Consumer medicine information

Briviact Tablets & Oral solution

Brivaracetam

BRAND INFORMATION

Brand name

Briviact

Active ingredient

Brivaracetam

Schedule

SUMMARY CMI

Briviact^® tablets and oral solution

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using Briviact^®?

Briviact^® contains the active ingredient brivaracetam. Briviact^® is used to are used in combination with other medicines to control epilepsy.

For more information, see Section 1. Why am I using Briviact^®? in the full CMI.

2. What should I know before I use Briviact^®?

Do not use if you have ever had an allergic reaction to Briviact^® or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Briviact^®? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Briviact^® and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Briviact^®?

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.

More instructions can be found in Section 4. How do I use Briviact^®? in the full CMI.

5. What should I know while using Briviact^®?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using Briviact^® Continue taking your medicine for as long as your doctor tells you to. You must take your medicine every day, even if you feel well.
Things you should not do	Do not stop using this medicine suddenly or change the dosage, unless your doctor tells you to.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how Briviact^® affects you.
Drinking alcohol	Combining Briviact^® with alcohol is not recommended. If you drink alcohol while taking Briviact^® the negative effects of alcohol may be increased.
Looking after your medicine	Store your tablets & oral solution in a cool dry place where the temperature stays below 30°C, away from moisture, heat or sunlight. Oral solution - Dispose of any unused oral solution within 5 months of opening the bottle.

For more information, see Section 5. What should I know while using Briviact^®? in the full CMI.

6. Are there any side effects?

The following are common side effects of dizziness, flu and upper respiratory tract infections, cough, nausea (feeling sick) or vomiting constipation, feeling tired, drowsy or sleepy.

The following are potential serious side effect feelings of depression, anxiety or nervousness, feeling aggressive, spinning sensations, recurrent infections, allergic reactions, thoughts of harming yourself and more frequent or more severe seizures, particular care should be taken.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicinal product is subject to additional monitoring in Australia due to the extension of indications to patients aged 4 to 16 years of age. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

FULL CMI

Briviact^® tablets and oral solution (pronounced "BREE-vee-act")

Active ingredient(s): Brivaracetam ("BREE-va-RA-se-tam")

Consumer Medicine Information (CMI)

This leaflet provides important information about using Briviact^®. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Briviact^®.

Where to find information in this leaflet:

1. Why am I using Briviact^®?
2. What should I know before I use Briviact^®?
3. What if I am taking other medicines?
4. How do I use Briviact^®?
5. What should I know while using Briviact^®?
6. Are there any side effects?
7. Product details

1. Why am I using Briviact^®?

Briviact^® contains the active ingredient brivaracetam. Briviact^® This medicine belongs to a group of medicines called antiepileptics.

Briviact^® is 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.

2. What should I know before I use Briviact^®?

Warnings

Do not use Briviact^® if:

you are allergic to brivaracetam or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

have any other medical conditions especially, kidney problems and liver problems.
take any medicines for any other condition, especially barbiturates (such as phenobarbitone) or any other antiepileptic medicines (such as carbamazepine, lamotrigine or levetiracetam).

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

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.

Children less than 4 years of age

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.

3. What if I am taking other medicines?

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

Some medicines may interfere with Briviact^® and affect how it works.

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.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Briviact^®.

4. How do I use 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.
Follow the instructions provided and use Briviact^® until your doctor tells you to stop.

When to take Briviact^®

Briviact^® should be used 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.

How to take Briviact^®

Tablets

Swallow Briviact^® tablets whole with a glass of water.

Oral Solution

Press the cap and turn it anticlockwise to open the bottle (figure 1). Separate the adaptor from the syringe (figure 2)

Insert the adaptor into the bottle neck. Ensure it is well fixed (figure 3). Take the syringe and put it in the adaptor opening (figure 4)

Turn the bottle upside down (figure 5) and

Fill the syringe with a small amount of solution by pulling the plunger down (figure 6), then push the plunger upward in order to remove any possible bubble (figure 7). Pull the plunger down to the graduation mark corresponding to the quantity in millilitres (mL) prescribed by your doctor (figure 8). The plunger may rise back up the barrel on the first dosage. Therefore, ensure that the plunger is kept in position until the dosing syringe is disconnected from the bottle.

Turn the bottle the right way up (figure 9) Remove the syringe from the adaptor (figure 10).

There are two ways in which you can choose to drink the medicine:

empty the contents of the oral syringe into a little water by pushing the plunger to the bottom of the oral syringe (figure 11) – you will then need to drink all of the water (add just enough to make it easy to drink) or,
drink the solution directly from the oral syringe without water (figure 12) – drink the whole contents of the oral syringe.

Close the bottle with the plastic screw cap (you do not need to remove the adaptor).

To clean the syringe, rinse with cold water only, moving the plunger several times up and down to take up and expel the water, without separating the two components (figure 13).

Keep the bottle, the oral syringe, and the leaflet in the carton.

If you forget to use Briviact^®

Briviact^® should be used regularly at the same time each day. If you miss your dose at the usual time, take a single dose as soon as you remember.

Do not take a double dose to make up for the dose you missed.

This may increase the chance of you getting an unwanted side effect.

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

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.

If you use too much Briviact^®

If you think that you have used too much Briviact^®, you may need urgent medical attention. Symptoms of overdose may include feeling dizzy or drowsy.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Briviact^®?

Things you should do:

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

Call your doctor straight away if you:

Notice an increase in seizures or a change in the type of seizures you usually have.
Have symptoms of depression or thoughts of harming yourself.

Tell your doctor if you:

Feel Briviact^® is not helping your condition. Your doctor may need to change your medicine.
For any reason, you have not taken this medicine exactly as prescribed. Otherwise, your doctor may change your treatment unnecessarily.
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.

Remind any doctor, dentist, or pharmacist you visit that you are using Briviact^®.

Things you should not do:

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. Your doctor will slowly reduce your dose before you can stop taking it completely.
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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Briviact^® affects you.

Briviact^® may cause dizziness in some people. If you are feeling dizzy or drowsy, do not drive a car, operate machinery, or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

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

Looking after your medicine

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.

Store your tablets & oral solution in a cool dry place where the temperature stays below 30°C, away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on windowsills.

Keep it where young children cannot reach it.

When to discard your medicine

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

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.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects

What to do

Nervous system related:

Dizziness

Cold and Flu symptoms:

Cough
flu and upper respiratory tract infections

Digestive system related:

nausea (feeling sick) or vomiting
constipation

Other:

Feeling tired, drowsy or sleepy

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Nervous system related:

Spinning sensations

Mental health related:

Thoughts of harming yourself
Feelings of depression,
Anxiety or nervousness
Feeling aggressive

Cold and Flu symptoms:

Recurrent infections

Allergic Reaction symptoms:

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

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What Briviact^® contains

Active ingredient
(main ingredient)

brivaracetam

Other ingredients
(inactive ingredients)

Oral Solution:

sodium citrate
citric acid anhydrous
methyl hydroxybenzoate
carmellose sodium
sucralose
sorbitol solution (70 percent)(crystallising)
glycerol
raspberry flavour 7557-A
purified water

Tablets:

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

The following strengths 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.

Potential allergens

Oral Solution - hydroxybenzoates and sorbitol
Tablets - Lactose

Do not take this medicine if you are allergic to any of these ingredients.

What Briviact^® looks like

Oral Solution

Briviact^® 10 mg/mL Oral Solution AUST R 243793 is packed in a 300 mL glass bottle. The pack also contains a 5 mL and 10 mL oral syringe and an adaptor for the syringe.

Tablets

Come in the following 5 strengths:

Briviact^® 10 mg tablets AUST R 24379410 – White to off white, round, film-coated, and debossed with "u10" on one side.
Briviact^® 25 mg tablets AUST R 243796 Grey, oval, film-coated, and debossed with "u25" on one side.
Briviact^® 50 mg tablets AUST R 243797– Yellow, oval, film-coated, and debossed with "u50" on one side.
Briviact^® 75 mg tablets AUST R 243798 - Purple, oval, film-coated, and debossed with “u75” on one side.
Briviact 100 mg tablets AUST R 243792 - Green-grey, oval, film-coated, and debossed with “u100” on one side.

Who distributes Briviact^®

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

This leaflet was prepared in February 2024

Published by MIMS December 2024

BRAND INFORMATION

Brand name

Briviact

Active ingredient

Brivaracetam

Schedule

1 Name of Medicine

Brivaracetam.

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.

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.

4.2 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).

4.3 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 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 C_max 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.
Brivaracetam is excreted in human breast 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.

4.7 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.

4.8 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.

4.9 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).

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 t_max for tablets taken without food is 1 hour (t_max range is 0.25 to 3 h).
Coadministration with a high fat meal slowed down the absorption rate 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 (t_1/2) 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.

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 Yellow (ARTG No: 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: 5 years.
Briviact oral solution: 4 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