Lacosamide G.L. 150 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

07-12-2018

Produktens egenskaper Produktens egenskaper (SPC)

17-12-2018

Aktiva substanser:
lakosamid
Tillgänglig från:
G.L. Pharma GmbH,
ATC-kod:
N03AX18
INN (International namn):
lacosamide
Dos:
150 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
lakosamid 150 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 14 tabletter; Blister, 20 tabletter; Blister, 28 tabletter; Blister, 30 tabletter; Blister, 40 tabletter; Blister, 56 tabletter; Blister, 60 tabletter; Blister, 84 tabletter; Blister, 90 tabletter; Blister, 100 tabletter; Blister, 112 tabletter; Blister, 120 tabletter; Blister, 10 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
55386
Tillstånd datum:
2018-06-20

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

17-02-2021

Produktens egenskaper Produktens egenskaper - engelska

17-02-2021

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

20-06-2018

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Package leaflet: Information for the patient

Lacosamide G.L. 50 mg film-coated tablets

Lacosamide G.L. 100 mg film-coated tablets

Lacosamide G.L. 150 mg film-coated tablets

Lacosamide G.L. 200 mg film-coated tablets

lacosamide

Read all of this leaflet carefully before you start taking this medicine because it

contains important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm

them, even if their signs of illness are the same as yours.

If you get any side effects talk to your doctor or pharmacist. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet

What [Lacosamide] is and what it is used for

What you need to know before you take [Lacosamide]

How to take [Lacosamide]

Possible side effects

How to store [Lacosamide]

Contents of the pack and other information

1.

What [Lacosamide] is and what it is used for

What [Lacosamide] is

[Lacosamide] contains lacosamide. This belongs to a group of medicines called ‘antiepileptic

medicines’. These medicines are used to treat epilepsy.

You have been given this medicine to lower the number of fits (seizures) you have.

What [Lacosamide] is used for

[Lacosamide] is used in adults, adolescents and children aged 4 years and older.

It is used to treat a certain type of epilepsy called ‘partial-onset seizure with or without

secondary generalisation’.

In this type of epilepsy, fits first affect only one side of your brain. However, these may

then spread to larger areas on both sides of your brain.

[Lacosamide] may be used on its own or with other antiepileptic medicines.

2.

What you need to know before you take [Lacosamide]

Do not take [Lacosamide]

if you are allergic to lacosamide or any of the other ingredients of this medicine (listed in

section 6). If you are not sure whether you are allergic, please discuss with your doctor.

if you have a certain type of heart beat problem called second or third degree AV block.

Do not take [Lacosamide] if any of the above apply to you. If you are not sure, talk to your

doctor or pharmacist before taking this medicine.

Warnings and precautions

Talk to your doctor before taking [Lacosamide] if

you have thoughts of harming or killing yourself. A small number of people being treated

with antiepileptic medicinal products such as lacosamide have had thoughts of harming or

killing themselves. If you have any of these thoughts at any time, tell your doctor straight

away.

you have a heart problem that affects the beat of your heart and you often have a

particularly slow, fast or irregular heart beat (such as AV block, atrial fibrillation or atrial

flutter).

you have severe heart disease such as heart failure or have had a heart attack.

you are often dizzy or fall over. [Lacosamide] may make you dizzy – this could increase

the risk of accidental injury or a fall. This means that you should take care until you are

used to the effects of this medicine.

If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before

taking [Lacosamide].

If you are taking [Lacosamide] and you are experiencing symptoms of abnormal heartbeat

(such

slow,

rapid

irregular

heartbeat,

palpitations,

shortness

breath,

feeling

lightheaded, fainting), seek medical advice immediately (see section 4).

Children under 4 years

[Lacosamide] is not recommended for children aged under 4 years. This is because we do not

yet know whether it will work and whether it is safe for children in this age group.

Other medicines and [Lacosamide]

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines.

In particular, tell your doctor or pharmacist if you are taking any of the following medicines that

affect your heart. This is because [Lacosamide] can also affect your heart:

medicines to treat heart problems

medicines

which

increase

‘PR

interval’

scan

heart

(ECG

electrocardiogram)

such

medicines

epilepsy

pain

called

carbamazepine,

lamotrigine or pregabalin

medicines used to treat certain types of irregular heart beat or heart failure

Also tell your doctor or pharmacist if you are taking any of the following medicines. This is

because they may increase or decrease the effect of [Lacosamide] on your body:

medicines for fungal infections called fluconazole, itraconazole or ketoconazole

a medicine for HIV called ritonavir

medicines used to treat bacterial infections called clarithromycin or rifampicin

a herbal medicine used to treat mild anxiety and depression called St. John’s Wort

If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before

taking [Lacosamide].

[Lacosamide] with alcohol

As a safety precaution do not take [Lacosamide] with alcohol.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a

baby, ask your doctor or pharmacist for advice before taking this medicine.

It is not recommended to take [Lacosamide] if you are pregnant

or breast-feeding, as the

effects of [Lacosamide] on pregnancy and the unborn baby or the new-born child are not

known. Also, it is not known whether [Lacosamide] passes into breast milk. Seek advice

immediately from your doctor if you get pregnant or are planning to become pregnant. They

will help you decide if you should take [Lacosamide] or not.

Do not stop treatment without talking to your doctor first as this could increase your fits

(seizures). A worsening of your disease can also harm your baby.

Driving and using machines

Do not drive, cycle or use any tools or machines until you know how this medicine affects you.

This is because [Lacosamide] may make you feel dizzy or cause blurred vision.

3.

How to take [Lacosamide]

Always take this medicine exactly as your doctor has told you. Check with your doctor or

pharmacist if you are not sure.

Taking [Lacosamide]

Take [Lacosamide] twice each day - once in the morning and once in the evening.

Try to take it at about the same time each day.

Swallow the [Lacosamide] tablet with a glass of water.

You may take [Lacosamide] with or without food.

The tablet can be divided into equal doses.

You will usually start by taking a low dose each day and your doctor will slowly increase this

over a number of weeks. When you reach the dose that works for you, this is called the

‘maintenance dose’, you then take the same amount each day. [Lacosamide] is used as a long

term treatment. You should continue to take [Lacosamide] until your doctor tells you to stop.

How much to take

Listed below are the normal recommended doses of [Lacosamide] for different age groups and

weights. Your doctor may prescribe a different dose if you have problems with your kidneys or

with your liver.

Adults, adolescents and children weighing 50 kg or more

When you take [Lacosamide] on its own

The usual starting dose of [Lacosamide] is 50 mg twice a day.

Your doctor may also prescribe a starting dose of 100 mg of [Lacosamide] twice a day.

Your doctor may increase your twice daily dose every week by 50 mg. This will be until you

reach a maintenance dose between 100 mg and 300 mg twice a day.

When you take [Lacosamide] with other antiepileptic medicines

The usual starting dose of [Lacosamide] is 50 mg twice a day.

Your doctor may increase your twice daily dose every week by 50 mg. This will be until you

reach a maintenance dose between 100 mg and 200 mg twice a day.

If you weigh 50 kg or more, your doctor may decide to start [Lacosamide] treatment with a

single ‘loading’ dose of 200 mg. You would then start your ongoing maintenance dose

12 hours later.

Children and adolescents below 50 kg

The dose depends on their body weight. They usually start treatment with the syrup and only

change to tablets if they are able to take tablets and get the correct dose with the different

tablet strengths. The doctor will prescribe the formulation that is best suited to them.

If you take more [Lacosamide] than you should

If you have taken more [Lacosamide] than you should, contact your doctor immediately. Do

not try to drive.

You may experience:

Dizziness

Feeling sick (nausea) or being sick (vomiting)

Fits (seizures), heart beat problems such as a slow, fast or irregular heart beat, coma or a

fall in blood pressure with rapid heartbeat and sweating.

If you forget to take [Lacosamide]

If you have missed a dose within the first 6 hours of the scheduled dose, take it as soon

as you remember.

If you have missed a dose beyond the first 6 hours of the scheduled dose, do not take the

missed tablet anymore. Instead take [Lacosamide] at the next time that you would

normally take it.

Do not take a double dose to make up for a forgotten dose.

If you stop taking [Lacosamide]

Do not stop taking [Lacosamide] without talking to your doctor, as your epilepsy may

come back again or become worse.

If your doctor decides to stop your treatment with [Lacosamide], he/she will instruct you

about how you should decrease the dose step by step.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Nervous system side effects such as dizziness may be higher after a loading dose.

Talk to your doctor or pharmacist if you get any of the following:

Very common (may affect more than 1 in 10 people)

Headache

Feeling dizzy or sick (nausea)

Double vision (diplopia)

Common (may affect up to 1 in 10 people)

Problems in keeping your balance, shaking (tremor), tingling (paresthesia) or muscle

spasms, falling easily and getting bruises

Trouble with your memory, thinking or finding words, confusion

Rapid and uncontrollable movements of the eyes (nystagmus), blurred vision

A spinning sensation (vertigo), feeling drunk

Being sick (vomiting), dry mouth, constipation, indigestion, excessive gas in the stomach

or bowel, diarrhoea

Decreased feeling or sensitivity, difficulty in articulating words, disturbance in attention

Noise in the ear such as buzzing, ringing or whistling

Irritability, trouble sleeping depression

Sleepiness, tiredness or weakness (asthenia)

Itching, rash

Uncommon (may affect up to 1 in 100 people)

Slow heart rate, palpitations, irregular pulse or other changes in the electrical activity of

your heart (conduction disorder)

Exaggerated feeling of wellbeing, seeing and/or hearing things which are not there

Allergic reaction to medicine intake, hives

Blood tests may show abnormal liver function, liver injury

Thoughts of harming or killing yourself or attempting suicide: tell your doctor straight away

Feeling angry or agitated

Abnormal thinking or losing of touch with reality

Serious allergic reaction which causes swelling of the face, throat, hand, feet, ankles, or

lower legs

Fainting

Difficulties in coordinating your movements or walking

Not known (frequency cannot be estimated from the available data)

A sore throat, high temperature and getting more infections than usual. Blood tests may

show a severe decrease in a specific class of white blood cells (agranulocytosis).

serious

skin

reaction

which

include

high

temperature

other

flu-like

symptoms, a rash on the face, extended rash, swollen glands (enlarged lymph nodes).

Blood tests may show increased levels of liver enzymes and a type of white blood cell

(eosinophilia).

A widespread rash with blisters and peeling skin, particularly around the mouth, nose,

eyes and genitals (Stevens-Johnson syndrome), and a more severe form causing skin

peeling in more than 30% of the body surface (toxic epidermal necrolysis).

Convulsion

Abnormal rapid heartbeat (ventricular tachyarrhythmia)

Additional side effects in children

Common (may affect up to 1 in 10 children)

Runny nose (nasopharyngitis)

Fever (pyrexia)

Sore throat (pharyngitis)

Eating less than usual

Uncommon (may affect up to 1 in 100 children)

Feeling sleepy or lacking in energy

Not known (frequency cannot be estimated from the available data)

Changes in behaviour, not acting like themselves

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via the national

reporting system. By reporting side effects you can help provide more information on the

safety of this medicine.

5.

How to store [Lacosamide]

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after

EXP. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist

how to throw away medicines you no longer use. These measures will help protect the

environment.

6.

Contents of the pack and other information

What [Lacosamide] contains

The active substance is lacosamide.

Each tablet of [Lacosamide] 50 mg contains 50 mg lacosamide.

Each tablet of [Lacosamide] 100 mg contains 100 mg lacosamide.

Each tablet of [Lacosamide] 150 mg contains 150 mg lacosamide.

Each tablet of [Lacosamide] 200 mg contains 200 mg lacosamide.

The other ingredients are:

Tablet

core:

microcrystalline

cellulose,

hydroxypropylcellulose

substituted,

hydroxylpropylcellulose, crospovidone, colloidal anhydrous silica, magnesium stearate

Film-coat: poly(vinyl alcohol), macrogol, titanium dioxide (E 171), talc, colourants*

* The colourants are:

50 mg tablet:

iron

oxide

172),

black

iron

oxide

172),

indigo

carmine

aluminium lake (E 132)

100 mg tablet:

yellow iron oxide (E 172)

150 mg tablet:

yellow iron oxide (E 172), red iron oxide (E 172), black iron oxide

(E 172)

200 mg tablet:

indigo carmine aluminium lake (E 132)

What [Lacosamide] looks like and contents of the pack

[Lacosamide] 50 mg are pink, oval film-coated tablets with a break-score on both sides.

tablet can be divided into equal doses.

[Lacosamide] 100 mg are yellow, oval film-coated tablets with a break-score on both sides.

The tablet can be divided into equal doses.

[Lacosamide] 150 mg are brown, oval film-coated tablets with a break-score on both sides.

The tablet can be divided into equal doses.

[Lacosamide] 200 mg are blue, oval film-coated tablets with a break-score on both sides. The

tablet can be divided into equal doses.

[Lacosamide] is available in packs of 10, 14, 20, 28, 30, 40, 56, 60, 84, 90, 100, 112, and 120

film-coated tablets. The packs are available with PVC/Al blister or PVC/PVdC/Al blister.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

G.L. Pharma GmbH, 8502 Lannach, Austria

Manufacturer

G.L. Pharma GmbH, 8502 Lannach, Austria

Delorbis Pharmaceuticals Ltd., 2643 Ergates, Lefkosia, Cyprus

This leaflet was last revised in 28 January 2021.

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Lacosamide G.L. 50 mg film-coated tablets

Lacosamide G.L. 100 mg film-coated tablets

Lacosamide G.L. 150 mg film-coated tablets

Lacosamide G.L. 200 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

[Lacosamide 50 mg film-coated tablets]

Each film-coated tablet contains 50 mg lacosamide.

[Lacosamide 100 mg film-coated tablets]

Each film-coated tablet contains 100 mg lacosamide.

[Lacosamide 150 mg film-coated tablets]

Each film-coated tablet contains 150 mg lacosamide.

[Lacosamide 200 mg film-coated tablets]

Each film-coated tablet contains 200 mg lacosamide.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet

[Lacosamide 50 mg film-coated tablets]

Pink coloured, oval and biconvex f/c tablets, with a break-score on both sides and with a

length of about 10.3 mm.

The tablet can be divided into equal doses.

[Lacosamide 100 mg film-coated tablets]

Yellow coloured, oval and biconvex f/c tablets, with a break-score on both sides and with a

length of about 13.1 mm.

The tablet can be divided into equal doses.

[Lacosamide 150 mg film-coated tablets]

Brown coloured, oval and biconvex f/c tablets, with a break-score on both sides and with a

length of about 15.1 mm.

The tablet can be divided into equal doses.

[Lacosamide 200 mg film-coated tablets]

Blue coloured, oval and biconvex f/c tablets, with a break-score on both sides and with a

length of about 16.5 mm.

The tablet can be divided into equal doses.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

[Lacosamide] is indicated as monotherapy and adjunctive therapy in the treatment of partial-

onset seizures with or without secondary generalisation in adults, adolescents and children

from 4 years of age with epilepsy.

4.2

Posology and method of administration

Posology

Lacosamide must be taken twice a day (usually once in the morning and once in the evening).

Lacosamide may be taken with or without food.

If a dose is missed, the patient should be instructed to take the missed dose immediately,

and then to take the next dose of lacosamide at the regularly scheduled time. If the patient

notices the missed dose within 6 hours of the next one, he/she should be instructed to wait to

take the next dose of lacosamide at the regularly scheduled time. Patients should not take a

double dose.

Adolescents and children weighing 50 kg or more, and adults

The following table summarises the recommended posology for adolescents and children

weighing

50 kg or more, and for adults. More details are provided in the table below.

Monotherapy

Adjunctive therapy

100 mg/day or 200 mg/day

100 mg/day

Starting dose

Single loading dose

(if applicable)

200 mg

200 mg

Titration (incremental steps)

50 mg twice a day (100 mg/day)

at weekly intervals

50 mg twice a day (100 mg/day)

at weekly intervals

Maximum recommended dose

up to 600 mg/day

up to 400 mg/day

Monotherapy

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.

Lacosamide can also be initiated at the dose of 100 mg twice a day based on the physician's

assessment of required seizure reduction versus potential side effects.

Depending on response and tolerability, the maintenance dose can be further increased at

weekly intervals by 50 mg twice a day (100 mg/day), up to a maximum recommended daily

dose of 300 mg twice a day (600 mg/day).

In patients having reached a dose greater than 400 mg/day and who need an additional

antiepileptic medicinal product, the posology that is recommended for adjunctive therapy

below should be followed.

Adjunctive therapy

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 at

weekly intervals by 50 mg twice a day (100 mg/day), up to a maximum recommended daily

dose of 400 mg (200 mg twice a day).

Initiation of lacosamide treatment with a loading dose

Lacosamide treatment may also be initiated with a single loading dose of 200 mg, followed

approximately 12 hours later by a 100 mg twice a day (200 mg/day) maintenance dose

regimen.

Subsequent

dose

adjustments

should

performed

according

individual

response and tolerability as described above. A loading dose may be initiated in patients in

situations when the physician determines that rapid attainment of lacosamide steady state

plasma concentration and therapeutic effect is warranted. It should be administered under

medical supervision with consideration of the potential for increased incidence of serious

cardiac

arrhythmia

central

nervous

system

adverse

reactions

(see

section

4.8).

Administration of a loading dose has not been studied in acute conditions such as status

epilepticus.

Discontinuation

In accordance with current clinical practice, if lacosamide has to be discontinued, it is

recommended this be done gradually (e.g. taper the daily dose by 200 mg/week).

In patients who develop serious cardiac arrhythmia, clinical benefit/risk assessment should

be performed and if needed lacosamide should be discontinued.

Special populations

Elderly (over 65 years of age)

No dose reduction is necessary in elderly patients. Age associated decreased renal clearance

with an increase in AUC levels should be considered in elderly patients (see following

paragraph ‘renal impairment’ and section 5.2).

There is limited clinical data in the elderly

patients with epilepsy, particularly at doses greater than 400 mg/day (see sections 4.4, 4.8,

and 5.1).

Renal impairment

No dose adjustment is necessary in mildly and moderately renally impaired adult and

paediatric patients (CL

> 30 ml/min). In paediatric patients weighing 50 kg or more and in

adult patients with mild or moderate renal impairment a loading dose of 200 mg may be

considered, but further dose titration (> 200 mg daily) should be performed with caution. In

paediatric patients weighing 50 kg or more and in adult patients with severe renal impairment

≤ 30 ml/min) or with end-stage renal disease, a maximum dose of 250 mg/day is

recommended and the dose titration should be performed with caution. If a loading dose is

indicated, an initial dose of 100 mg followed by a 50 mg twice daily regimen for the first week

should be used. In paediatric patients weighing less than 50 kg with severe renal impairment

(CLCR ≤ 30 ml/min) and in those with end-stage renal disease, a reduction of 25% of the

maximum dose is recommended. For all 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).

Hepatic impairment

A maximum dose of 300 mg/day is recommended for paediatric patients weighing 50 kg or

more and for adult patients with mild to moderate hepatic impairment.

The dose titration in these patients should be performed with caution considering co-existing

renal impairment. In adolescents and adults weighing 50 kg or more, a loading dose of

200 mg may be considered, but further dose titration (> 200 mg daily) should be performed

with caution. Based on data in adults, in paediatric patients weighing less than 50 kg 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).

Lacosamide

should

administered

adult

paediatric patients with severe hepatic impairment only when the expected therapeutic

benefits are anticipated to outweigh the possible risks. The dose may need to be adjusted

while carefully observing disease activity and potential side effects in the patient.

Paediatric population

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

weight and dose.

Adolescents and children weighing 50 kg or more

Dosage in adolescents and children weighing 50 kg or more is the same as in adults (see

above).

Children (from 4 years of age) and adolescents weighing less than 50 kg

The dose is determined based on body weight. It is therefore recommended to initiate

treatment with the syrup and switch to tablets, if desired.

Monotherapy

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.

dose

should

gradually

increased

until

optimum

response is obtained. In children weighing less than 40 kg, a maximum dose of up to

12 mg/kg/day is recommended. In children weighing from 40 to under 50 kg, a maximum

dose of 10 mg/kg/day is recommended.

The following table summarises the recommended posology in monotherapy for children and

adolescents weighing less than 50 kg.

2 mg/kg/day

Starting dose

Single loading dose

not recommended

Titration (incremental steps)

2 mg/kg/day every week

Maximum recommended dose in patients < 40 kg

up to 12 mg/kg/day

Maximum recommended dose in patients ≥ 40 kg

to < 50 kg

up to 10 mg/kg/day

Adjunctive therapy

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. The dose should be gradually adjusted until the optimum response

is obtained. In children weighing less than 20 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

20 to under 30 kg, a maximum dose of 10 mg/kg/day is recommended and 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 sections 4.8 and 5.2), a dose up to 12 mg/kg/day has

been used by a small number of these children.

The following table summarises the recommended posology in adjunctive therapy for children

and adolescents weighing less than 50 kg.

2 mg/kg/day

Starting dose

Single loading dose

not recommended

Titration (incremental steps)

2 mg/kg/day every week

Maximum recommended dose in patients < 20 kg

up to 12 mg/kg/day

Maximum recommended dose in patients ≥ 20 kg

to < 30 kg

up to 10 mg/kg/day

Maximum recommended dose in patients ≥ 30 kg

to < 50 kg

up to 8 mg/kg/day

Loading dose

Administration of a loading dose has not been studied in children. Use of a loading dose is

not recommended in adolescents and children weighing less than 50 kg.

Children less than 4 years

The safety and efficacy of lacosamide in children aged below 4 years have not yet been

established. No data are available.

Method of administration

Oral use.

Lacosamide may be taken with or without food.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Known second- or third-degree atrioventricular (AV) block.

4.4

Special warnings and precautions for use

Suicidal ideation and behaviour

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic

medicinal products in several indications. A meta-analysis of randomised placebo controlled

trials of anti-epileptic medicinal products has also shown a small increased risk of suicidal

ideation and behaviour. The mechanism of this risk is not known and the available data do not

exclude the possibility of an increased risk for lacosamide. Therefore, patients should be

monitored for signs of suicidal ideation and behaviours and appropriate treatment should be

considered. Patients (and caregivers of patients) should be advised to seek medical advice

should signs of suicidal ideation or behaviour emerge (see section 4.8).

Cardiac rhythm and conduction

Dose-related prolongations in PR interval with lacosamide have been observed in clinical

studies. Lacosamide 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 ischaemia/infarction, heart failure,

structural heart disease or

cardiac sodium channelopathies), or patients treated with medicinal products affecting

cardiac conduction, including antiarrhythmics and sodium channel blocking antiepileptic

medicinal products (see section 4.5), as well as in elderly patients.

In these patients it should

be considered to perform an ECG before a lacosamide dose increase above 400 mg/day and

after lacosamide is titrated to steady-state.

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.

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 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 if these symptoms occur.

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 medicinal product (see section

4.8).

Potential for electro-clinical worsening in specific paediatric epilepsy syndromes

The safety and efficacy of lacosamide in paediatric patients with epilepsy syndromes in which

focal and generalised seizures may coexist have not been determined.

4.5

Interaction with other medicinal products and other forms of interaction

Lacosamide should be used with caution in patients treated with medicinal products known to

be associated with PR prolongation (including sodium channel blocking antiepileptic medicinal

products) and in patients treated with antiarrhythmics. 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 studies

indicate that the enzymes CYP1A2, CYP2B6, and CYP2C9 are not induced and that

CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP2E1 are not

inhibited by lacosamide at plasma concentrations observed in clinical trials. An in vitro study

indicated that lacosamide is not transported by P-glycoprotein in the intestine. In vitro data

show that CYP2C9, CYP2C19 and CYP3A4 are capable of catalysing the formation of the O-

desmethyl metabolite.

In vivo data

Lacosomide does not inhibit or induce CYP2C19 and CYP3A4 to a clinically relevant extent.

Lacosamide did not affect the AUC of midazolam (metabolised by CYP3A4, lacosamide given

200 mg twice a day) but C

of midazolam was slightly increased (30%). Lacosamide did not

affect

pharmacokinetics

omeprazole

(metabolised

CYP2C19

CYP3A4,

lacosamide given 300 mg twice a day).

The CYP2C19 inhibitor omeprazole (40 mg once daily) did not give rise to a clinically

significant change in lacosamide exposure. Thus moderate inhibitors of CYP2C19 are unlikely

to affect systemic lacosamide exposure to a clinically relevant extent.

Caution is recommended in concomitant treatment with strong inhibitors of CYP2C9 (e.g.

fluconazole) and CYP3A4 (e.g. itraconazole, ketoconazole, ritonavir, clarithromycin), which

may lead to increased systemic exposure of lacosamide. Such interactions have not been

established in vivo but are possible based on in vitro data.

Strong enzyme inducers such as rifampicin or St. John’s wort (Hypericum perforatum) may

moderately reduce the systemic exposure of lacosamide. Therefore, starting or ending

treatment with these

enzyme inducers should be done with caution.

Antiepileptic medicinal products

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. Population pharmacokinetic analyses in different age

groups estimated that concomitant treatment with other anti-epileptic medicinal products

known to be enzyme inducers (carbamazepine, phenytoin, phenobarbital, in various doses)

decreased the overall systemic exposure of lacosamide by 25% in adults and 17% in

paediatric patients.

Oral contraceptives

In an interaction trial there was no clinically relevant 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.

Co-administration of warfarin with lacosamide does not result in a clinically relevant change in

the pharmacokinetics and pharmacodynamics of warfarin.

Although no pharmacokinetic data on the interaction of lacosamide with alcohol are available,

a pharmacodynamic effect cannot be excluded.

Lacosamide has a low protein binding of less than 15%. Therefore, clinically relevant

interactions with other medicinal products through competition for protein binding sites are

considered unlikely.

4.6

Fertility, pregnancy and lactation

Pregnancy

Risk related to epilepsy and antiepileptic medicinal products in general

For all anti-epileptic medicinal products, it has been shown that in the offspring of women

treated with epilepsy, the prevalence of malformations is two to three times greater than the

rate of approximately 3% in the general population. In the treated population, an increase in

malformations has been noted with polytherapy, however, the extent to which the treatment

and/or the illness is responsible has not been elucidated.

Moreover, effective anti-epileptic therapy must not be interrupted, since the aggravation of the

illness is detrimental to both the mother and the foetus.

Risk related to lacosamide

There are no adequate data from the use of lacosamide in pregnant women. Studies in

animals did not indicate any teratogenic effects in rats or rabbits, but embryotoxicity was

observed in rats and rabbits at maternal toxic doses (see section 5.3). The potential risk for

humans is unknown.

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.

Breast-feeding

unknown

whether

lacosamide

excreted

human

breast

milk.

risk

newborns/infants cannot be excluded. Animal studies have shown excretion of lacosamide in

breast milk. For precautionary measures, breast-feeding should be discontinued during

treatment with lacosamide.

Fertility

No adverse reactions on male or female fertility or reproduction were observed in rats at

doses producing plasma exposures (AUC) up to approximately 2 times the plasma AUC in

humans at the maximum recommended human dose (MRHD).

4.7

Effects on ability to drive and use machines

Lacosamide has 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 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

Undesirable effects

Summary of the safety profile

Based on the analysis of pooled placebo-controlled clinical trials in adjunctive therapy in 1,308

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 (≥ 10%) 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

central

nervous

system

(CNS)

gastrointestinal

(GI)

adverse

reactions

usually

decreased over time.

In all of these 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.

Incidence of CNS adverse reactions such as dizziness may be higher after a loading dose.

Based on the analysis of data from a non-inferiority monotherapy clinical trial comparing

lacosamide to carbamazepine controlled release (CR), the most frequently reported adverse

reactions (≥ 10%) for lacosamide were headache and dizziness. The discontinuation rate due

to adverse reactions was 10.6% for patients treated with lacosamide and 15.6% for patients

treated with carbamazepine CR.

Tabulated list of adverse reactions

The table below shows the frequencies of adverse reactions which have been reported in

clinical trials and post-marketing experience. The frequencies are defined as follows: very

common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and not known

(frequency cannot be

estimated from available data). Within each frequency grouping,

undesirable effects are presented in order of decreasing seriousness.

System organ

class

Very common

Common

Uncommon

Not known

Blood and

lymphatic system

disorders

Agranulocytosis

Immune system

disorders

Drug

hypersensitivity

Drug reaction with

eosinophilia and

systemic

symptoms

(DRESS)

(1, 2)

Psychiatric

disorders

Depression

Confusional state

Insomnia

Aggression

Agitation

Euphoric mood

Psychotic

disorder

Suicide attempt

Suicidal ideation

Hallucination

Nervous system

disorders

Dizziness

Headache

Balance disorder

Memory

impairment

Cognitive disorder

Somnolence

Tremor

Nystagmus

Hypoesthesia

Dysarthria

Disturbance in

attention

Paraesthesia

Syncope

Coordination

abnormal

Convulsion

Eye disorders

Diplopia

Vision blurred

Ear and labyrinth

disorders

Vertigo

Tinnitus

System organ

class

Very common

Common

Uncommon

Not known

Cardiac disorders

Atrioventricular

block

(1, 2)

Bradycardia

(1, 2)

Atrial fibrillation

(1, 2)

Atrial flutter

(1, 2)

Ventricular

tachyarrhythmia

Gastrointestinal

disorders

Nausea

Vomiting

Constipation

Flatulence

Dyspepsia

Dry mouth

Diarrhoea

Hepatobiliary

disorders

Liver function test

abnormal

Hepatic enzyme

increased

(> 2 x ULN)

Skin and

subcutaneous

tissue disorders

Pruritus

Rash

Angioedema

Urticaria

Stevens-Johnson

syndrome

Toxic epidermal

necrolysis

Musculoskeletal

and connective

tissue disorders

Muscle spasms

General disorders

and administration

site conditions

Gait disturbance

Asthenia

Fatigue

Irritability

Feeling drunk

Injury, poisoning

and procedural

complications

Fall

Skin laceration

Contusion

Adverse reactions reported in post marketing experience

See Description of selected adverse reactions

Reported in open-label studies

Description of selected adverse reactions

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 adjunctive 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 these studies. However, cases with second and third degree AV Block associated

with

lacosamide

treatment

have

been

reported

post-

marketing

experience.

monotherapy clinical trial comparing lacosamide to carbamazepine CR the extent of increase

in PR interval was comparable between lacosamide and carbamazepine.

The incidence rate for syncope reported in pooled adjunctive therapy clinical trials is

uncommon and did not differ between lacosamide (n = 944) treated epilepsy patients (0.1%)

and placebo (n = 364) treated epilepsy patients (0.3%).

In the monotherapy clinical trial

comparing

lacosamide

carbamazepine

syncope

reported

7/444

(1.6%)

lacosamide patients and in 1/442 (0.2%) carbamazepine CR patients.

Atrial fibrillation or flutter were not reported in short term clinical trials; however both have

been reported in open-label epilepsy trials and in post-marketing experience.

Laboratory abnormalities

Abnormalities in liver function tests have been observed in placebo-controlled trials with

lacosamide in adult patients with partial-onset seizures who were taking 1 to 3 concomitant

anti-epileptic medicinal products. Elevations of ALT to ≥ 3 x ULN occurred in 0.7% (7/935) of

lacosamide-treated patients and 0% (0/356) of placebo patients.

Multi-organ hypersensitivity reactions

Multi-organ hypersensitivity reactions (also known as Drug Reaction with Eosinophilia and

Systemic Symptoms, DRESS) have been reported in patients treated with some antiepileptic

medicinal products. These reactions are variable in expression but typically present with fever

and rash and can be associated with involvement of different organ systems. If multi-organ

hypersensitivity reaction is suspected, lacosamide should be discontinued.

Paediatric population

The safety profile of lacosamide in placebo-controlled (see study details in section 5.1) and in

open-label studies (n = 408) in adjunctive therapy in children from 4 years of age was

consistent with the safety profile observed in adults although the frequency of some adverse

reactions (somnolence, vomiting and convulsion) was increased and additional adverse

reactions (nasopharyngitis, pyrexia, pharyngitis, decreased appetite, lethargy and abnormal

behaviour) have been reported in paediatric patients: nasopharyngitis (15.7%), vomiting

(14.7%),

somnolence

(14.0%),

dizziness

(13.5%),

pyrexia

(13.0%),

convulsion

(7.8%),

decreased appetite (5.9%), pharyngitis (4.7%), lethargy (2.7%) and abnormal behaviour

(1.7%).

A total of 67.8% of patients randomised to lacosamide and 58.1% of patients randomised to

placebo reported at least 1 adverse reaction.

Behavioural, cognition and emotional functioning were measured by the questionnaires

Achenbach CBCL and BRIEF that were applied at baseline and throughout the studies and

where mainly stable during the course of the trials.

Elderly population

In the monotherapy study comparing lacosamide to carbamazepine CR, the types of adverse

reactions related to lacosamide in elderly patients (≥ 65 years of age) appear 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. The most frequent cardiac-related adverse reaction reported in elderly

compared to the younger adult population was first degree AV block. This was reported with

lacosamide in 4.8% (3/62) in elderly patients versus 1.6% (6/382) in younger adult patients.

The discontinuation rate due to adverse events observed with lacosamide was 21.0% (13/62)

in elderly patients versus 9.2% (35/382) in younger adult patients. These differences between

elderly and younger adult patients were similar to those observed in the active comparator

group.

Reporting of suspected adverse reactions

Reporting

suspected

adverse

reactions

after

authorisation

medicinal

product

important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the

national reporting system.

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 reactions experienced by patients exposed to doses above 400 mg

were

clinically

different

from

those

patients

administered

recommended doses of lacosamide.

Reactions reported after an intake of more than 800 mg are dizziness, nausea, vomiting,

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

There

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).

5.

PHARMACOLOGICAL

PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX18

Mechanism of action

The active substance, lacosamide

R-2-acetamido-N-benzyl-3-methoxypropionamide)

is a

functionalised amino acid.

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 stabilisation of hyper-excitable

neuronal

membranes.

Pharmacodynamic effects

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 efficacy and safety

Adult population

Monotherapy

Efficacy of lacosamide as monotherapy was established in a double-blind, parallel group,

non-inferiority comparison to carbamazepine CR in 886 patients 16 years of age or older

with newly or recently diagnosed epilepsy. The patients had to present with unprovoked

partial

onset

seizures

with

without

secondary

generalisation.

patients

were

randomised to carbamazepine CR or lacosamide, provided as tablets, in a 1:1 ratio. The

dose

based

dose-response

ranged

from

1.200

mg/day

carbamazepine CR and from 200 to 600 mg/day for lacosamide. The duration of the

treatment was up to 121 weeks depending on the response.

The estimated 6-month seizure freedom rates were 89.8% for lacosamide-treated patients

and 91.1% for carbamazepine CR treated patients using the Kaplan-Meier survival analysis

method. The adjusted absolute difference between treatments was -1.3% (95% CI: -5.5,

2.8). The Kaplan-Meier estimates of 12-month seizure freedom rates were 77.8% for

lacosamide-treated patients and 82.7% for carbamazepine CR treated patients.

The 6-month seizure freedom rates in elderly patients of 65 and above (62 patients in

lacosamide, 57 patients in carbamazepine CR) were similar between both treatment groups.

The rates were also similar to those observed in the overall population. In the elderly

population, the maintenance lacosamide dose was 200 mg/day in 55 patients (88.7%),

400 mg/day in 6 patients (9.7%) and the dose was escalated to over 400 mg/day in 1 patient

(1.6%).

Conversion to monotherapy

The efficacy and safety of lacosamide in conversion to monotherapy has been assessed in a

historical- controlled, multi-centre, double-blind, randomised trial. In this study, 425 patients

aged 16 to 70 years with uncontrolled partial-onset seizures taking stable doses of 1 or 2

marketed antiepileptic medicinal products were randomised to be converted to lacosamide

monotherapy (either 400 mg/day or 300 mg/day in a 3:1 ratio). In treated patients who

completed titration and started withdrawing antiepileptic medicinal products (284 and 99

respectively), monotherapy was maintained in 71.5% and 70.7% of patients respectively for

57-105 days (median 71 days), over the targeted observation period of 70 days.

Adjunctive therapy

The efficacy of lacosamide as adjunctive therapy at recommended doses (200 mg/day,

400 mg/day) was established in 3 multicenter, randomised, placebo-controlled clinical trials

with a 12-week maintenance period. Lacosamide 600 mg/day was also shown to be

effective

controlled

adjunctive

therapy

trials,

although

efficacy

similar

400 mg/day and patients were less likely to tolerate this dose because of CNS- and

gastrointestinal-related adverse reactions. Thus, the 600 mg/day dose is not recommended.

The maximum recommended dose is 400 mg/day. These trials, involving 1,308 patients with

a history of an average of 23 years of partial-onset seizures, were designed to evaluate the

efficacy and safety of lacosamide when administered concomitantly with 1-3 antiepileptic

medicinal

products

patients

with

uncontrolled

partial-onset

seizures

with

without

secondary generalisation. Overall the proportion of subjects with a 50% reduction in seizure

frequency was 23%, 34%, and 40% for placebo, lacosamide 200 mg/day and lacosamide

400 mg/day.

The pharmacokinetics and safety of a single loading dose of intravenous lacosamide were

determined in a multicenter, open-label study designed to assess the safety and tolerability of

rapid initiation of lacosamide using a single intravenous loading dose (including 200 mg)

followed by twice daily oral dosing (equivalent to the intravenous dose) as adjunctive therapy

in adult subjects 16 to 60 years of age with partial-onset seizures.

Paediatric population

Partial-onset seizures have a similar clinical expression in children from 4 years of age and in

adults. The efficacy of lacosamide in children aged 4 years and older has been extrapolated

from data of adolescents and adults with partial-onset seizures, for whom a similar response

was expected provided the paediatric dose adaptations are established (see section 4.2) and

safety has been demonstrated (see section 4.8).

The efficacy supported by the extrapolation principle stated above was confirmed by a

double-blind,

randomised,

placebo-controlled

study.

study

consisted

8-week

baseline period followed by a 6-week titration period. Eligible patients on a stable dose

regimen of 1 to ≤ 3 antiepileptic medicinal products, 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 1or 2 mg/kg/day increments in subjects weighing less

than 50 kg or 50 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 Pediatric Quality of Life Inventory indicated that subjects in

both lacosamide and placebo groups had a similar and stable health-related quality of life

during the entire treatment period.

5.2

Pharmacokinetic properties

Absorption

Lacosamide

rapidly

completely

absorbed

after

oral

administration.

oral

bioavailability of lacosamide tablets is approximately 100%. Following oral administration, the

plasma concentration of unchanged lacosamide increases rapidly and reaches C

about 0.5

to 4 hours post-dose. [Lacosamide] tablets and oral syrup are bioequivalent. Food does not

affect the rate and extent of absorption.

Distribution

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

plasma proteins.

Biotransformation

95% of the dose is excreted in the urine as lacosamide 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.

In vitro data show that CYP2C9, CYP2C19 and CYP3A4 are capable of catalysing the

formation of the O-desmethyl metabolite but the main contributing isoenzyme has not been

confirmed in vivo.

clinically

relevant

difference

lacosamide

exposure

observed

comparing

pharmacokinetics in extensive metabolisers (EMs, with a functional CYP2C19) and poor

metabolisers (PMs, lacking a functional CYP2C19). Furthermore an interaction trial with

omeprazole (CYP2C19-inhibitor) demonstrated no clinically relevant changes in lacosamide

plasma concentrations indicating that the importance of this pathway is minor. 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.

Elimination

Lacosamide is primarily eliminated from the systemic circulation by renal excretion and

biotransformation. After oral and intravenous 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 lacosamide 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

period.

plasma

concentration

increases

with

accumulation

factor

approximately 2.

A single loading dose of 200 mg approximates steady-state concentrations comparable to

100 mg twice daily oral administration.

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 C

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). 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

showed

higher

plasma

concentrations of lacosamide (approximately 50% higher AUC

norm

). The higher exposure was

partly due to a reduced renal function in the studied subjects. The decrease in non-renal

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).

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

body weight. The body weight 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).

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 aged

6 months to 17 years. The administered lacosamide doses ranged from 2 to 17.8 mg/kg/day

in twice daily intake, with a maximum of 600 mg/day for children weighing 50 kg or more.

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

In the toxicity studies, the plasma concentrations of lacosamide obtained were similar or only

marginally higher than those observed in patients, which leaves low or non-existing margins to

human exposure.

A safety pharmacology study with intravenous 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 cardio-depressant action. These transient changes started

same

concentration

range

after

maximum recommended clinical

dosing.

anesthetised dogs and Cynomolgus monkeys, at intravenous doses of 15-60 mg/kg, slowing

of atrial and ventricular conductivity, atrioventricular block and atrioventricular dissociation

were seen.

In the repeated dose toxicity studies, mild reversible liver changes were observed in rats

starting at about 3 times the clinical exposure. These changes included an increased organ

weight, hypertrophy of hepatocytes, increases in serum concentrations of liver enzymes and

increases in total cholesterol and triglycerides. Apart from the hypertrophy of hepatocytes, no

other histopathologic changes were observed.

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 similar to the expected clinical

exposure. Since higher exposure levels could not be tested in animals due to maternal

toxicity, data are insufficient to fully characterise the embryo-foetotoxic and teratogenic

potential of lacosamide.

Studies in rats revealed that lacosamide and/or its metabolites readily crossed the placental

barrier.

In juvenile rats and dogs, the types of toxicity do not differ qualitatively from those observed

in adult animals. In juvenile rats, a reduced body weight was observed at systemic exposure

levels similar to the expected clinical exposure. In juvenile dogs, transient and dose-related

CNS clinical signs started to be observed at systemic exposure levels below the expected

clinical exposure.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core

Microcrystalline cellulose

Hydroxypropylcellulose - low substituted

Hydroxypropylcellulose

Crospovidone

Colloidal anhydrous silica

Magnesium stearate

Tablet coat

Poly(vinyl alcohol)

Macrogol

Titanium dioxide (E 171)

Talc

50 mg tablets:

red iron oxide (E 172), black iron oxide (E 172), indigo carmine aluminium

lake (E 132)

100 mg tablets:

yellow iron oxide (E 172)

150 mg tablets:

yellow iron oxide (E 172), red iron oxide (E 172), black iron oxide (E 172)

200 mg tablets:

indigo carmine aluminium lake (E 132)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

50 mg, 100 mg, 150 mg, 200 mg:

10, 14, 20, 28, 30, 40, 56, 60, 84, 90, 100, 112, and 120 film-coated tablets in PVC/Al blister

or PVC/PVdC/Al blister.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

G.L. Pharma GmbH, 8502 Lannach

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

2021-01-28

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