily. The estimated plasma clearance was 1.61 L/h, 2.18 L/h and 3.19 L/h for children weighing 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.

Race.

The pharmacokinetics of brivaracetam was not significantly affected by race (Caucasian, black/ African American, Asian, American Indian/ Alaska Native, Hispanic/ Latino) in a population pharmacokinetic modeling from epilepsy patients.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity was evaluated in vitro in bacterial (Ames test) and mammalian cells (mouse lymphoma assay, chromosomal aberration test in CHO cells) and in vivo in rats (bone marrow micronucleus assay) and mice (Muta mice). Brivaracetam showed no evidence of mutagenicity or clastogenicity.

Carcinogenicity.

In a carcinogenicity study in mice, oral administration of brivaracetam for 104 weeks increased the incidence of liver tumours (hepatocellular adenoma and carcinoma) in males at the two highest doses (550, 700 mg/kg/day). At the no effect dose (400 mg/kg/day), exposure (plasma AUC) was similar to clinical exposure at the MRHD. These findings are considered to result from a nongenotoxic mode of action linked to a phenobarbitone-like liver enzyme induction, a known rodent specific phenomenon. In rats, oral administration of brivaracetam for 104 weeks (150, 230, 450, 700 mg/kg/day) resulted in an increased incidence of benign thymomas in females at the highest dose. At the no effect dose, exposure (plasma AUC) was about eight times the clinical exposure at the MRHD. The human relevance of the findings in rats is uncertain.

4 Clinical Particulars

4.1 Therapeutic Indications

Briviact tablets and oral solution are indicated as add-on therapy in the treatment of partial onset seizures with or without secondary generalisation in patients from 4 years of age with epilepsy.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Suicidal behaviour and ideation.

Antiepileptic drugs, including Briviact, increase the risk of suicidal thoughts or behaviour 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 behaviour, and/or any unusual changes in mood or behaviour.
Pooled analyses of 199 placebo controlled clinical trials (monotherapy and adjunctive therapy) of 11 different AEDs showed that patients randomised 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 behaviour compared to patients randomised to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behaviour 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 behaviour 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 behaviour 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 behaviour beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behaviour 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.
The relative risk for suicidal thoughts or behaviour was higher in clinical trials for epilepsy than in clinical trials for 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 this risk 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 behaviour. Should suicidal thoughts and behaviour emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behaviour and should be advised of the need to be alert for the emergence of worsening of the signs and symptoms of depression, any unusual changes in mood or behaviour, or the emergence of suicidal thoughts, behaviour, or thoughts about self harm. Behaviours of concern should be reported immediately to the treating doctor.

Hypersensitivity: bronchospasm and angioedema.

Briviact can cause hypersensitivity reactions. Bronchospasm and angioedema have been reported in patients taking Briviact. If a patient develops hypersensitivity reactions after treatment with Briviact, the drug should be discontinued. Briviact is contraindicated in patients with a prior hypersensitivity reaction to brivaracetam or any of the inactive ingredients (see Section 4.3 Contraindications).

Discontinuation.

In accordance with current clinical practice, if Briviact has to be discontinued it is recommended this be done gradually to minimise the potential for rebound seizures.

Use in 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 (see Section 4.2 Dose and Method of Administration).
No adverse liver changes were seen in rats and monkeys following chronic administration of brivaracetam at exposure well above (up to 33-fold) the mean human exposure at the clinical dose of 200 mg/day. In dogs, brivaracetam administration resulted in adverse liver changes, mainly porphyria, at an exposure level close to mean human exposure at the clinical dose of 200 mg/day. 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.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration.

Use in the elderly.

The three pivotal double blind placebo controlled studies included 38 elderly patients aged between 65 and 80 years. Although data are limited, the efficacy was comparable to younger subjects. No dose adjustment is needed in elderly patients.

Paediatric use.

Briviact is not recommended for use in children under 4 years of age as safety and efficacy has not yet been established in this population. Limited efficacy data is available from open label studies in children 1 month to < 16 years of age with partial onset seizures and other epilepsy syndromes.
The potential adverse effects of long-term oral administration of brivaracetam on neonatal growth and development were investigated in juvenile rats and dogs. In juvenile rats, the highest dose tested, 600 mg/kg/day, was associated with adverse developmental effects (i.e. mortality, clinical signs, decreased bodyweight, lower brain weight and nonreversible effects on auditory startle responses). There were no adverse neuropathological or brain histopathological findings. The NOAEL was considered to be 300 mg/kg/day. In juvenile dogs, the dose of 100 mg/kg/day induced adverse liver changes similar to those observed in adult animals. There were no adverse effects on growth, bone density or strength, brain and neurobehavioral assessments and neuropathology evaluation. Similar exposure to brivaracetam was achieved in adult vs juvenile animals at the NOAEL, except at postnatal day 4 where higher exposure was achieved in juveniles compared to adults.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interaction studies have only been performed in adults.

Effects of other substances on brivaracetam.

The hydrolysis of brivaracetam is mediated by non-CYP dependent amidase. The hydroxylation of brivaracetam appears to be a minor elimination pathway primarily mediated by CYP2C19 (see Section 5 Pharmacological Properties). CYP mediated oxidation is responsible for a limited portion of brivaracetam's elimination.
Thus, coadministration with CYP inhibitors is unlikely to significantly affect brivaracetam exposure. Coadministration with CYP450 strong inducer, rifampicin decreases brivaracetam plasma concentrations by 45%. Prescribers should consider increasing the brivaracetam dose in patients starting treatment with rifampicin and decreasing when stopping rifampicin therapy. Brivaracetam concentrations were not significantly modified by CYP3A inhibitors and CYP2C19 inhibitors. In vitro assays showed that brivaracetam disposition should not be significantly affected by any CYP (e.g. CYP1A, 2C8, 2C9, 2C19, 2D6 and 3A4) or transporter (e.g. P-glycoprotein, BCRP, MRPs) inhibitors.

Effects of brivaracetam on other medicinal products.

Brivaracetam is not expected to cause clinically significant inhibition or induction of the clearance of other drugs metabolized by CYP450 isoforms. In vitro studies have shown that brivaracetam exhibits little or no inhibition of CYP450 isoforms at plasma concentrations achieved following a therapeutic dose. Brivaracetam did not induce CYP enzymes at therapeutic concentrations. Interaction studies to determine the potential inhibitory effects on transporters concluded that there were no clinically relevant effects.

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 and in a population exposure response analysis of placebo controlled phase 3 studies in adjunctive therapy in the treatment of partial onset seizures. The effect of the interactions on the plasma concentration is summarised in the Table 2.
Brivaracetam is a moderate reversible inhibitor of epoxide hydrolase resulting in an increased concentration of carbamazepine epoxide, an active metabolite of carbamazepine. In controlled 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 toxicity was observed, however, if tolerability issues arise when coadministered, carbamazepine dose reduction should be considered.

Oral contraceptives.

Coadministration 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 estrogen and progestin AUCs of 27% and 23%, respectively, was observed without impact on suppression of ovulation (no change was observed in the endogenous markers estradiol, progesterone, luteinizing hormone, follicle stimulating hormone, and sex hormone binding globulin). No study with lower doses of oral contraceptives has been performed.

Alcohol.

Brivaracetam increased the effect of alcohol on psychomotor function, attention and memory in a pharmacokinetic and pharmacodynamic interaction study in healthy subjects. There was no pharmacokinetic interaction.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No human data on the effect of brivaracetam on fertility are available. In rats, there was no adverse effect on male or female fertility following oral administration of brivaracetam at doses at least 15 times the maximal recommended human dose based on body surface area and plasma concentrations.
(Category B3)
There are no adequate data on the use of brivaracetam in pregnant women. Brivaracetam was used as adjunctive therapy in clinical studies and when used with carbamazepine, it induced a dose related increase in the concentration of an active metabolite, carbamazepine epoxide (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). There is insufficient data to determine the clinical significance of this effect in pregnancy. There are no data on human placental transfer. In rats, brivaracetam was shown to readily cross the placenta. The potential risk for humans is unknown.
As a precautionary measure, brivaracetam should not be used during pregnancy unless clinically necessary (if the benefit to the mother clearly outweighs the potential risk to the foetus). Discontinuation of antiepileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus. If a woman decides to become pregnant, the use of brivaracetam should be carefully re-evaluated. To monitor outcome of pregnancy in women exposed to Briviact, doctors are encouraged to register pregnant patients taking Briviact on the Australian Pregnancy Register for Women on Antiepileptic Medication with Epilepsy and Allied Conditions by calling 1800 069 722.
Animal studies did not detect any teratogenic potential of brivaracetam in either the rat or the rabbit. There were no adverse effects on embryofetal development following oral administration of brivaracetam to rats during the period of organogenesis at doses up to 600 mg/kg/day (AUC exposure 25 times clinical exposure at the MRHD), or following intravenous administration of the brivaracetam metabolite ucb-107092-1 at doses up to 1000 mg/kg/day (plasma concentration at least 40 times the plasma Cmax in healthy or renally impaired subjects). In rabbits, adverse effects on embryofetal development were not apparent at oral doses up to 120 mg/kg/day (AUC exposure 3 times clinical exposure at the MRHD) during organogenesis despite the presence of overt maternotoxicity. Maternotoxic exposure at 6 times the clinical AUC at the MRHD resulted in increased postimplantation loss, fewer live fetuses and reduced fetal bodyweight. The potential risk for humans is unknown.
It is unknown whether brivaracetam is excreted in human milk. Studies in rats have shown excretion of brivaracetam and/or its metabolites in milk where levels are similar to the plasma level. Oral administration of brivaracetam to rats from early gestation to weaning was associated with mild developmental delays (plasma AUC 14 times clinical exposure at the MRHD); the no effect dose was 5 times clinical exposure. Because many drugs are excreted into human milk, a decision should be made whether to discontinue nursing or to discontinue brivaracetam, taking into account the benefit of the drug to the mother.

4.8 Adverse Effects (Undesirable Effects)

Clinical studies.

In all controlled and uncontrolled trials in patients with epilepsy, 2388 subjects have received brivaracetam, of whom 1740 have been treated for ≥ 6 months, 1363 for ≥ 12 months, 923 for ≥ 24 months, 733 for ≥ 36 months and 569 for ≥ 60 months (5 years).
In pooled placebo controlled adjunctive therapy studies involving 1558 adult patients with partial onset seizures (1099 patients treated with brivaracetam and 459 treated with placebo), 68.3% of patients treated with brivaracetam and 62.1% of patients treated with placebo experienced adverse events.
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 types of adverse events reported during the first 7 days of treatment were similar to those reported for the overall treatment period.
The discontinuation rate due to adverse events was 6.0%, 7.4% and 6.8% for patients randomized to brivaracetam at respectively the dose of 50 mg/day, 100 mg/day and 200 mg/day and 3.5% for patients randomized to placebo. The adverse reaction most frequently resulting in discontinuation of brivaracetam therapy was dizziness. See Table 3.

Paediatric population.

A long-term, uncontrolled, open-label safety study included children (from 4 years to less than 16 years) who continued treatment after completing the PK study (see Section 5 Pharmacological Properties) and children directly enrolled into the safety study. Children who directly enrolled received a brivaracetam starting dose of 1 mg/kg/day and depending on response and tolerability, the dose was increased up to 5 mg/kg/day by doubling the dose at weekly intervals. No child received a dose greater than 200 mg/day. For children weighing 50 kg or greater the brivaracetam starting dose was 50 mg/day and depending on response and tolerability, the dose was increased up to a maximum of 200 mg/day by weekly increments of 50 mg/day.
From the pooled open-label safety and PK studies in adjunctive therapy, 149 children with partial onset seizures in the age range of 4 - < 16 years of age have received brivaracetam, of whom 116 have been treated for ≥ 6 months, 104 for ≥ 12 months, 58 for ≥ 24 months, 20 for ≥ 36 months. The safety profile of brivaracetam observed in children was consistent with the safety profile observed in adults. As has been seen in patients with epilepsy, behavioural adverse reactions were more common in children than in adults. The types of events were, in general, consistent with the established brivaracetam safety profile in adults. The majority of events were mild or moderate in intensity, were non-serious, and did not lead to dose reduction or discontinuation of study drug. An additional adverse reaction reported in children was psychomotor hyperactivity (4.7%). As these are uncontrolled data, definitive causality cannot be concluded.
Suicidal ideation was reported in 4.7% of paediatric patients (more common in adolescents) compared with 2.4% of adults and behavioural disorders were reported in 24.8% of paediatric patients compared with 15.1% of adults.

Other adverse reactions (< 1%).

Other adverse reactions with a lower incidence rate which are considered important are listed below:

Immune system disorders.

Hypersensitivity including bronchospasm and angioedema (see Section 4.4 Special Warnings and Precautions for Use).

Blood and lymphatic system disorders.

Neutropenia.

Psychiatric disorders.

Aggression, agitation, psychotic disorder.
Suicidal ideation has been reported in 0.3% (3/1099) 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.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Adults.

Briviact at doses between 50 and 200 mg/day has been shown to be effective as adjunctive therapy in the treatment of partial onset seizures. Initial dose titration to an effective dose is not required for tolerability.
The daily dose is administered in two equally divided doses, once in the morning and once in the evening. The recommended starting dose as per clinical trials is 100 mg/day. In accordance with good prescribing practice, Briviact may be initiated at a dose of 50 mg per day. Based on individual patient response, the dose may be adjusted between 50 mg/day and 200 mg/day in steps of 50 mg per day every 2 weeks. Briviact may be taken with or without food.
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.
In accordance with current clinical practice, if Briviact has to be discontinued, it is recommended to withdraw it gradually.
If patients missed one dose or more, it is recommended that they take a single dose as soon as they remember.
The film coated tablets must be taken orally whole with liquid.
The oral solution does not need to be diluted before swallowing. A nasogastric tube or gastrostomy tube may be used when administering the oral solution.

Use in patients with impaired renal function.

The dose should be monitored in any form of renal impairment. Briviact is not recommended in endstage renal disease patients undergoing dialysis due to lack of data.

Use in patients with impaired hepatic function.

Exposure to brivaracetam was increased by 50%, 57% and 59% in adult patients with chronic liver disease belonging to Child-Pugh classes A, B and C, relatively to matched healthy controls. In adults, a 50 mg/day starting dose should be considered. In adolescents weighing 50 kg or greater, a 50 mg/day starting dose is recommended. A maximum daily dose of 150 mg administered in 2 divided doses is recommended for all stages of hepatic impairment. In paediatric patients weighing less than 50 kg, a 1 mg/kg/day starting dose is recommended. The maximum dose should not exceed 3 mg/kg/day.

Use in elderly (65 years and older).

No dose reduction is necessary in elderly patients.

Use in children.

Adolescents weighing 50 kg or greater.

The daily dose is administered in two equally divided doses, once in the morning and once in the evening. The recommended starting dose is 50 mg/day. Brivaracetam may also be initiated at 100 mg/day based on physician assessment of need for seizure control. The recommended maintenance dose is 100 mg/day. Based on individual patient response, the dose may be adjusted between the effective dose range of 50 mg/day and 200 mg/day.

Children from 4 years of age or adolescents weighing less than 50 kg.

The daily dose is administered in two equally divided doses, once in the morning and once in the evening. The recommended starting dose is 1 mg/kg/day. Brivaracetam may also be initiated at 2 mg/kg/day based on physician 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 between the effective dose range of 1 mg/kg/day and 4 mg/kg/day.
The physician should prescribe the most appropriate formulation and strength according to weight and dose.
There are insufficient data to recommend the use of Briviact in children under 4 years of age (see Section 4.4 Special Warnings and Precautions for Use).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. 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, as brivaracetam treatment has been associated with somnolence and other CNS related symptoms.

4.9 Overdose

Symptoms.

There is limited clinical experience with Briviact overdose in humans. Somnolence and dizziness have been reported in a healthy subject taking a single dose of 1400 mg of Briviact.

Management of overdose.

There is no specific antidote for overdose with Briviact. 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. For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Briviact film-coated tablets contain the following excipients: croscarmellose sodium, lactose, betadex, lactose anhydrous, magnesium stearate and the proprietary film coating agents specified below.

10 mg tablets.

Opadry II complete film coating system 85F18422 White (ARTG No: 11376).

25 mg tablets.

Opadry II complete film coating system 85F275014 Grey (ARTG No: 110507).

50 mg tablets.

Opadry II complete film coating system 85F38197 (ARTG No: Yellow 110509).

75 mg tablets.

Opadry II complete film coating system 85F200021 Purple (ARTG No: 110513).

100 mg tablets.

Opadry II complete film coating system 85F270000 Tan (ARTG No: 110508).
Briviact oral solution contains the following excipients: sodium citrate, citric acid anhydrous, methyl hydroxybenzoate, carmellose sodium, sucralose, sorbitol solution (70 percent) (crystallising), glycerol, Raspberry Flavour 7557-A (ARTG No: 110532) and purified water.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

Briviact film coated tablets: 4 years.
Briviact oral solution: 3 years.

6.4 Special Precautions for Storage

Store Briviact film coated tablets below 30°C.
Store unopened Briviact oral solution below 30°C. Once opened, store below 30°C and discard any remnants after 5 months.

6.5 Nature and Contents of Container

Briviact film-coated tablets.

Are blister packed and available in strengths of 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg brivaracetam.

10 mg.

Available in blister packs containing 14, 56, 100^ tablets and a multipack of 168^ (3 x 56) tablets.

25 mg.

Available in blister packs containing 14, 56, 100^ tablets and a multipack of 168^ (3 x 56) tablets.

50 mg.

Available in blister packs containing 14, 56, 100^ tablets and a multipack of 168^ (3 x 56) tablets.

75 mg.

Available in blister packs containing 14, 56, 100^ tablets and a multipack of 168^ (3 x 56) tablets.

100 mg.

Available in blister packs containing 14, 56, 100^ tablets and a multipack of 168^ (3 x 56) tablets.
*Not all pack sizes may be marketed.
^For hospital use only.

Briviact oral solution.

Briviact oral solution is packed in a 300 mL glass bottle and is available as 10 mg/mL strength. The pack also contains a 5 mL and 10 mL oral syringe and an adaptor for the syringe.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes