Vimpat - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Lacosamide

Vimpat 50 mg film-coated tablets
Vimpat 100 mg film-coated tablets
Vimpat 150 mg film-coated tablets
Vimpat 200 mg film-coated tablets

Vimpat package inserts are available for pack sizes:
  • Vimpat 50 mg film-coated tablets, Vimpat 100 mg film-coated tablets, Vimpat 150 mg film-coated tablets, Vimpat 200 mg film-coated tablets
  • Vimpat 10 mg / ml syrup
  • Vimpat 10 mg / ml solution for infusion

Indications Why is Vimpat used? What is it for?

Lacosamide (Vimpat) is used to treat a certain form of epilepsy (see below) in patients aged 16 years or older. Vimpat is used in addition to other antiepileptic medicines. Epilepsy is a condition in which patients have recurring seizures (seizures). Vimpat is used for that form of epilepsy in which seizures initially involve only one side of the brain, but can later spread to larger areas on both sides. the sides of the brain (partial onset seizures with or without secondary generalization) Vimpat has been prescribed to you by your doctor to reduce the number of seizures.

Contraindications When Vimpat should not be used

Do not take Vimpat

  • if you are allergic to lacosamide or any of the other ingredients of this medicine (listed in section 6). If you are unsure whether you are allergic, consult your doctor
  • if you suffer from a particular type of heart rhythm disorder (second or third degree AV block)

Precautions for use What you need to know before taking Vimpat

A small number of patients being treated with antiepileptic medicines such as lacosamide have had thoughts of harming or killing themselves. If you have any such thoughts at all, contact your doctor immediately.

Talk to your doctor before taking Vimpat if you have a condition that is associated with impaired electrical conduction through the heart (AV block, atrial fibrillation and atrial flutter) or severe heart conditions such as heart failure or heart attack. The symptoms of AV block are slow or irregular pulse, feeling lightheaded, and fainting. In case of atrial fibrillation and flutter you may experience symptoms such as palpitations, rapid or irregular pulse and shortness of breath.

Vimpat can cause dizziness, which can increase the risk of accidental injury or falls. Therefore, be careful until you are used to the possible side effects that this medicine can cause.

Children and adolescents

Vimpat is not recommended for children and adolescents under the age of 16. The safety and efficacy in this age group are not yet known.

Interactions Which drugs or foods can change the effect of Vimpat

Other medicines and Vimpat

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is particularly important if you are taking medicines to treat heart disease or if you are taking any medicines that can cause abnormalities of the ECG (electrocardiogram) called prolongation of the PR interval including carbamazepine, lamotrigine, pregabalin (medicines used to treat heart disease). epilepsy) and medicines used to treat some forms of irregular heartbeat or heart failure. If you are not sure whether any medicines you are taking may have this effect, consult your doctor. Medicines such as fluconazole, itraconazole, ketoconazole (medicines used to treat fungal infections), ritonavir (a medicine used to treat HIV infections), clarithromycin, rifampicin (medicines used to treat bacterial infections) and St. John's wort (a medicine used to treat mild anxiety) may affect the how the liver breaks down lacosamide.

Vimpat with alcohol

As a safety precaution, do not take Vimpat with alcohol.

Warnings It is important to know that:

Pregnancy and breastfeeding

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 recommended not to take Vimpat during pregnancy, as the effects of Vimpat on the fetus are not known. If you are pregnant or planning to become pregnant, tell your doctor immediately, who will decide whether you can take Vimpat.

Breastfeeding is not recommended during treatment with Vimpat, as it is not known whether Vimpat passes into breast milk. If you are breastfeeding, tell your doctor immediately, who will decide whether you can take Vimpat.

Research has shown an increased risk of birth defects in babies born to women on antiepileptic therapy. On the other hand, effective antiepileptic therapy must not be interrupted, since a worsening of the disease can be harmful to both the mother and the fetus.

Driving and using machines

Vimpat can cause dizziness or blurred vision. This can affect the ability to drive or use tools or machines. Do not drive or use machines until you have checked whether this medicine affects your ability to perform these activities.

Dose, Method and Time of Administration How to use Vimpat: Posology

Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

Dosage

Take Vimpat twice a day, once in the morning and once in the evening, at about the same time each day. Vimpat is used as a long-term treatment.

Starting therapy (first 4 weeks) This pack (therapy initiation pack) is for you to start therapy with Vimpat. The pack contains 4 different packages for the first 4 weeks of therapy, one for each week. Each package contains 14 tablets, which corresponds to 2 tablets per day for 7 days. Each packet contains a different strength of Vimpat, to allow you to gradually increase the dose. You will start treatment with a low dose of Vimpat, usually 50 mg twice a day, and increase the dose gradually week by week. The dose that can most commonly be taken each day for the first 4 weeks of therapy is shown in the table below. Your doctor will tell you if you need to use all 4 packs.

Table: start of therapy (the first 4 weeks)

Week Package to use First dose (in the morning) Second dose (in the evening) TOTAL daily dose Week 1 Package marked "Week 1" 50 mg (1 tablet of Vimpat 50 mg) 50 mg (1 tablet of Vimpat 50 mg) 100 mg Week 2 Package marked "Week 2" 100 mg (1 tablet of Vimpat 100 mg) 100 mg (1 tablet of Vimpat 100 mg) 200 mg Week 3 Package marked "Week 3" 150 mg (1 tablet of Vimpat 150 mg) 150 mg (1 tablet of Vimpat 150 mg) 300 mg Week 4 Package marked "Week 4" 200 mg (1 tablet of Vimpat 200 mg) 200 mg (1 tablet of Vimpat 200 mg) 400 mg

Maintenance therapy (after the first 4 weeks)

After the first 4 weeks of treatment, your doctor may adjust the dose you will continue to take for long-term therapy. This dose is called the maintenance dose, and it depends on your response to Vimpat. In most patients, the maintenance dose is between 200 mg and 400 mg per day.

Your doctor may prescribe a different dose if you have kidney problems.

How to take Vimpat tablets

You must swallow the Vimpat tablets with a sufficient amount of water (e.g. a glass). You can take Vimpat with or without food.

Duration of treatment with Vimpat

Vimpat is used as a long-term treatment. You must continue to take Vimpat until your doctor tells you to stop the treatment.

Overdose What to do if you have taken too much Vimpat

If you take more Vimpat than you should

Contact your doctor immediately if you have taken more Vimpat than you should. You may have dizziness, nausea, vomiting, heart attacks or problems. Don't try to drive.

If you forget to take Vimpat

If you have forgotten to take a dose of Vimpat, and it is a few hours after you usually take it, take Vimpat as soon as you remember. If it is almost time for your next dose (less than 6 hours), do not take the forgotten tablet. Take your next Vimpat tablet at your usual time. Do not take a double dose to make up for a forgotten dose.

If you stop taking Vimpat

Do not stop taking Vimpat without consulting your doctor as your symptoms may return or get worse. If your doctor decides to stop Vimpat therapy, he will instruct you on how to gradually decrease the dose.

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

Side Effects What are the side effects of Vimpat

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

Very common: may affect more than 1 in 10 patients

  • Dizziness, headache
  • Nausea
  • Double vision (diplopia)

Common: may affect 1 to 10 in 100 patients

  • Problems in maintaining balance, difficulty coordinating movements, memory problems, sleepiness, tremors, difficulty thinking or finding words, rapid and uncontrolled movements of the eyes (nystagmus), tingling (paraesthesia)
  • Blurred vision
  • Feeling of "spinning" (vertigo)
  • Vomiting, constipation, excess gas in the stomach or intestines, diarrhea
  • Itching
  • Falls, contusion
  • Tiredness, difficulty walking, unusual tiredness and weakness (asthenia), feeling drunk
  • Depression
  • Confusion
  • Reduced touch or sensitivity, difficulty articulating words, attention disturbance
  • Noises in the ear such as buzzing or whistling
  • Indigestion, dry mouth
  • Irritability
  • Muscle spasms
  • Rash
  • Difficulty sleeping

Uncommon: may affect 1 to 10 in 1000 patients

  • Reduction of heart rate
  • Cardiac conduction disorder
  • Exaggerated feeling of well-being
  • Allergic reaction after taking the medicine
  • Abnormal liver function tests
  • Suicide attempt
  • Thoughts regarding suicide or self-harm
  • Palpitations and / or rapid or irregular pulsations
  • Aggression
  • Agitation
  • Abnormal thoughts and / or loss of contact with reality
  • Serious allergic reaction which causes swelling of the face, throat, hands, feet, ankles or lower legs
  • Urticaria
  • Hallucinations (seeing and / or hearing things that aren't real)

Not known: frequency cannot be estimated from the available data

  • Severe decrease in the number of cells of a specific class of white blood cells (agranulocytosis)
  • Serious skin reaction which may include flu-like symptoms, a rash of the face, extensive rash with fever, increase in liver enzyme levels seen in blood tests and an increase in a type of white blood cell (eosinophilia) and lymph nodes swollen
  • An extensive rash with blisters and peeling of the skin, particularly around the mouth, nose, eyes and genitals (Stevens-Johnson syndrome) and a more severe form that causes skin peeling in more than 30% of the body surface (toxic epidermal necrolysis).

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 listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

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 after EXP and on the 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 any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

What Vimpat contains

The active ingredient is lacosamide.

One Vimpat 50 mg tablet contains 50 mg of lacosamide.

One Vimpat 100 mg tablet contains 100 mg of lacosamide.

One Vimpat 150 mg tablet contains 150 mg of lacosamide.

One tablet of Vimpat 200 mg contains 200 mg of lacosamide.

The other ingredients are:

Tablet core: microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylcellulose (low-substituted), colloidal anhydrous silica, crospovidone (pharmaceutical grade XL-10 polyplasdon), magnesium stearate

Coating: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E171), dyes *

* The dyes are: 50 mg tablets: red iron oxide (E172), black iron oxide (E172), indigo carmine (E132) 100 mg tablets: yellow iron oxide (E172) Document made available by AIFA on 31 / 03/2015 144 150 mg tablets: yellow iron oxide (E172), red iron oxide (E172), black iron oxide (E172) 200 mg tablets: indigo carmine (E132)

Description of what Vimpat looks like and contents of the pack

Vimpat 50 mg film-coated tablets are pink, oval with 'SP' debossed on one side and '50' on the other.

Vimpat 100 mg film-coated tablets are dark yellow, oval with 'SP' engraved on one side and '100' on the other.

Vimpat 150 mg film-coated tablets are salmon-colored, oval with 'SP' debossed on one side and '150' on the other.

Vimpat 200 mg film-coated tablets are blue, oval with 'SP' debossed on one side and '200' on the other.

The therapy initiation pack contains 56 film-coated tablets, divided into 4 packs:

  • The package marked 'Week 1' contains 14 tablets of 50 mg,
  • The package marked 'Week 2' contains 14 tablets of 100 mg,
  • The package marked 'Week 3' contains 14 tablets of 150 mg,
  • The package marked 'Week 4' contains 14 tablets of 200 mg.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

More information about Vimpat can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER 09 .0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

VIMPAT 50 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 50 mg of lacosamide.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablet.

Pink, oval-shaped, film-coated tablets debossed with "SP" on one side and "50" debossed on the other side of the tablet.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Vimpat is indicated as adjunct therapy in the treatment of partial onset seizures with or without secondary generalization in adult and adolescent patients (16-18 years) with epilepsy.


04.2 Posology and method of administration

Dosage

Lacosamide must be taken twice a day (usually once in the morning and once in the evening). The recommended starting dose is 50 mg twice daily, which should be increased to an initial therapeutic dose of 100 mg twice daily after one week. Lacosamide treatment can also be initiated with a single loading dose of 200 mg, followed approximately 12 hours later by a maintenance dose of 100 mg twice daily (200 mg / day). A loading dose can be used to initiate treatment of patients in those situations where the physician determines that rapid achievement of steady state plasma lacosamide concentration and therapeutic effect must be ensured. This should be administered under medical supervision while taking considering the potential increase in the 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.

The maintenance dose may be further increased by 50 mg twice daily every week depending on clinical response and tolerability, up to a maximum recommended dose of 400 mg / day (200 mg twice daily). Lacosamide can be taken with or without food.

Based on current clinical practice, in the event that lacosamide has to be discontinued, it is recommended to do so gradually (e.g. taper the daily dose by 200 mg every week).

Special populations

Older people (over 65 years of age)

No dose reduction is required in elderly patients. Experience with lacosamide in elderly patients with epilepsy is limited. In elderly patients, an age-associated reduction in renal clearance with increased AUC levels should be considered (see the following section "Renal impairment" and section 5.2).

Kidney failure

No dose adjustment is necessary in patients with mild and moderate renal impairment (CLCR> 30 ml / min). In patients with mild or moderate renal impairment, a loading dose of 200 mg may be considered, but subsequent dose titration (> 200 mg per day) should be performed with caution.

In patients with severe renal insufficiency (CLCR ≤30 ml / min) and in patients with end-stage renal insufficiency, a maximum maintenance dose of 250 mg / day is recommended. In these patients, dose titration should be performed with caution. If a loading dose is indicated, a starting dose of 100 mg followed by a regimen of 50 mg twice daily for the first week should be used. In patients requiring hemodialysis, it is recommended that an additional dose be administered, up to 50% of the single dose used to achieve the daily dose, at the end of each dialysis session. Treatment of patients with end-stage renal insufficiency should be undertaken with caution as there is limited clinical experience and the potential for accumulation of a metabolite (with no known pharmacological activity) exists.

Hepatic insufficiency

No dose adjustment is required in patients with mild to moderate hepatic impairment.

Titration in these patients should be done with caution, taking into account "possible coexisting renal insufficiency. A loading dose of 200 mg may be considered, but subsequent dose titration (> 200 mg per day) should be performed with caution. The pharmacokinetics of lacosamide have not been studied in patients with severe hepatic impairment (see section 5.2).

Pediatric population

The safety and efficacy of lacosamide in children aged less than 16 years have not yet been established. There are no data available.

Method of administration

Lacosamide film-coated tablets are for oral use. Lacosamide can be taken with or without food.


04.3 Contraindications

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

Pre-existing second or third degree atrioventricular (AV) block.


04.4 Special warnings and appropriate precautions for use

Suicidal ideation and behavior

Cases of suicidal ideation and behavior have been reported in patients treated with antiepileptic drugs in their various indications. A meta-analysis of randomized, placebo-controlled clinical trials performed with antiepileptic drugs also found a slightly increased risk of suicidal ideation and behavior. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk with lacosamide. Therefore, patients should be monitored for signs of suicidal ideation and behavior, and appropriate treatment considered. Patients (and their carers) should be advised to consult their physician if signs of suicidal ideation or behavior emerge (see section 4.8).

Rhythm and cardiac conduction

Prolongation of the PR interval was observed during clinical trials with lacosamide. Lacosamide should be administered with caution in patients with pre-existing cardiac conduction defects, as well as in subjects with severe heart disease such as a history of myocardial infarction or heart failure. Lacosamide should be administered with caution especially in elderly patients who may be at an increased risk of heart disease or when lacosamide is used in combination with products known to lead to prolongation of the PR interval.

Second degree or higher AV block has been reported in post-marketing experience. In placebo-controlled clinical trials with lacosamide in patients with epilepsy, no atrial fibrillation or flutter were reported; however, both were reported in epilepsy studies. open label and 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 lightheaded and fainting) and symptoms of atrial fibrillation and flutter (e.g. palpitations, rapid pulse or irregular, shortness of breath). Patients should be advised to consult their physician if any of these symptoms occur.

Dizziness

Treatment with lacosamide is associated with dizziness, which may increase the risk of accidental injury or falls. Patients should therefore be advised to exercise caution until they are familiar with the potential effects of the medicinal product (see section 4.8).


04.5 Interactions with other medicinal products and other forms of interaction

Lacosamide should be administered with caution in patients treated with medicinal products known to lead to prolongation of the PR interval (e.g. carbamazepine, lamotrigine, pregabalin), and in patients treated with class I antiarrhythmics. However, subgroup analyzes in the studies clinical trials showed no more marked prolongation of the PR interval in patients receiving concomitant treatment with carbamazepine or lamotrigine.

Data in vitro

Experimental data suggest a low interaction potential for lacosamide. Studies carried out in vitro indicate that lacosamide does not induce CYP1A2, 2B6 and 2C9 cytochromes or inhibition of CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6 and 2E1 at plasma concentrations observed in clinical studies. A study conducted in vitro demonstrated that lacosamide is not transported by P-glycoprotein in the intestine. Data in vitro demonstrate that the cytochromes CYP2C9, CYP2C19 and CYP3A4 are able to catalyze the formation of the O-desmethyl metabolite.

Data in vivo

Lacosamide does not inhibit or induce CYP2C19 and 3A4 cytochromes in a clinically relevant manner. Lacosamide did not affect the AUC of midazolam (metabolised by cytochrome CYP3A4, lacosamide given at a dose of 200 mg twice daily), but the Cmax of midazolam was slightly increased (30%). Lacosamide had no effect on the pharmacokinetics of midazolam. "omeprazole (metabolised by cytochromes CYP2C19 and 3A4, lacosamide administered at a dose of 300 mg twice daily). The CYP2C19 inhibitor omeprazole (40 mg q.d.) did not result in a clinically relevant change in lacosamide exposure. Consequently, moderate inhibitors of CYP2C19 are unlikely to affect systemic exposure to lacosamide in a clinically relevant manner. Caution is recommended in concomitant treatment with potent inhibitors of CYP2C9 (eg fluconazole) and CYP3A4 (eg itraconazole, ketoconazole, ritonavir, clarithromycin), which may lead to an increase in systemic exposure to lacosamide. Such interactions have not been established in vivo, but they are possible on the basis of the data in vitro.

Potent enzyme inducers such as rifampicin or St. John's wort (Hypericum perforatum) may moderately reduce systemic lacosamide exposure. Consequently, any treatment with these enzyme inducers should be initiated or discontinued with caution.

Antiepileptics

In interaction studies, lacosamide did not significantly affect the plasma concentrations of carbamazepine and valproic acid. Plasma levels of lacosamide were not altered by carbamazepine and "valproic acid. A" population pharmacokinetic analysis showed that concomitant treatment with other antiepileptics known to be enzyme inducers (carbamazepine, phenytoin and phenobarbital, at various dosages) reduced the overall systemic exposure of lacosamide by 25%.

Oral contraceptives

In an interaction study, no clinically relevant interaction was found between lacosamide and the oral contraceptives ethinylestradiol and levonorgestrel. The progesterone concentrations were not affected when the two drugs were administered simultaneously.

Other

Interaction studies have shown that lacosamide has no effect on the pharmacokinetics of digoxin. There is no clinically relevant interaction between lacosamide and metformin. Although no data regarding the interaction of lacosamide with alcohol are available, a pharmacodynamic effect cannot be excluded.

Lacosamide is low in plasma protein binding (less than 15%). Consequently, the presence of clinically relevant interactions with other drugs by competition for protein binding sites is considered unlikely.


04.6 Pregnancy and breastfeeding

Pregnancy

Risk related to epilepsy and antiepileptic drugs in general

It has been shown that in the offspring of women treated with antiepileptic drugs, the prevalence of malformations is two to three times higher than that of approximately 3% in the general population. In the treated population, an increase in malformations was observed in women undergoing polytherapy; however, it was not possible to understand to what extent these malformations were caused by the treatment and / or the disease. Furthermore, effective antiepileptic therapy should not be interrupted, as an exacerbation of the disease can be harmful to both the mother and the fetus.

Risk related to lacosamide

There are no adequate data regarding the use of lacosamide in pregnant women. Animal studies show no teratogenic effects in rats or rabbits, while embryotoxic effects were observed in rats and rabbits following administration of toxic doses for the mother (see section 5.3). The potential risk to humans is unknown. Lacosamide should not be administered during pregnancy unless clearly needed (if the benefit to the mother clearly outweighs the potential risk to the fetus ). If a woman is planning to become pregnant, the use of this medicine should be carefully re-evaluated.

Feeding time

It is not known whether lacosamide is excreted in human breast milk. Animal studies have shown that lacosamide is excreted in breast milk. As a precaution, breastfeeding should be discontinued during lacosamide therapy.

Fertility

In rats, no adverse reactions on male or female fertility or reproduction were observed at doses resulting in plasma exposure (AUC) up to approximately 2 times the human plasma AUC following administration of the maximum recommended human dose. (MRHD).


04.7 Effects on ability to drive and use machines

Lacosamide has a "mild to moderate influence on the ability to drive and use machines. Lacosamide treatment has been associated with dizziness and blurred vision. As a result, patients should not drive or operate potentially dangerous machinery until they have familiarized with the effects of lacosamide on their ability to perform these activities.


04.8 Undesirable effects

Summary of the safety profile

Based on a meta-analysis of placebo-controlled clinical trials in 1308 patients with partial onset seizures, 61.9% of patients randomized to the lacosamide group and 35.2% of those randomized to the placebo group reported at least one adverse reaction . The most frequently reported adverse reactions following lacosamide treatment were dizziness, headache, nausea and diplopia. These reactions were usually mild to moderate in intensity. Some were dose dependent and improved with dose reduction. The incidence and severity of adverse reactions affecting the central nervous system (CNS) and gastrointestinal (GI) tract normally decreased over time. In all controlled studies, the percentage of patients who discontinued therapy due to adverse reactions was was 12.2% for patients randomized to the lacosamide group and 1.6% for patients randomized to the placebo group. The most common adverse reaction leading to discontinuation of therapy was dizziness. The incidence of central nervous system adverse reactions, such as dizziness, may be higher following a loading dose.

Table of adverse reactions

The following table lists by frequency the adverse reactions reported in placebo-controlled clinical trials (with an incidence rate ≥1% in the lacosamide group and which are

> 1% compared to placebo) and in post-marketing experience. Frequencies are defined as follows: very common (≥1 / 10); common (≥1 / 100 to

System and organ classification Very common common Uncommon Not known Disorders of the blood and lymphatic system Agranulocytosis Disorders of the immune system Hypersensitivity to the drug Psychiatric disorders Depression Confusional state Insomnia Aggression Agitation Euphoric mood Psychotic disorder Attempted suicide Suicidal ideation Hallucination Nervous system disorders Dizziness Headache Balance disorder Abnormal coordination Memory impairment Cognitive disorder Somnolence Tremor Nystagmus Hypoesthesia Dysarthria Attention disturbance Eye disorders Diplopia Blurred vision Ear and labyrinth disorders Vertigo Tinnitus Cardiac pathologies Atrioventricular block Bradycardia Atrial fibrillation Atrial flutter Gastrointestinal disorders Nausea Vomiting Constipation Flatulence Dyspepsia Dry mouth Hepatobiliary disorders Abnormalities in liver function tests Skin and subcutaneous tissue disorders Itching Skin rash Angioedema Urticaria Musculoskeletal and connective tissue disorders Muscle spasms General disorders and administration site conditions Alteration of gait Asthenia Fatigue Irritability Injury, poisoning and procedural complications Falls Skin laceration

potentially important adverse drug reactions reported in clinical trials with an incidence rate not matching the above criteria.

adverse reactions reported in post-marketing experience.

Description of selected adverse reactions

The use of lacosamide is associated with a dose-dependent prolongation of the PR interval. Adverse reactions (e.g. atrioventricular block, syncope, bradycardia) associated with this prolongation are possible. In clinical studies in patients with epilepsy, the incidence rate of first degree atrioventricular (AV) block reported is uncommon, 0.7%, 0%, 0.5% and 0% in the lacosamide 200 mg, 400 mg groups. , 600 mg or placebo, respectively. No episodes of second degree or major AV block were observed in these studies. However, cases of second and third degree AV block associated with lacosamide treatment have been reported in post-marketing experience. The incidence rate of syncope in clinical trials is uncommon and does not differ in epileptic patients of the lacosamide group (0, 1%) and placebo group (0.3%). No atrial fibrillation or flutter were reported in short-term clinical trials; however, both were reported in open-label clinical trials in patients with epilepsy and in post-treatment experience. marketing.

Abnormalities in laboratory tests

In controlled clinical trials with lacosamide, liver function test abnormalities were observed in adult patients with partial onset seizures taking 1 to 3 antiepileptic drugs concomitantly. Elevations in ALT up to ≥3 x ULN (Upper Limit of Normal) occurred in 0.7% (7/935) of patients treated with Vimpat and 0% (0/356) of patients treated with placebo.

Multi-organ hypersensitivity reactions

Multiple organ hypersensitivity reactions have been reported in patients treated with some antiepileptic drugs. These reactions occur in a variable manner, but typically present with fever and rash and may be associated with involvement of various organ systems. Potential cases have been reported rarely with lacosamide; if a multi-organ hypersensitivity reaction is suspected, lacosamide treatment should be discontinued.

Pediatric population

The frequency, type and intensity of adverse reactions in adolescents aged 16-18 years are assumed to be the same as in adults. The safety of lacosamide in children aged below 16 has not yet been established. no data is available.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous 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. in "Annex V.


04.9 Overdose

Clinical data regarding lacosamide overdose in humans are limited.

Symptoms

Clinical symptoms (dizziness and nausea) observed following intake of 1200 mg / day were predominantly affecting the central nervous system and gastrointestinal system, and resolved by dose adjustment. The highest lacosamide overdose reported in the clinical history it is 12 g, taken in association with toxic doses of various other antiepileptics The subject, initially entered into a coma, subsequently recovered completely without permanent damage.

Management

There is no specific antidote for lacosamide overdose. Management of overdose should include general supportive measures and, if necessary, may include hemodialysis (see section 5.2).

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

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

Mechanism of action

The active ingredient, lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide) is an amino acid to which other functional groups have been added.

The precise mechanism of action by which lacosamide exerts the antiepileptic effect in humans has not yet been fully explained. Electrophysiological studies conducted in vitro demonstrated that lacosamide selectively potentiates the slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes.

Pharmacodynamic effects

Lacosamide showed a protective effect against seizures in a broad spectrum of animal models of partial and primary generalized seizures and delayed the onset of kindling. In pre-clinical studies, lacosamide, in combination with levetiracetam, carbamazepine, phenytoin, valproate , lamotrigine, topiramate or gabapentin, showed synergistic or additive anticonvulsant effects.

Clinical efficacy and safety

The efficacy of Vimpat as add-on therapy at recommended doses (200 mg / day, 400 mg / day) was evaluated in 3 multicenter, randomized, placebo-controlled clinical trials with a 12-week maintenance period. in which it was used as add-on therapy, Vimpat was also shown to be effective at a dose of 600 mg / day. The efficacy was similar to that obtained with 400 mg / day, however the dose was less tolerated by patients. due to adverse reactions affecting the CNS and gastrointestinal tract. Therefore the dose of 600 mg / day is not recommended. The maximum recommended dose is 400 mg / day. These studies involved a total of 1308 patients with a mean history of 23 years of partial onset seizures, and were designed to evaluate the efficacy and safety of lacosamide, in combination with 1-3 antiepileptics, in patients with partial onset seizures with or without secondary generalization not well controlled by therapy. Overall, the percentage of patients who achieved a 50% reduction in seizure frequency was 23%, 34% and 40% for placebo, lacosamide 200 mg / day and lacosamide 400 mg / day.

There are insufficient data regarding the discontinuation of concomitant antiepileptic treatments in order to be able to use lacosamide alone.

The pharmacokinetics and safety of a single intravenous loading dose of lacosamide were determined in an open-label multicenter study designed to evaluate the safety and tolerability of rapid initiation of lacosamide treatment using a single intravenous loading dose. (including the 200 mg dose) followed by the administration of two daily oral doses (equivalent to the intravenous dose) as add-on therapy in adults aged 16 to 60 years with partial onset seizures.


05.2 "Pharmacokinetic properties

Absorption

Lacosamide is rapidly and completely absorbed following oral administration. The oral bioavailability of lacosamide tablets is close to 100%. Following oral administration, the plasma concentration of unchanged lacosamide increases rapidly and reaches Cmax approximately 0.5 to 4 hours after dosing. Vimpat tablets and Vimpat oral syrup are bioequivalent. Rate and extent of absorption are not affected by food.

Distribution

The volume of distribution is approximately 0.6 L / kg. The plasma protein binding of lacosamide is less than 15%.

Biotransformation

95% of the administered dose is excreted in the urine as drug and metabolites. The metabolism of lacosamide has not been fully characterized.

The major compounds excreted in the urine are unchanged lacosamide (approximately 40% of the dose) and its O-desmethyl metabolite (less than 30%).

A polar fraction hypothesized to be a serine derivative is found to be approximately 20% in the urine, but has been detected in small amounts (0-2%) in the plasma of some subjects. Small amounts of additional metabolites (0.5-2%) were found in the urine.

Data in vitro show that cytochromes CYP2C9, CYP2C19 and CYP3A4 are able to catalyze the formation of the O-desmethyl metabolite, however no confirmation in vivo of the main isoenzyme involved. There was no clinically relevant difference in "lacosamide exposure when comparing its pharmacokinetics in subjects defined as" extensive metabolisers "(with a functional CYP2C19) and" poor metabolisers "(in the absence of a functional CYP2C19). In addition, an interaction study with omeprazole (a CYP2C19 inhibitor) did not show clinically relevant changes in the plasma concentrations of lacosamide, thus indicating that this pathway is of little importance. The plasma concentration of O-desmethyl-lacosamide is approximately 15% of the plasma concentration of lacosamide This major metabolite has no known pharmacological activity.

Elimination

The major routes of elimination of lacosamide from the systemic circulation are renal excretion and biotransformation. Following oral and intravenous administration of radiolabelled lacosamide, approximately 95% of the administered radioactivity was recovered in the urine, and less than 0.5 % in faeces. The half-life of unchanged drug is approximately 13 hours. Pharmacokinetics are dose-dependent and constant over time, with little intra- and inter-patient variability. Following twice daily administration, steady state is achieved over 3 days. Plasma concentration increases with an accumulation factor of approximately 2.

A single 200 mg loading dose results in steady-state concentrations comparable to those of two 100 mg oral doses daily.

Pharmacokinetics in special categories of patients

Sex

Clinical studies indicate that gender does not significantly affect the plasma concentration of lacosamide.

Kidney failure

The AUC of lacosamide increases approximately 30% in patients with mild and moderate renal impairment and 60% in patients with severe and end-stage renal impairment requiring hemodialysis, compared to healthy subjects, while Cmax remains unchanged. is able to effectively remove lacosamide from plasma. The reduction in lacosamide AUC is approximately 50% following a 4-hour hemodialysis treatment. Consequently, an additional dose is recommended in patients undergoing hemodialysis (see section 4.2). The plasma concentration of the metabolite O- demethylated was increased several-fold in patients with moderate and severe renal insufficiency. In patients with end-stage renal insufficiency, in the absence of hemodialysis, the levels of the metabolite were increased and continuously increasing during the 24-hour sampling. It is not known. whether the increased plasma concentration of the metabolite in end-stage renal failure could lead to adverse events, but no pharmacological activity of this metabolite has been identified.

Hepatic insufficiency

Subjects with moderate hepatic impairment (Child-Pugh B) had higher plasma concentrations of lacosamide (AUCnorm increased by approximately 50%). The higher exposure was partly due to decreased renal function in the subjects studied. The reduction in non-renal clearance in these patients is estimated to be responsible for a 20% increase in lacosamide AUC. Lacosamide pharmacokinetics are not has been evaluated in patients with severe hepatic impairment (see section 4.2).

Older people (over 65 years of age)

In a study in elderly subjects of both sexes, which included 4 patients over the age of 75, the AUC was increased by approximately 30% in men and 50% in women, compared to young male subjects. This is partly due to lower body weight. The normalized difference for body weight is 26 and 23%, respectively. An increase in the variability of drug exposure was also observed. In this study, the renal clearance of lacosamide was only slightly reduced in elderly patients.

No general dose reduction is considered necessary unless indicated due to impaired renal function (see section 4.2).


05.3 Preclinical safety data

In toxicity studies, the plasma concentrations of lacosamide obtained were similar or slightly higher than those observed in patients, leaving no additional margin for human exposure.

A study by safety pharmacology in which lacosamide was administered intravenously to anesthetized dogs showed transient increases in the PR interval and duration of the QRS complex, as well as decreases in blood pressure most likely due to a cardiodepressive effect. These transient changes began in the same concentration range. obtained following administration of the maximum recommended dose.In anesthetized dogs and Cynomolgus monkeys, slowed atrio-ventricular conduction, atrio-ventricular block and atrio-ventricular dissociation were observed at doses ranging from 15-60 mg / kg, administered intravenously.

In repeated dose toxicity studies, mild and reversible hepatic changes were observed in rats starting at doses 3 times the clinical exposure levels. These changes included liver weight gain, hepatocyte hypertrophy, increased serum liver enzyme levels, and increased total cholesterol and triglyceride levels. With the exception of hepatocyte hypertrophy, no further histopathological changes were detected.

In reproductive and developmental toxicity studies in rodents and rabbits, the only teratogenic effects found were an increase in the number of stillbirths and perinatal deaths, and a slight reduction in body weight and litter liver size in rats. maternal toxic doses corresponding to a systemic exposure similar to that found in clinical practice. Since it has not been possible to test higher exposure levels in animals due to the maternal toxicity of these doses, the data are not sufficient to establish the embryo-fetotoxic and teratogenic potential of lacosamide.

Studies in rats indicate that lacosamide and / or its metabolites readily cross the placenta.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Core of the tablet:

Microcrystalline cellulose

Hydroxypropylcellulose

Low-substituted hydroxypropylcellulose

Anhydrous colloidal silica

Crospovidone (Pharmaceutical Grade XL-10 Polyplasdon)

Magnesium stearate

Tablet coating:

Polyvinyl alcohol

Polyethylene glycol 3350

Talc

Titanium dioxide (E171)

Red iron oxide (E172), black iron oxide (E172), indigo carmine (E132)


06.2 Incompatibility

Not relevant.


06.3 Period of validity

5 years.


06.4 Special precautions for storage

This medicine does not require any special storage conditions.


06.5 Nature of the immediate packaging and contents of the package

Packs of 14, 56 and 168 film-coated tablets in PVC / PVDC blister sealed with aluminum foil.

Pack size of 56 x 1 tablet in PVC / PVDC perforated unit dose blister sealed with aluminum foil.

Not all pack sizes may be marketed.


06.6 Instructions for use and handling

No special instructions for disposal.

07.0 MARKETING AUTHORIZATION HOLDER

UCB Pharma SA

Allée de la Recherche 60

B-1070 Brussels

Belgium

08.0 MARKETING AUTHORIZATION NUMBER

EU / 1/08/470 / 001- A.I.C. n. 038919015

EU / 1/08/470 / 002- A.I.C. n 038919027

EU / 1/08/470 / 003- A.I.C. n 038919039

EU / 1/08/470/020

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 29 August 2008

10.0 DATE OF REVISION OF THE TEXT

July 2013

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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