Consumer medicine information

Lacosamide ARX

Lacosamide

BRAND INFORMATION

Brand name

Lacosamide ARX

Active ingredient

Lacosamide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lacosamide ARX.

SUMMARY CMI

LACOSAMIDE ARX

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.

1. Why am I using LACOSAMIDE ARX?

LACOSAMIDE ARX contains the active ingredient lacosamide. LACOSAMIDE ARX is used by itself (in patients over 16 years) or in combination with other medicines (in patients over 4 years) to control epilepsy.

For more information, see Section 1. Why am I using LACOSAMIDE ARX? in the full CMI.

2. What should I know before I use LACOSAMIDE ARX?

Do not use if you have ever had an allergic reaction to LACOSAMIDE ARX 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 LACOSAMIDE ARX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with LACOSAMIDE ARX 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 LACOSAMIDE ARX?

  • Swallow LACOSAMIDE ARX tablets whole with a glass of water.

More instructions can be found in Section 4. How do I use LACOSAMIDE ARX? in the full CMI.

5. What should I know while using LACOSAMIDE ARX?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using LACOSAMIDE ARX.
  • If you are pregnant or become pregnant while taking LACOSAMIDE ARX.
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not take LACOSAMIDE ARX to treat any other complaints unless your doctor tells you to.
  • Do not drink alcohol before or after taking this medicine.
Driving or using machines
  • Be careful driving or operating machinery until you know how this medicine affects you.
Drinking alcohol
  • Do not drink alcohol before or after taking this medicine.
Looking after your medicine
  • Keep your tablets in the pack until it is time to take them.
  • Keep the medicine in a cool dry place where the temperature stays below 25°C

For more information, see Section 5. What should I know while using LACOSAMIDE ARX? in the full CMI.

6. Are there any side effects?

LACOSAMIDE ARX helps most people with epilepsy but 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. Common side effects include: dizziness or problems with balance or coordination, headache, nausea, feeling tired, drowsy or sleepy, forgetfulness, tremors or itching.

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.



FULL CMI

LACOSAMIDE ARX

Active ingredient(s): lacosamide

Consumer Medicine Information (CMI)

This leaflet provides important information about using LACOSAMIDE ARX. 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 LACOSAMIDE ARX.

Where to find information in this leaflet:

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

1. Why am I using LACOSAMIDE ARX?

LACOSAMIDE ARX contains the active ingredient lacosamide. LACOSAMIDE ARX 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.

LACOSAMIDE ARX is used to by itself (in patients over 16 years) or in combination with other medicines (in patients over 4 years) 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 LACOSAMIDE ARX?

Warnings

Do not use LACOSAMIDE ARX if:

  • you are allergic to lacosamide, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • you have, or have had, a heart condition causing an uneven heart beat.

Check with your doctor or pharmacist if you:

  • have any other medical conditions:
    - heart problems
    - kidney problems
    - liver problems.
    - Any mental health condition, such as depression.
  • 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.

LACOSAMIDE ARX 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 LACOSAMIDE ARX during pregnancy to help decide whether or not you should take it.

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

Your doctor will discuss the risks and benefits of using LACOSAMIDE ARX if you are breastfeeding.

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 LACOSAMIDE ARX and affect how it works.

  • medicines to treat heart problems
  • medicine which may have an effect on your heart beat such as carbamazepine, lamotrigine or pregabalin.

LACOSAMIDE ARX does not interact with the oral contraceptive pill.

However, you may be given LACOSAMIDE ARX 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 LACOSAMIDE ARX 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 LACOSAMIDE ARX.

4. How do I use LACOSAMIDE ARX?

How much to take / use

  • Your doctor will tell you how much LACOSAMIDE ARX you will need to take each day.
  • This may depend on your condition, your body weight, and whether or not you are taking any other medicines.
  • Your doctor may start you on a low dose of LACOSAMIDE ARX first of 50 mg twice a day. Your doctor may slowly increase your dose up to a maximum of 300 mg twice a day, until you are taking enough to control your epilepsy and you are not having any seizures.
  • Swallow LACOSAMIDE ARX tablets whole with a glass of water.
  • Follow the instructions provided and use LACOSAMIDE ARX until your doctor tells you to stop.

When to take / use LACOSAMIDE ARX

  • Take LACOSAMIDE ARX twice a day, once in morning and once in night.
    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 use LACOSAMIDE ARX

LACOSAMIDE ARX should be used regularly at the same time each day.

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 use too much LACOSAMIDE ARX

If you think that you have used too much LACOSAMIDE ARX, you may need urgent medical attention.

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 LACOSAMIDE ARX?

Things you should do

Call your doctor straight away if you:

  • Notice an increase in seizures
  • Have symptoms of depression or thoughts of harming yourself.
  • Become pregnant while taking this medicine, tell your doctor.
  • Before you have any surgery or emergency treatment, tell your doctor or dentist that you are taking LACOSAMIDE ARX.
  • Tell your doctor if you feel LACOSAMIDE ARX is not helping your condition.
  • For any reason, you have not taken this medicine exactly as prescribed.

Remind any doctor, dentist or pharmacist you visit that you are using LACOSAMIDE ARX.

Things you should not do

  • Do not stop using this medicine suddenly.
  • Do not give LACOSAMIDE ARX to anyone else, even if their symptoms seem similar to yours or they have the same condition as you.
  • Do not take LACOSAMIDE ARX 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 LACOSAMIDE ARX affects you.

As with other antiepileptic medicines LACOSAMIDE ARX may cause dizziness or drowsiness. This is more frequent at the beginning of treatment or after an increase in the dose.

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

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

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

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

Drinking alcohol

Tell your doctor if you drink alcohol.

As a safety precaution, do not take LACOSAMIDE ARX with alcohol.

Looking after your medicine

  • Keep your tablets 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 in a cool dry place where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place 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 window sills.

Keep it where young children cannot reach it.

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 effectsWhat to do
  • dizziness or problems with balance or coordination
  • Headache
  • Nausea (feeling sick) or vomiting
  • Feeling tired, drowsy or sleepy
  • Forgetfulness
  • Tremors
  • Itching.
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Feelings of depression
  • Feeling aggressive or agitated
  • Spinning sensations
  • Double vision or blurred vision
  • Having trouble sleeping.
  • Thoughts of harming yourself
  • More frequent or more severe seizures
  • Fainting or feeling lightheaded
  • Heart palpitations or a rapid or irregular pulse
  • 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 LACOSAMIDE ARX contains

Active ingredient
(main ingredient)		50 mg, 100mg, 150 mg or 200 mg of lacosamide
Other ingredients
(inactive ingredients)
  • microcrystalline cellulose
  • hyprolose
  • colloidal anhydrous silica,
  • magnesium stearate

The following strengths also contain:

  • 50 mg - Opadry II complete film-coating system 85G500007 purple
  • 100 mg - Opadry II complete film-coating system 85G52072 yellow
  • 150 mg - Opadry II complete film-coating system 85G565024 brown
  • 200 mg - Opadry II complete film-coating system 85G505009 blue

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

What LACOSAMIDE ARX looks like

LACOSAMIDE ARX are available in four strengths:

  • 50 mg –Pink, oval, coated tablets, debossed “L” on one side and “50” on other side (Aust R 296750).
  • 100 mg – Dark yellow, oval, coated tablets, debossed “L” on one side and “100” on other side (Aust R 296752).
  • 150 mg –Salmon, oval, coated tablets, debossed “L” on one side and “150” on other side (Aust R 296760).
  • 200 mg –Blue, oval, coated tablets, debossed “L” on one side and “200” on other side (Aust R 296758).

Who distributes LACOSAMIDE ARX

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121

This leaflet was prepared in June 2022.

Published by MIMS August 2022

BRAND INFORMATION

Brand name

Lacosamide ARX

Active ingredient

Lacosamide

Schedule

S4

 

1 Name of Medicine

Lacosamide.

2 Qualitative and Quantitative Composition

Lacosamide ARX film-coated tablets are available in strengths of 50 mg, 100 mg, 150 mg and 200 mg lacosamide.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablets.

50 mg.

Pink-coloured, oval, film-coated tablets, debossed "L" on one side and "50" on other side.

100 mg.

Dark yellow-coloured, oval, film-coated tablets, debossed "L" on one side and "100" on other side.

150 mg.

Salmon-coloured, oval, film-coated tablets, debossed "L" on one side and "150" on other side.

200 mg.

Blue-coloured, oval, film-coated tablets, debossed "L" on one side and "200" on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Lacosamide ARX tablets are indicated as:
monotherapy in the treatment of partial-onset seizures with or without secondary generalisation in patients with epilepsy aged 16 years and older;
add-on therapy in the treatment of partial-onset seizures with or without secondary generalisation in patients with epilepsy aged 4 years and older;
add-on therapy in the treatment of primary generalised tonic-clonic seizures in patients with idiopathic generalised epilepsy aged 4 years and older.

4.2 Dose and Method of Administration

Lacosamide film-coated tablets may be taken with or without food.
Lacosamide oral solution and solution for injection formulations are unavailable in this brand however are available in other brands. Where correct dosing requires lacosamide oral solution or solution for injection formulations; other suppliers should be used and the specific product information for these formulations should be referred to for the complete dosage and administration instructions.
In accordance with current clinical practice, if Lacosamide ARX has to be discontinued, it is recommended this be done gradually (e.g. taper the daily dose by 200 mg/week).
Table 1 summarises the recommended dose for lacosamide. More details are provided in Table 1.

Adults.

Monotherapy (partial-onset seizures).

Lacosamide ARX must be taken twice a day. The recommended starting dose is 100 mg twice a day.
Depending on response and tolerability, the dose can be further increased by 50 mg twice a day every week, to a maximum recommended daily dose of 600 mg (300 mg twice a day).
In patients having reached a dose greater than 400 mg/day and who need an additional antiepileptic drug, the dosage that is recommended for add-on therapy below should be followed.

Add-on therapy (partial-onset seizures or primary generalised tonic-clonic seizures).

Lacosamide ARX must be taken twice a day. The recommended starting dose is 50 mg twice a day which should be increased to an initial therapeutic dose of 100 mg twice a day after one week.
Depending on response and tolerability, the maintenance dose can be further increased by 50 mg twice a day every week, to a maximum recommended daily dose of 400 mg (200 mg twice a day).

Add-on therapy converting to monotherapy (partial-onset seizures).

For patients on add-on therapy who will convert to lacosamide monotherapy, once the maintenance dose has been administered for at least 3 days, a gradual withdrawal of the concomitant antiepileptic drugs over at least 6 weeks is recommended. If the patient is on more than one antiepileptic drug, the antiepileptic drugs should be withdrawn sequentially. Safety and efficacy of lacosamide have not been established for simultaneous conversion to monotherapy from two or more concomitant antiepileptic drugs.

Initiation of lacosamide treatment with a loading dose (partial-onset seizures or primary generalised tonic-clonic seizures).

Lacosamide treatment may also be initiated with a single loading dose of 200 mg, followed approximately 12 hours later by a 100 mg twice daily (200 mg/day) maintenance dose regimen. Subsequent dose adjustment should be performed according to individual response and tolerability as described above. A loading dose should be administered under medical supervision with consideration of the lacosamide pharmacokinetics (see Section 5.2 Pharmacokinetic Properties) and the potential for increased incidence of CNS adverse reactions (see Section 4.8 Adverse Effects (Undesirable Effects)). Administration of a loading dose has not been studied in acute conditions such as status epilepticus.

Use in children.

Lacosamide is not indicated for monotherapy in children and is not recommended for use in children below the age of 4 as there is limited data on safety and efficacy in these age groups. The physician should prescribe the most appropriate formulation and strength according to weight and dose.
The dosage in children and adolescents is based on PK modelling targeting plasma concentrations in the same range as in adults.

Add-on therapy (partial-onset seizures or primary generalised tonic-clonic seizures).

Adolescents and children weighing 50 kg or more.
Dosage is the same as in adults (see above).
Children from 4 years of age or adolescents weighing less than 50 kg.
The recommended starting dose is 2 mg/kg/day which should be increased to an initial therapeutic dose of 4 mg/kg/day after one week.
Depending on response and tolerability, the maintenance dose can be further increased by 2 mg/kg/day every week. In children weighing less than 30 kg, due to an increased clearance compared to adults, a maximum dose of up to 12 mg/kg/day is recommended. In children weighing from 30 to under 50 kg, a maximum dose of 8 mg/kg/day is recommended, although in open-label studies (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.2 Pharmacokinetic Properties) a dose up to 12 mg/kg/day has been used by a small number of these children. The maintenance dose should be gradually adjusted until the optimal response is obtained.
Dosage in adolescents or children 50 kg or greater is the same as in adults (see above).

Loading dose.

Loading dose has not been studied in children.
However, for add-on therapy in adolescents or children weighing 50 kg or greater, lacosamide treatment may also be initiated with a single loading dose. Dosage is the same as in adults (see above). A loading dose should be administered under medical supervision with consideration of the lacosamide pharmacokinetics (see Section 5.2 Pharmacokinetic Properties) and the potential for increased incidence of CNS adverse reactions (see Section 4.8 Adverse Effects (Undesirable Effects)).
Administration of a loading dose has not been studied in acute conditions such as status epilepticus.

Use in patients with impaired renal function.

No dose adjustment is necessary in mild to moderate renally impaired adult patients (CLCR > 30 mL/min). Based on data in adults, no dose adjustment is necessary in paediatric patients with mild to moderate renal impairment (CLCR > 30 mL/min). A maximum dose of 250 mg/day is recommended for adult patients with severe renal impairment (CLCR ≤ 30 mL/min) and in adult patients with endstage renal disease. In paediatric patients with severe renal impairment (CLCR ≤ 30 mL/min) and in those with endstage renal disease, a reduction of 25% of the maximum dose is recommended. For patients requiring haemodialysis a supplement of up to 50% of the divided daily dose directly after the end of haemodialysis is recommended. Treatment of patients with end-stage renal disease should be made with caution as there is little clinical experience and accumulation of a metabolite (with no known pharmacological activity). In all patients with renal impairment, the dose titration should be performed with caution (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special patient groups).

Use in patients with impaired hepatic function.

A maximum dose of 300 mg/day is recommended for patients with mild to moderate hepatic impairment. The dose titration in these patients should be performed with caution considering coexisting renal impairment. Based on data in adults, in paediatric patients with mild to moderate hepatic impairment a reduction of 25% of the maximum dose should be applied. The pharmacokinetics of lacosamide has not been evaluated in severely hepatic impaired patients (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special patient groups). Lacosamide should be administered to patients with severe hepatic impairment only when the expected therapeutic benefits outweigh the possible risks, and the dosage and administration need to be adjusted while carefully observing the symptoms of the patient.

Use in elderly (65 years and older).

No dose reduction is necessary in elderly patients. Age-associated decreased renal clearance should be considered in elderly patients (see Use in patients with impaired renal function; see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special patient groups).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Known second- or third-degree atrioventricular (AV) block.

4.4 Special Warnings and Precautions for Use

Suicidal behaviour and ideation.

Antiepileptic drugs, including lacosamide, 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 (mono- 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 2 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 lacosamide 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.

Dizziness.

Treatment with lacosamide has been associated with dizziness which could increase the occurrence of accidental injury or falls. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication (see Section 4.8 Adverse Effects (Undesirable Effects)).

Cardiac rhythm and conduction.

Dose-dependent prolongations in PR interval with lacosamide were observed in clinical studies. When Lacosamide ARX is given with other drugs that prolong the PR interval, further PR prolongation is possible.
Lacosamide ARX should be used with caution in patients with underlying proarrhythmic conditions such as patients with known cardiac conduction problems or severe cardiac disease (e.g. myocardial ischemia/infarction, heart failure, structural heart disease or cardiac sodium channelopathies), or patients treated with medicinal products affecting cardiac conduction, including antiarrhythmics and sodium channel blockers (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). In such patients, obtaining an ECG before beginning Lacosamide ARX, and after Lacosamide ARX is titrated to steady-state, is recommended.
Lacosamide ARX may predispose patients with diabetic neuropathy and/or cardiovascular disease to atrial arrhythmias (atrial fibrillation or flutter).
In the placebo-controlled trials of lacosamide in epilepsy patients, atrial fibrillation or flutter were not reported; however both have been reported in open label epilepsy trials and in post-marketing experience (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience). In post-marketing experience, AV block (including second degree or higher AV block) has been reported. In patients with proarrhythmic conditions, ventricular tachyarrhythmia has been rarely reported. In rare cases, these events have led to asystole, cardiac arrest and death in patients with underlying proarrhythmic conditions.
Patients should be made aware of the symptoms of cardiac arrhythmia (e.g. slow, rapid or irregular pulse, palpitations, shortness of breath, feeling lightheaded, fainting). Patients should be counselled to seek immediate medical advice should any of these symptoms occur.
In patients who develop serious cardiac arrhythmia, lacosamide should be discontinued and a thorough clinical benefit/risk assessment should be performed before possibly restarting therapy.

Discontinuation.

In accordance with current clinical practice, if Lacosamide ARX has to be discontinued in patients with partial-onset seizures, it is recommended this be done gradually (e.g. taper the daily dose by 200 mg/week).

Use with alcohol.

No data on the interaction of lacosamide with alcohol are available.

Non-clinical cardiac safety.

A safety pharmacology study with intravenous1 administration of lacosamide in anesthetised dogs showed transient increases in PR interval and QRS complex duration and decreases in blood pressure most likely due to a cardiodepressant action. These transient changes started in the same concentration range as after maximum recommended clinical dosing. In anesthetised dogs and Cynomolgus monkeys, at intravenous1 doses of 15-60 mg/kg, slowing of atrial and ventricular conductivity, atrioventricular block and atrioventricular dissociation were seen.
1 Lacosamide ARX is available as film-coated tablets only, but intravenous formulations are available in other brands.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.

Use in the elderly.

The experience with lacosamide in elderly patients with epilepsy is limited. Age-associated decreased renal clearance with an increase in AUC levels should be considered in elderly patients (see Section 5.2 Pharmacokinetic Properties, Renal impairment).

Paediatric use.

Lacosamide ARX is not recommended for use in children under 4 years of age.
Administration of lacosamide to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory). The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. The no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide exposure (based on AUC) below that in humans at the maximum recommended dose. In juvenile dogs, transient CNS clinical signs were similar to those observed in adult dogs. Non-adverse microscopic changes (commonly reported in juvenile dogs and of unknown clinical significance) were seen in the periventricular region. Both findings were associated with lacosamide exposures (based on AUC) below those anticipated clinically at the maximum recommended dose. Thus, potential adverse effects on CNS development cannot be ruled out.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Lacosamide should be used with caution in patients treated with medicinal products known to be associated with PR prolongation (including sodium channel blocking antiepileptic drugs such as carbamazepine, lamotrigine and pregabalin) and, in patients treated with antiarrhythmic drugs. However, subgroup analysis in clinical trials did not identify an increased magnitude of PR prolongation in patients with concomitant administration of carbamazepine or lamotrigine.

In vitro data.

Data generally suggest that lacosamide has a low interaction potential. In vitro metabolism studies indicate that lacosamide does not induce the enzyme activity of drug metabolising cytochrome P450 isoforms CYP1A2, 2B6, 2C9 and 3A4. Lacosamide did not inhibit CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1 and 3A4/5 at plasma concentrations observed in clinical trials. In vitro data suggest that lacosamide has the potential to inhibit CYP2C19 at therapeutic concentrations.
Lacosamide was not a substrate or inhibitor for P-glycoprotein.

In vivo data.

Clinical data indicate that lacosamide does not inhibit or induce CYP2C19 and 3A4. Furthermore, an interaction trial with omeprazole (CYP2C19-inhibitor) demonstrated no clinically relevant changes in lacosamide plasma concentrations and no inhibitory effect on omeprazole pharmacokinetics.
Since < 15% of lacosamide is bound to plasma proteins, a clinically relevant interaction with other drugs through competition for protein binding sites is unlikely.

Antiepileptic drugs.

In interaction trials lacosamide did not significantly affect the plasma concentrations of carbamazepine and valproic acid. Lacosamide plasma concentrations were not affected by carbamazepine and by valproic acid.
The placebo-controlled clinical studies in patients with partial-onset seizures showed that steady-state plasma concentrations of levetiracetam, carbamazepine, carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine monohydroxy derivative (MHD), phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam and zonisamide were not affected by concomitant intake of lacosamide at any dose.
Population PK analysis in different age groups estimated that concomitant treatment with other anti-epileptic drugs known to be enzyme inducers (carbamazepine, phenytoin, phenobarbital, in various doses) decreased the overall systemic exposure of lacosamide by 25%.

Oral contraceptives.

In an interaction trial there was no interaction between lacosamide and the oral contraceptives ethinylestradiol and levonorgestrel. Progesterone concentrations were not affected when the medicinal products were co-administered.

Others.

Interaction trials showed that lacosamide had no effect on the pharmacokinetics of digoxin. There was no clinically relevant interaction between lacosamide and metformin.
Omeprazole 40 mg q.d. increased the AUC of lacosamide by 19%. The effect probably lacks clinical relevance. Lacosamide did not affect the single-dose pharmacokinetics of omeprazole.
Co-administration of warfarin with lacosamide does not result in a clinically relevant change in the pharmacokinetics and pharmacodynamic effects of warfarin.
Lacosamide has a low protein binding of less than 15%. Therefore, clinically relevant interactions with other drugs through competition for protein binding sites are considered unlikely.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no human data on the effects of lacosamide on male or female fertility. Male or female fertility in rats was unaffected by oral lacosamide doses resulting in an estimated drug exposure (based on plasma AUC0-24h) that was one to two times that in humans with the maximum recommended dose. Test doses were limited by CNS adverse effects.
(Category B3)
There are no adequate data from the use of lacosamide in pregnant women. In reproductive and developmental toxicity studies in rodents and rabbits, no teratogenic effects but an increase in numbers of stillborn pups and pup deaths in the peripartum period, and slightly reduced live litter sizes and pup body weights were observed at maternal toxic doses in rats corresponding to systemic exposure levels below the expected clinical exposure. Test doses were limited by CNS adverse effects.
Lacosamide and/or its metabolites were shown to cross the placental barrier in rats after treatment of dams, and foetal tissue concentrations were similar to those for maternal tissue.
Lacosamide should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the foetus). If women decide to become pregnant, the use of this product should be carefully re-evaluated. To monitor outcome of pregnancy in women exposed to Lacosamide ARX, doctors are encouraged to register pregnant patients taking Lacosamide ARX on the Australian Pregnancy Register for Women on Antiepileptic Medication with Epilepsy and Allied Conditions by calling 1800 069 722.
 Lacosamide is excreted in human breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Lacosamide ARX should be made taking into account the benefit of breast-feeding to the child and the benefit of Lacosamide ARX therapy to the woman.

4.7 Effects on Ability to Drive and Use Machines

Lacosamide ARX may have minor to moderate influence on the ability to drive and use machines. Lacosamide treatment has been associated with dizziness or blurred vision. Accordingly, patients should be advised not to drive a car or to operate other potentially hazardous machinery until they are familiar with the effects of lacosamide on their ability to perform such activities.

4.8 Adverse Effects (Undesirable Effects)

Clinical studies.

Partial-onset seizures - add-on therapy. Based on the analysis of pooled placebo-controlled clinical trials in 1308 patients with partial-onset seizures, a total of 61.9% of patients randomised to lacosamide and 35.2% of patients randomised to placebo reported at least 1 adverse reaction. The most frequently reported adverse reactions with lacosamide treatment were dizziness, headache, nausea and diplopia. They were usually mild to moderate in intensity. Some were dose-related and could be alleviated by reducing the dose. Incidence and severity of CNS and gastrointestinal (GI) adverse reactions usually decreased over time. Overall in controlled studies the discontinuation rate due to adverse reactions was 12.2% for patients randomised to lacosamide and 1.6% for patients randomised to placebo. The most common adverse reaction resulting in discontinuation of lacosamide therapy was dizziness.
Table 3 shows the incidence of very common (> 1/10) and common (> 1/100 to < 1/10) adverse reactions by randomised treatment group which have been reported in pooled placebo-controlled clinical trials.

Effect on liver function tests.

Abnormalities in liver function tests have been observed in controlled trials with lacosamide in adult patients with partial-onset seizures who were taking 1 to 3 concomitant antiepileptic drugs. Elevations of ALT to ≥ 3 x ULN occurred in 0.7% (7/935) of lacosamide patients and 0% (0/356) of placebo patients. One case of hepatitis with transaminases > 20 x ULN was observed in one healthy subject 10 days after lacosamide treatment completion, along with nephritis (proteinuria and urine casts). Serologic studies were negative for viral hepatitis. Transaminases returned to normal within one month without specific treatment. At the time of this event, bilirubin was normal. The hepatitis/ nephritis was interpreted as a delayed hypersensitivity reaction to lacosamide.
Partial-onset seizures - monotherapy. Based on the analysis of data from a non-inferiority monotherapy clinical trial comparing lacosamide to carbamazepine controlled release (CR), the most common adverse reactions for lacosamide were headache (13.7%), dizziness (11.7%). The discontinuation rate due to adverse reactions was 10.6% for patients randomised to lacosamide and 15.6% for patients randomised to carbamazepine CR. See Table 4.
The use of lacosamide is associated with dose-related increase in the PR interval. Adverse reactions associated with PR interval prolongation (e.g. atrioventricular block, syncope, bradycardia) may occur. In add-on clinical trials in epilepsy patients the incidence rate of reported first degree AV Block is uncommon, 0.7%, 0%, 0.5% and 0% for lacosamide 200 mg, 400 mg, 600 mg or placebo, respectively. No second or higher degree AV Block was seen in lacosamide treated epilepsy patients.
In the monotherapy trial the incidence of prolonged PR intervals was similar across treatment groups: 40 subjects (9.6%) in the lacosamide treatment group and 37 subjects (8.9%) in the carbamazepine CR treatment group experienced a treatment-emergent PR interval of > 200 ms and 16 subjects (3.7%) in the lacosamide treatment group and 13 subjects (3.0%) in the carbamazepine CR treatment group experienced a treatment-emergent PR interval of > 220 ms. Three subjects in each treatment group (0.7% in each treatment group) experienced a PR interval of > 250 ms.
The incidence rate for syncope reported in pooled add-on therapy clinical trials is uncommon and did not differ between lacosamide treated (n=944) epilepsy patients (0.1%) and placebo treated (n=364) epilepsy patients (0.3%). In the monotherapy clinical trial comparing lacosamide to carbamazepine CR, syncope was reported in 7/444 (1.6%) lacosamide patients and 1/442 (0.2%) carbamazepine CR patients.
In the short-term investigational trials of lacosamide in epilepsy patients, there were no cases of atrial fibrillation or flutter, however both have been reported in open-label epilepsy trials.
In addition, the following potentially important adverse drug reactions have been identified as being reported in clinical trials:

Psychiatric disorders.

Common: confusional state, insomnia.

Nervous system disorders.

Common: myoclonic epilepsy, ataxia, hypoesthesia, dysarthria, disturbance in attention, paraesthesia.

Ear and labyrinth disorders.

Common: tinnitus.

Gastrointestinal disorders.

Common: dyspepsia, dry mouth, diarrhoea.

General disorders and administration site conditions.

Common: irritability, feeling drunk.

Musculoskeletal and connective tissue disorders.

Common: muscle spasms.

Injury, poisoning and procedural complications.

Common: contusion.
Primary generalised tonic-clonic seizures. The safety profile of lacosamide reported in a study conducted in patients aged 4 years and older with idiopathic generalised epilepsy with primary generalised tonic-clonic seizures (PGTCS) was consistent with the safety profile reported from the pooled placebo-controlled clinical trials in partial-onset seizures. Additional adverse reaction reported in PGTCS patients was myoclonic epilepsy (2.5% in the lacosamide-group and 0% in the placebo-group). The most frequently reported adverse reactions were dizziness and somnolence. The most common adverse reactions resulting in discontinuation of lacosamide therapy were dizziness and suicidal ideation. The discontinuation rate due to adverse reactions was 9.1% of the lacosamide group and 4.1% in the placebo group.
Loading dose administration. Incidence of CNS adverse reactions such as dizziness may be higher after a loading dose.
Elderly population. In the monotherapy study comparing lacosamide to carbamazepine CR, the safety profile of lacosamide in elderly patients (≥ 65 years of age) appears to be similar to that observed in patients less than 65 years of age. However, a higher incidence (≥ 5% difference) of fall, diarrhoea and tremor has been reported in elderly patients compared to younger adult patients.
Paediatric population. The safety profile of lacosamide in placebo-controlled and in open-label studies in add-on therapy in children from 4 years of age was consistent with the safety profile observed in adults. In a 16-week placebo-controlled study (n=343), the most common adverse reactions were somnolence (14.0%) and, as commonly observed in the paediatric population a high incidence of infections and associated symptoms, such as nasopharyngitis (9.9%), pyrexia (8.2%) and pharyngitis (4.7%). The discontinuation rate during the treatment period due to adverse reactions was 4.1% for patients randomised to lacosamide and 5.8% for patients randomised to placebo. In the placebo-controlled study, the additional adverse reactions reported in children, decreased appetite and lethargy were observed at the rate of 3.5%, 0.6%, respectively, and no cases of abnormal behaviour were reported. In the open-label studies (n=408) with a duration of up to 2 years, these adverse reactions were reported at the rate of 5.9% for decreased appetite, 2.7% for lethargy and 1.7% for abnormal behaviour. In these open-label studies, the most frequently reported adverse reactions were nasopharyngitis (15.7%), vomiting (14.7%), dizziness (13.5%) and pyrexia (13.0%). Table 5 shows the incidence of treatment-emergent adverse event occurred in ≥ 3% of all children aged from 4 years in the placebo-controlled trial.
In addition, the following adverse drug reactions have been identified as being reported in clinical trials.

Psychiatric disorders.

Common: abnormal behaviour.

Nervous system disorders.

Common: lethargy.

Metabolism and nutrition disorders.

Common: decreased appetite.

Post-marketing experience.

In addition to the adverse reactions reported during clinical studies and listed above, the following adverse reactions have been reported in post-marketing experience. Data are insufficient to support an estimate of their incidence in the population to be treated.

Blood and lymphatic system disorders.

Agranulocytosis.

Immune system disorders.

Drug hypersensitivity reactions.
Multiorgan hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms, DRESS) have been reported in patients with some antiepileptic agents. These reactions are variable in expression but typically present with fever and rash and can be associated with involvement of different organ systems. Potential cases have been reported rarely with lacosamide and if multiorgan hypersensitivity reaction is suspected, Lacosamide ARX should be discontinued.

Psychiatric disorders.

Euphoric mood, suicide attempt and suicidal ideation, aggression, agitation, psychotic disorder, hallucination.

Nervous system disorders.

Dyskinesia, seizure. Very few cases of seizure worsening (including occurrence of status epilepticus) have been reported.

Cardiac disorders.

Ventricular tachyarrhythmia, bradycardia, atrioventricular block, atrial fibrillation and atrial flutter.

Hepatobiliary disorders.

Liver function test abnormal, hepatic enzyme increased (> 2 x ULN).

Skin and subcutaneous tissue disorders.

Toxic epidermal necrolysis, Stevens-Johnson syndrome, rash, angioedema, urticaria.

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 www.tga.gov.au/reporting-problems and contact Arrotex Medical Information enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms.

Symptoms observed after an accidental or intentional overdose of lacosamide are primarily associated with CNS and gastrointestinal system.
The types of adverse events experienced by patients exposed to doses above 400 mg up to 800 mg were not clinically different from those of patients administered recommended doses of lacosamide.
Events reported after an intake of more than 800 mg are dizziness, nausea, seizures (generalised tonic clonic seizures, status epilepticus). Cardiac conduction disorders, shock, and coma have also been observed. Fatalities have been reported in patients following an intake of acute single overdose of several grams of lacosamide.

Management of overdose.

There is no specific antidote for overdose with lacosamide. Treatment of lacosamide overdose should include general supportive measures and may include haemodialysis if necessary (see Section 5.2 Pharmacokinetic Properties).
For information on the management of overdose, contact the poisons information centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The precise mechanism by which lacosamide exerts its antiepileptic effect in humans remains to be fully elucidated. In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in reduced hyperexcitability of neuronal membranes.
Lacosamide protected against seizures in a broad range of animal models of partial and primary generalised seizures and delayed kindling development. In non-clinical experiments lacosamide in combination with levetiracetam, carbamazepine, phenytoin, valproate, lamotrigine, topiramate or gabapentin showed synergistic or additive anticonvulsant effects.

Clinical trials (partial-onset seizures).

Monotherapy.

Efficacy of lacosamide as monotherapy was established in a double-blind, parallel group, non-inferiority comparison to carbamazepine CR in patients 16 years of age or older with newly or recently diagnosed epilepsy. Patients with idiopathic generalised epilepsy were excluded. The patients were randomised to carbamazepine CR or lacosamide. The dose was based on dose response and ranged from 400 to 1200 mg/day for carbamazepine CR and 200 - 600 mg/day for lacosamide. The duration of the treatment was up to 121 weeks depending on the response.
In the full analysis set (FAS) for the patients with partial-onset seizures, the estimated 6-month seizure freedom rates were 89.5% for lacosamide-treated patients (n=405) and 91.2% for carbamazepine CR treated patients (n=405) using the Kaplan-Meier survival analysis method. The adjusted absolute difference between treatments was -1.8% (95% CI: -6.1, 2.8). Similar results were observed in the per-protocol set (PPS). See Table 6.

Add-on therapy.

The efficacy of lacosamide as add-on therapy in partial-onset seizures was established in three 12-week, randomised, double-blind, placebo-controlled, multicenter trials in adult patients. Patients enrolled had partial-onset seizures with or without secondary generalisation and were not adequately controlled with 1 to 3 concomitant AEDs. During an 8-week baseline period, patients were required to have an average of ≥ 4 partial-onset seizures per 28 days with no seizure-free period exceeding 21 days. In these 3 trials, patients had a mean duration of epilepsy of 24 years and a median baseline seizure frequency ranging from 10 to 17 per 28 days. Overall, 84% of patients were taking 2 to 3 concomitant AEDs with or without concurrent vagal nerve stimulation (VNS). In addition, 45% of patients had taken 7 or more AEDs throughout their lifetime.
Trial SP667 compared doses of lacosamide 200 mg, 400 mg, and 600 mg/day with placebo.
Trial SP754 compared doses of lacosamide 400 mg and 600 mg/day with placebo. Trial SP755 compared doses of lacosamide 200 mg and 400 mg/day with placebo. The trials required forced up-titration to the target (randomized) dose over up to 6 weeks (Trial SP667 and Trial SP754) or 4 weeks (Trial SP755). In all 3 trials, active treatment was initiated at 100 mg/day (50 mg given twice daily) and increased in weekly increments of 100 mg/day to the target dose. Subjects randomised to lacosamide 600 mg/day in Trial SP667, lacosamide 400 mg and 600 mg/day in Trial SP754, and lacosamide 400 mg/day in Trial SP755 received active drug beginning at Week 1. To facilitate trial blinding, subjects randomised to lacosamide 200 mg and 400 mg/day in Trial SP667 received placebo for the first 4 or 2 weeks, respectively, and subjects randomised to lacosamide 200 mg/day in Trial SP755 received placebo for the first 2 weeks.
In all three trials, following an 8-week Baseline Phase to establish Baseline seizure frequency prior to randomisation, subjects were randomised and titrated to the randomised dose (a 1-step back-titration of lacosamide 100 mg/day or placebo was allowed in the case of intolerable adverse events at the end of the Titration Phase). Treatment was maintained for 12 weeks.
A reduction over placebo in seizure frequency per 28 days, the primary variable in all three trials, was significant with lacosamide treatment at doses of 200 mg (Trial SP755, but not Trial SP667), 400 mg (Trials SP667, SP754, and SP755), and 600 mg/day (Trials SP667 and SP754). (See Table 7, Figure 1.) The 50% responder rates for 400 mg and 600 mg/day lacosamide were also statistically superior to placebo. (See Figure 2.)
Among the subjects who completed the 12-week Maintenance Phase, a total across all three trials of 12 (3.3%) and 6 (4.8%) subjects taking lacosamide 400 mg and 600 mg/day, respectively, were seizure-free compared with 3 (0.9%) subjects taking placebo.

Loading dose.

The pharmacokinetics and safety of a single loading dose of iv1 lacosamide were determined in a multicenter, open-label study designed to assess the safety and tolerability of rapid initiation of lacosamide using a single iv1 loading dose (including 200 mg) followed by twice daily oral dosing (equivalent to the iv1 dose) as add-on therapy in adult subjects 16 to 60 years of age with partial-onset seizures.

Paediatric population.

In children aged 4 years and older, partial-onset seizures have a similar clinical expression to those in adolescents and adults. The results of efficacy trials performed in adults can be extrapolated to children down to the age of 4 provided the dose is established and safety has been demonstrated. Weight-based dose adaptations have been established to achieve similar plasma concentrations to the ones observed in adults taking efficacious doses.
The extrapolation principle stated above was confirmed in a double-blind, randomised, placebo-controlled study. The study consisted of an 8-week baseline period followed by a 6-week titration period. Eligible patients on a stable dose regimen of 1 to ≤ 3 AEDs, who still experienced at least 2 partial-onset seizures during the 4 weeks prior to screening with seizure-free phase no longer than 21 days in the 8-week period prior to entry into the baseline period, were randomised to receive either placebo (N=172) or lacosamide (N=171).
Dosing was initiated at a dose of 2 mg/kg/day in subjects weighing less than 50 kg or 100 mg/day in subjects weighing 50 kg or more in 2 divided doses. During the titration period, lacosamide doses were adjusted in 1 or 2 mg/kg/day increments in subjects weighing less than 50 kg or 50 or 100 mg/day or 100 mg/day in subjects weighing 50 kg or more at weekly intervals to achieve the target maintenance period dose range.
Subjects must have achieved the minimum target dose for their body weight category for the final 3 days of the titration period to be eligible for entry into the 10-week maintenance period. Subjects were to remain on stable lacosamide dose throughout the maintenance period or were withdrawn and entered in the blinded taper period.
Statistically significant (p=0.0003) and clinically relevant reduction in partial-onset seizure frequency per 28 days from baseline to the maintenance period was observed between the lacosamide and the placebo group. The percent reduction over placebo based on analysis of covariance was 31.72% (95% CI: 16.342,44.277).
Overall, the proportion of subjects with at least a 50% reduction in partial-onset seizure frequency per 28 days from baseline to the maintenance period was 52.9% in the lacosamide group compared with 33.3% in the placebo group.
The quality of life assessed by The Paediatric Quality of Life Inventory (PedsQL) indicated that subjects in both lacosamide and placebo groups had a similar and stable health-related quality of life during the entire treatment period.
1 Lacosamide ARX is available as film-coated tablets only, but intravenous formulations are available in other brands.

Clinical trials (primary generalised tonic-clonic seizures).

The efficacy of lacosamide as add-on therapy in patients 4 years of age and older with idiopathic generalised epilepsy experiencing primary generalised tonic-clonic seizures (PGCTS) was established in a 24-week double-blind, randomised, placebo-controlled, parallel-group, multicentre study. The study consisted of a 12-week historical baseline period, a 4-week prospective baseline period and a 24-week treatment period (which included a 6-week titration period and an 18-week maintenance period). Eligible patients on a stable dose of 1 to 3 antiepileptic drugs experiencing at least 3 documented PGTCS during the 16-week combined baseline period were randomized 1 to 1 to receive lacosamide or placebo (lacosamide N=121, placebo N=121).
Patients were dosed on a fixed-dose regimen. Dosing was initiated at a dose of 2 mg/kg/day in patients weighing less than 50 kg or 100 mg/day in patients weighing 50 kg or more in 2 divided doses. During the titration period, lacosamide doses were adjusted in 2 mg/kg/day increments in patients weighing less than 50 kg or 100 mg/day in patients weighing 50 kg or more at weekly intervals to achieve the target maintenance period dose of 12 mg/kg/day in patients weighing less than 30 kg, 8 mg/kg/day in patients weighing from 30 to less than 50 kg or 400 mg/day in patients weighing 50 kg or more.
The primary efficacy endpoint (patients in the full analysis set: lacosamide N=118, placebo N=121) was time to second PGTCS during the 24-week treatment period. The key secondary endpoint of efficacy was seizure freedom for PGTCS during the 24-week treatment period. See Table 8.
During the 24-week treatment period, the proportion of patients with at least a 50% reduction in PGTCS frequency per 28 days from baseline to the treatment period was 68.1% in the lacosamide group compared with 46.3% in the placebo group; the proportion of patients with at least a 75% reduction in PGTCS frequency per 28 days from baseline to the treatment period was 57.1% in the lacosamide group compared to 36.4% in the placebo group.
The findings in the paediatric subgroup (20.2% of enrolment) were consistent with the results of the overall population for the primary, secondary and other efficacy endpoints. See Figure 3.

5.2 Pharmacokinetic Properties

Absorption.

Lacosamide is rapidly and completely absorbed after oral administration. The oral bioavailability of lacosamide tablets is approximately 100%. Following oral administration, the plasma concentration of unchanged lacosamide increases rapidly and reaches Cmax about 0.5 to 4 hours post-dose. Food does not affect the rate and extent of absorption.
After intravenous1 administration Cmax is reached at the end of infusion. The plasma concentration increases proportionally with dose after oral (100 mg-800 mg) and intravenous1 (50-300 mg) administration.

Distribution.

The volume of distribution is approximately 0.6 L/kg. Lacosamide is less than 15% bound to plasma proteins.

Metabolism.

95% of the dose is excreted in the urine as drug and metabolites. The metabolism of lacosamide has not been completely characterised. The major compounds excreted in urine are unchanged lacosamide (approximately 40% of the dose) and its O-desmethyl metabolite less than 30%. A polar fraction proposed to be serine derivatives accounted for approximately 20% in urine, but was detected only in small amounts (0-2%) in human plasma of some subjects. Small amounts (0.5-2%) of additional metabolites were found in the urine.
CYP2C19, 2C9 and 3A4 are mainly responsible for the formation of the O-desmethyl metabolite, with a minor contributing role by CYP2C19. No clinically relevant difference in lacosamide exposure was observed comparing its pharmacokinetics in extensive metabolisers (EMs, with a functional CYP2C19) and poor metabolisers (PMs, lacking a functional CYP2C19). No other enzymes have been identified to be involved in the metabolism of lacosamide.
The plasma concentration of O-desmethyl-lacosamide is approximately 15% of the concentration of lacosamide in plasma. This major metabolite has no known pharmacological activity.

Excretion.

Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation. After oral and intravenous1 administration of radiolabeled lacosamide, approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the faeces. The elimination half-life of the unchanged drug is approximately 13 hours. The pharmacokinetics is dose-proportional and constant over time, with low intra- and inter-subject variability. Following twice daily dosing, steady state plasma concentrations are achieved after a 3 day period. The plasma concentration increases with an accumulation factor of approximately 2.
Modelling shows a single loading dose of 200 mg approximates steady-state concentrations comparable to 100 mg twice daily oral administration.
1 Lacosamide ARX is available as film-coated tablets only, but intravenous formulations are available in other brands

Pharmacokinetics in special patient groups.

Gender.

Clinical trials indicate that gender does not have a clinically significant influence on the plasma concentrations of lacosamide.

Renal impairment.

The AUC of lacosamide was increased by approximately 30% in mildly and moderately and 60% in severely renal impaired patients and patients with end-stage renal disease requiring haemodialysis compared to healthy subjects, whereas Cmax was unaffected.
Lacosamide is effectively removed from plasma by haemodialysis. Following a 4 hour haemodialysis treatment, AUC of lacosamide is reduced by approximately 50%. Therefore, dosage supplementation following haemodialysis is recommended (see Section 4.2 Dose and Method of Administration). The exposure of the O-desmethyl metabolite was several-fold increased in patients with moderate and severe renal impairment. In absence of haemodialysis in patients with end-stage renal disease, the levels were increased and continuously rising during the 24-hour sampling. It is unknown whether the increased metabolite exposure in end-stage renal disease subjects could give rise to adverse effects, but no pharmacological activity of the metabolite has been identified.

Hepatic impairment.

Subjects with moderate hepatic impairment (Child-Pugh B) showed higher plasma concentrations of lacosamide (approximately 50% higher AUCnorm). The higher exposure was partly due to a reduced renal function in the studied subjects. The decrease in nonrenal clearance in the patients of the study was estimated to give a 20% increase in the AUC of lacosamide. The pharmacokinetics of lacosamide has not been evaluated in severe hepatic impairment (see Section 4.2 Dose and Method of Administration).

Elderly (over 65 years of age).

In a study in elderly men and women including 4 patients > 75 years of age, AUC was about 30 and 50% increased compared to young men, respectively. This is partly related to lower bodyweight. The bodyweight normalised difference is 26 and 23%, respectively. An increased variability in exposure was also observed. The renal clearance of lacosamide was only slightly reduced in elderly subjects in this study.
A general dose reduction is not considered to be necessary unless indicated due to reduced renal function (see Section 4.2 Dose and Method of Administration).

Paediatric population.

The paediatric pharmacokinetic profile of lacosamide was determined in a population pharmacokinetic analysis using sparse plasma concentration data obtained in one placebo-controlled randomised study and three open-label studies in 414 children with epilepsy.
The typical volume of distribution (V/F) was 0.71 L/kg. The typical plasma clearance was estimated to be 1.04 L/h, 1.32 L/h and 1.86 L/h for children weighing 20 kg, 30 kg and 50 kg, respectively. In comparison, plasma clearance was estimated at 1.92 L/h in adults (70 kg body weight).

5.3 Preclinical Safety Data

Genotoxicity.

Lacosamide was inactive in an in vitro mouse L5178Y lymphoma assay (tk locus) with positive or equivocal response only at excessive concentrations of 3 mg/mL (12 mM) and above. No genotoxicity was observed in tests for bacterial gene mutation in vitro and unscheduled DNA synthesis in rat hepatocytes ex vivo, or in an in vivo mouse micronucleus test for clastogenicity.

Carcinogenicity.

Lacosamide did not show any tumourigenic responses in long-term carcinogenicity studies in mice and rats. The highest oral doses used resulted in systemic drug exposures (based on plasma AUC0-24h) that were similar to (mice) or about three times (rats) that in humans treated with the maximum recommended dose.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lacosamide ARX film-coated tablets contain the following inactive ingredients: microcrystalline cellulose, crospovidone, hyprolose, colloidal anhydrous silica and magnesium stearate.
Lacosamide 50 mg tablets also contain film-coating (Opadry II complete film-coating system 85G500007 purple) is made of polyvinyl alcohol, talc, titanium dioxide, polyethylene glycol, lecithin (soya), iron oxide red, iron oxide black and indigo carmine aluminium lake.
Lacosamide 100 mg tablets also contain film-coating (Opadry II complete film-coating system 85G52072 yellow) is made of polyvinyl alcohol, talc, titanium dioxide, polyethylene glycol, iron oxide yellow and lecithin (soya).
Lacosamide 150 mg tablets also contain film-coating (Opadry II complete film-coating system 85G565024 brown) is made of polyvinyl alcohol, talc, titanium dioxide, polyethylene glycol, lecithin (soya), iron oxide red, iron oxide black and iron oxide yellow.
Lacosamide 200 mg tablets also contain film-coating (Opadry II complete film-coating system 85G505009 blue) is made of polyvinyl alcohol, talc, titanium dioxide, polyethylene glycol, iron oxide yellow and lecithin (soya) and indigo carmine aluminium lake.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian register of therapeutic goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

50 mg film-coated tablets.

Packed in PVC/PVDC-Aluminium blister packs of 14 tablets.

100 mg film-coated tablets.

Packed in PVC/PVDC-Aluminium blister packs of 14 and 56 tablets.

150 mg film-coated tablets.

Packed in PVC/PVDC-Aluminium blister packs of 14 and 56 tablets.

200 mg film-coated tablets.

Packed in PVC/PVDC-Aluminium blister packs of 56 tablets.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical name: (R)-2-Acetamido-N-benzyl-3-methoxypropionamide.
Molecular formula: C13H18N2O3.
MW: 250.30.

Chemical structure.


CAS number.

175481-36-4.
The active ingredient lacosamide is a white to light yellow powder. It is sparingly soluble in water (32.4 mg/mL at 25°C) and slightly soluble in acetonitrile and ethanol.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes