VIMPAT 100 MG

Patient leaflet in accordance with the Pharmacists’ regulations (preparations) - 1986

The medicine is to be supplied upon a physician’s prescription only

Vimpat

®

50 mg

film-coated tablets

Vimpat

®

100 mg

film-coated tablets

Vimpat

®

150 mg

film-coated tablets

Vimpat

®

200 mg

film-coated tablets

Each film-coated Vimpat tablet contains Lacosamide 50 mg, 100 mg, 150 mg or 200 mg.

For information regarding the excipients see section 6 - "

Additional information".

Read the entire leaflet carefully before using this medicine. This leaflet contains concise

information about the medicine. If you have any further questions, refer to the physician or the

pharmacist.

This medicine has been prescribed for the treatment of your illness. Do not pass it on to others.

It may harm them even if it seems to you that their illness is similar.

Epilepsy is an illness characterized by repeated fits (seizures).

Vimpat is administered when the state of epilepsy in which the fits are initially partial (affecting

only one side of the brain), but may develop into generalised fits (affecting larger areas on both

sides of the brain). Treatment with Vimpat is long-term. Do not stop treatment without an explicit

instruction from the physician. Discontinuation of treatment may cause a recurrence or

worsening of the illness’ symptoms. See section "If you stop taking the medicine".

1.

WHAT IS THE MEDICINE INTENDED FOR?

Vimpat is used in adults, adolescents and children aged 4 years and older.

Vimpat is indicated for the treatment of a certain type of epilepsy characterised by the

occurrence of "partial-onset seizure with or without secondary generalisation".

Vimpat may be used on its own or with other antiepileptic medicines.

Vimpat contains lacosamide. This belongs to a group of medicines called "antiepileptic

medicines". These medicines are used to treat epilepsy.

Therapeutic group: Anticonvulsant.

2.

BEFORE USING THE MEDICINE

X

Do not use the medicine if:

- You are hypersensitive (allergic) to the active ingredient, or to any of the other ingredients of

the medicine (see section 6 - "

Additional Information").

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

Do not take Vimpat if any of the above applies to you. If you are not sure, talk to your physician

or pharmacist before taking this medicine.

Special warnings regarding the use of the medicine:

Do not use the medicine without consulting a physician before starting treatment

- 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 physician straight

away.

- If 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).

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

- If you are often dizzy or fall over. Vimpat may make you dizzy - this could increase the risk of

accidental injury or a fall. This means that you should take care until you get used to the effects

of this medicine.

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

taking Vimpat.

Children under 4 years

Vimpat is not recommended for children aged under 4 years. This is because it is yet unknown

whether Vimpat will work and whether Vimpat is safe for children in this age group.

! Interaction with other medicinal products

If you are taking or have recently taken other medicines including non-prescription

medicines and nutritional supplements, tell the physician or pharmacist.

It is especially important to inform the physician or pharmacist if you are taking any of the

following medicines that affect your heart - this is because Vimpat 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.

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

taking Vimpat.

It is also especially important to inform the physician or pharmacist if you are taking any of the

following medicines - this is because they may increase or decrease the effect of Vimpat 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 physician or pharmacist before

taking Vimpat.

! Use of the medicine and food

The medicine may be taken with or without a meal.

! Use of the medicine and alcohol consumption

As a safety precaution do not take Vimpat with alcohol.

! Pregnancy and breast-feeding

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

ask your physician or pharmacist for advice before taking this medicine.

It is not recommended to take Vimpat if you are pregnant or breast-feeding, as the effects of

Vimpat on pregnancy and the unborn baby or the new-born child are not known. Also, it is not

known whether Vimpat passes into breast milk. Seek advice immediately from your physician

if you get pregnant or are planning to become pregnant. The physician will help you decide if

you should take Vimpat or not.

Do not stop treatment without talking to your physician 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 Vimpat may make you feel dizzy or cause blurred vision.

3. HOW SHOULD YOU USE THE MEDICINE?

Always use according to the physician’s instructions. Check with the physician or pharmacist if

you are unsure.

Dosage

The dosage and treatment regimen will be determined by the physician only.

Take Vimpat 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 Vimpat tablet with a glass of water.

You will usually start by taking a low dose each day and your physician 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. Vimpat is used as a long term

treatment. You should continue to take Vimpat until your physician tells you to stop.

How much to take

Listed below are the normal recommended doses of Vimpat for different age groups and

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

or with your liver.

Adolescents and children weighing 50 kg or more and adults

When you take Vimpat on its own:

The usual starting dose of Vimpat is 50 mg twice a day.

Your physician may also prescribe a starting dose of 100 mg of Vimpat twice a day.

Your physician 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 Vimpat with other antiepileptic medicines:

The usual starting dose of Vimpat is 50 mg twice a day.

Your physician 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 physician may decide to start Vimpat treatment with a single

"loading" dose of 200 mg. You would then start your ongoing maintenance dose 12 hours later.

Children and adolescent weighing less than 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 physician will prescribe the formulation that is best suited to them.

Do not exceed the recommended dose

Instructions for use

Crushing/splitting/chewing

If necessary, the tablet may be crushed and immediately swallowed with water. The crushed

tablet may have a bitter taste. Do not halve the tablets.

Duration of treatment

Vimpat is intended for long-term treatment.

You should complete the treatment recommended by the physician. Do not stop the treatment

without a physician’s instruction.

If you accidentally take a higher dosage

If you took an overdose or if a child accidentally swallowed this medicine, proceed to a physician

or a hospital emergency room immediately and bring the package of the medicine with you. Do

not try to drive.

You may experience:

Dizziness;

Feeling sick (nausea) or being sick (vomiting);

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

fall in blood pressure with rapid heartbeat and sweating.

If you forgot to take the medicine

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 dose anymore. Instead take Vimpat at the next time that you would normally take

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

If you stop taking the medicine

Do not stop taking Vimpat without talking to your physician as your epilepsy may come

back again or become worse.

If your physician decides to stop your treatment with Vimpat, he will tell you how to decrease

the dose step by step.

You should continue the treatment as recommended by the physician.

Even if there is an improvement in your health, do not stop treatment with the medicine without

consulting the physician.

Do not take medicines in the dark! Check the label and the dose each time

you take the

medicine. Wear glasses if you need them.

If you have any further questions regarding the use of this medicine, consult the

physician or pharmacist.

4.

SIDE EFFECTS

As with any medicine, using Vimpat may cause side effects in some users. Do not be alarmed

when reading the list of side effects. You may not experience any of them.

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

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

Very common side effects (may affect more than 1 in 10 patients):

Headache;

Feeling dizzy or sick (nausea);

Double vision (diplopia).

Common side effects (may affect up to 1 in 10 patients):

Problems in keeping your balance, difficulties in coordinating your movements or walking,

shaking (tremor), tingling (paresthesia) or muscle spasm, falling easily and getting bruises;

Troubles 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, diarrhea;

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 side effects (may affect up to 1 in 100 patients):

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 physician straight

away;

Feeling angry or agitated;

Abnormal thinking or losing touch with reality;

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

lower legs;

Fainting.

Not known side effects (which frequency cannot be determined 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);

A serious skin reaction which may include a high temperature and 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 cells (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.

Additional side effects in children

Common side effects (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 (lethargy).

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

Changes in behaviour, not acting like themselves

If a side effect appears, if one of the side effects worsens or if you suffer from a side

effect not mentioned in the leaflet, consult a physician.

Reporting side effects

Side effects can be reported to the Ministry of Health by clicking on the link "Report Side Effects

of Drug Treatment"

that appears on the homepage of the Ministry of Health’s website

(www.health.gov.il

) which links to an online form for reporting side effects, or by the following

link: https://sideeffects.health.gov.il

In addition, you can report to the Registration Holder’s Patient Safety Unit by mail:

drugsafety@neopharmgroup.com

5. HOW TO STORE THE MEDICINE?

Avoid poisoning! This medicine and any other medicine must be kept in a closed place out

of the reach and sight of children and/or infants to avoid poisoning. Do not induce vomiting

without an explicit instruction from the physician.

Do not use the medicine after the expiry date (exp. date) appearing on the package and

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

Storage conditions:

Store below 30°C.

Store in the original package.

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. ADDITIONAL INFORMATION

In addition to the active ingredient, the medicine also contains:

Silicified microcrystalline cellulose, Cellulose microcrystalline, Hydroxypropylcellulose

substituted, Crospovidone, Magnesium stearate, Hydroxypropylcellulose.

In addition, the film-coat contains:

Vimpat 50 mg:

Opadry 85F20249: Polyvinyl alcohol, Polyethylene glycol, Talc, Titanium dioxide, Red iron

oxide, Black iron oxide, Indigo carmine aluminium lake.

Vimpat 100 mg:

Opadry 85F38040: Polyvinyl alcohol, Polyethylene glycol, Talc, Titanium dioxide, Yellow

iron oxide.

Vimpat 150 mg:

Opadry 85F27043: Polyvinyl alcohol, Polyethylene glycol, Talc, Titanium dioxide, Yellow

iron oxide, Red iron oxide, Black iron oxide.

Vimpat 200 mg:

Opadry 85F30675: Polyvinyl alcohol, Polyethylene glycol, Talc, Titanium dioxide, Indigo

carmine aluminium lake.

What does the medicine looks like and what are the contents of the package:

Vimpat 50 mg tablets are pinkish, oval film-coated tablets

of approximately 10.4 mm x

4.9 mm with a debossed ‘SP’ on one side and ‘50’ on the other side.

Vimpat 100 mg tablets are dark yellow, oval film-coated tablets of approximately 13.2 mm

x 6.1 mm with a debossed ‘SP’ on one side and ‘100’ on the other side.

Vimpat 150 mg tablets are salmon-colored, oval film-coated tablets

of approximately

15.1 mm x 7.0 mm with a debossed ‘SP’ on one side and ‘150’ on the other side.

Vimpat 200 mg tablets are blue, oval film-coated tablets

of approximately 16.6 mm x

7.8 mm with a debossed ‘SP’ on one side and ‘200’ on the other side.

Vimpat is available in packs of 14, 56 film-coated tablets and in multipacks comprising 3

cartons, each containing 56 tablets. The packs are available with PVC/PVDC blisters

sealed with an aluminium foil. Not all pack sizes may be marketed.

Manufacturer’s name and address:

UCB Pharma S.A., Bruxelles, Belgium.

Registration holder’s name and address:

Neopharm LTD., Hashiloach 6, P.O.Box 7063, Petach Tikva 4917001.

The content of this leaflet was approved by the Ministry of Health in 10/2018 and updated

according to the guidelines of the Ministry of Health in 08/2019.

Registration numbers of the medicines in the National Drug Registry of the Ministry

of Health:

Vimpat

®

50 mg film-coated tablets: 149-09-33546

Vimpat

®

100 mg film-coated tablets: 149-10-33548

Vimpat

®

150 mg film-coated tablets: 149-11-33551

Vimpat

®

200 mg film-coated tablets: 149-12-33549

Summary of product characteristics

1.

NAME OF THE MEDICINAL PRODUCT

Vimpat 50

mg

Vimpat 100

mg

Vimpat 150

mg

Vimpat 200

mg

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Vimpat 50 mg:

Each film-coated tablet contains 50 mg lacosamide.

Vimpat 100 mg:

Each film-coated tablet contains 100 mg lacosamide.

Vimpat 150 mg:

Each film-coated tablet contains 150 mg lacosamide.

Vimpat 200 mg:

Each film-coated tablet contains 200 mg lacosamide.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet

Vimpat 50 mg film-coated tablets

Pinkish, oval film-coated tablets with approximate dimensions of 10.4 mm x 4.9 mm, and debossed with

‘SP’ on one side and ‘50’ on the other side.

Vimpat 100 mg film-coated tablets

Dark yellow, oval film-coated tablets with approximate dimensions of 13.2 mm x 6.1 mm, and debossed

with ‘SP’ on one side and ‘100’ on the other side.

Vimpat 150 mg film-coated tablets

Salmon, oval film-coated tablets with approximate dimensions of 15.1 mm x 7.0 mm, and debossed with

‘SP’ on one side and ‘150’ on the other side.

Vimpat 200 mg film-coated tablets

Blue, oval film-coated tablets with approximate dimensions of 16.6 mm x 7.8 mm, and debossed with

‘SP’ on one side and ‘200’ on the other side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Vimpat 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

Starting dose

100 mg/day or 200 mg/day

100 mg/day

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

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

also

initiated

with

single

loading

dose

followed

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

Subsequent dose adjustments should be performed according to 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 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).

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

> 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 (CL

≤ 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 (CL

≤ 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

severely

hepatic

impaired

patients

(see

section

5.2).

Lacosamide

should

administered to adult and 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. The dose should be gradually increased until the 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.

following

table

summarises

recommended

posology

monotherapy

children

adolescents weighing less than 50 kg.

Starting dose

2 mg/kg/day

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

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

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.

Starting dose

2 mg/kg/day

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

Lacosamide film-coated tablets are for 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 antiepileptic medicinal

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

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 known conduction problems, severe cardiac

disease (e.g. history of myocardial infarction or heart failure), in elderly patients, or when lacosamide is

used in combination with products known to be associated with PR prolongation.

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.

Second-degree or higher AV block has been reported in post-marketing experience. 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).

Patients should be made aware of the symptoms of second-degree or higher AV block (e.g. slow or

irregular pulse, feeling of lightheaded and fainting) and of the symptoms of atrial fibrillation and flutter

(e.g. palpitations, rapid or irregular pulse, shortness of breath). Patients should be counselled to seek

medical advice should any of 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 medicine (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 (e.g. carbamazepine, lamotrigine, eslicarbazepine, pregabalin) and in

patients treated with class I antiarrhythmics. However, subgroup analysis did not identify an increased

magnitude of PR prolongation in patients with concomitant administration of carbamazepine or

lamotrigine in clinical trials.

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

Lacosamide 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 the

pharmacokinetics of omeprazole (metabolised by CYP2C19 and 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 antiepileptic 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 antiepileptic medicinal products, it has been shown that in the offspring of treated women with

epilepsy, the prevalence of malformations is two to three times greater than the rate of approximately

3 % in the general population. In the treated population, an increase in malformations has been noted

with polytherapy, however, the extent to which the treatment and/or the illness is responsible has not

been elucidated.

Moreover, effective antiepileptic 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.

Breastfeeding

It is unknown whether lacosamide is excreted in human breast milk. A risk to the newborns/infants

cannot

excluded.

Animal

studies

have

shown

excretion

lacosamide

breast

milk.

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 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 of central nervous system (CNS) and 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.

Not known

Uncommon

Common

Very

common

System organ class

Agranulocytosis

Blood and

lymphatic

disorders

Drug reaction with

eosinophilia and

systemic symptoms

(DRESS)

(1,2)

Drug

hypersensitivity

Immune system

disorders

Aggression

Agitation

Euphoric mood

Psychotic disorder

Suicide attempt

Suicidal ideation

Hallucination

Depression

Confusional state

Insomnia

Psychiatric

disorders

Convulsion

Syncope

Balance disorder

Coordination

abnormal

Memory

impairment

Cognitive disorder

Somnolence

Tremor

Nystagmus

Hypoesthesia

Dysarthria

Disturbance in

attention

Paraesthesia

Dizziness

Headache

Nervous system

disorders

Vision blurred

Diplopia

Eye disorders

Vertigo

Tinnitus

Ear and labyrinth

disorders

Atrioventricular

block

(1,2)

Bradycardia

(1,2)

Atrial Fibrillation

(1,2)

Atrial Flutter

(1,2)

Cardiac disorders

Vomiting

Constipation

Flatulence

Dyspepsia

Dry mouth

Diarrhoea

Nausea

Gastrointestinal

disorders

Liver function test

abnormal

Hepatic enzyme

increased

(> 2x ULN)

Hepatobiliary

disorders

Stevens-Johnson

syndrome

Toxic epidermal

necrolysis

Angioedema

Urticaria

Pruritus

Rash

Skin and

subcutaneous

tissue disorders

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 %

lacosamide

200 mg,

400 mg,

600 mg

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 in

post-marketing experience. In the 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 to carbamazepine CR,

syncope was reported in 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 controlled trials with lacosamide in adult

patients with partial-onset seizures who were taking 1 to 3 concomitant antiepileptic medicinal products.

Elevations of ALT to ≥ 3x ULN occurred in 0.7 % (7/935) of Vimpat patients and 0 % (0/356) of

placebo patients.

Multiorgan hypersensitivity reactions

Multiorgan 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 multiorgan hypersensitivity reaction is suspected,

lacosamide should be discontinued.

Paediatric population

Muscle spasms

Musculoskeletal

and connective

tissue disorders

Gait disturbance

Asthenia

Fatigue

Irritability

Feeling drunk

General disorders

and administration

site conditions

Fall

Skin laceration

Contusion

Injury, poisoning

and procedural

complications

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 of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

: https://sideeffects.health.gov.il

and emailed to the Registration

Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com

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 up to

800 mg were not clinically different from those of 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 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).

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

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

Mechanism of action

active

substance,

lacosamide

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

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 stabilization of hyperexcitable 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 or without

secondary generalisation. The patients were randomised to carbamazepine CR or lacosamide,

provided

as tablets, in a 1:1 ratio. The dose was based on dose-response and ranged from 400 to 1,200

mg/day

for 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 %

lacosamide-treated

patients

82.7 %

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, multicentre, 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

converted

lacosamide

monotherapy

(either

400 mg/day

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 in controlled adjunctive therapy trials,

although the efficacy was similar to 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 in

patients with uncontrolled partial-onset seizures with or 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. 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 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 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 C

about 0.5 to 4 hours post-dose. Vimpat 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

. 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).

Furthermore

interaction

trial

with

omeprazole

(CYP2C19-inhibitor)

demonstrated no clinically relevant changes in lacosamide plasma concentrations indicating that the

importance

this

pathway

minor.

plasma

concentration

O-desmethyl-lacosamide

approximately 15 % of the concentration of lacosamide in plasma. This major metabolite has no known

pharmacological activity.

Elimination

Lacosamide

primarily

eliminated

from

systemic

circulation

renal

excretion

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

lacosamide

approximately

13 hours.

pharmacokinetics

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.

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 B) 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 normalized 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 cardiodepressant action. These transient changes started in the same concentration

range as after maximum recommended clinical dosing. In 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 embryofetotoxic

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

Tablets:

Tablet core

Microcrystalline cellulose

Hydroxypropylcellulose

Hydroxypropylcellulose (low substituted)

Silicified microcrystalline cellulose

Crospovidone

Magnesium stearate

Tablet coat:

Polyvinyl alcohol

Polyethylene glycol 3350

Talc

Titanium dioxide

50 mg tablet: Red iron oxide, Black iron oxide, Indigo carmine aluminium lake

mg tablet: Yellow iron oxide

mg tablet: Yellow iron oxide, Red iron oxide, Black iron oxide

mg tablet: Indigo carmine aluminium lake

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials

6.4

Special precautions for storage

Store below 30°C.

6.5

Nature and contents of container

Packs of 14, 56 or 168 film-coated tablets in PVC/PVDC blister sealed with an aluminium foil.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements for disposal.

7.

MANUFACTURER

UCB Pharma S.A.

Allée de la Recherche 60

B-1070 Bruxelles

Belgium

8.

REGISTRATION HOLDER

Neopharm Ltd.,

6 Hashiloach St.,

P.O.B. 7063,

Petach-Tikva 4917001.

Drug Regitration No.:

Vimpat Tablets:

VIMPAT 50 MG 149-09-33546

VIMPAT 100 MG 149-10-33548

VIMPAT 150 MG 149-11-33551

VIMPAT 200 MG 149-12-33549

The content of this leaflet was approved by the Ministry of Health in 10/2018 and updated according

to the guidelines of the Ministry of Health in 08/2019.