ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Vimpat 50 mg film-coated tablets
2.
Each film-coated tablet contains 50 mg lacosamide.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Pinkish, oval film-coated tablet debossed with ‘SP’ on one side and ‘50’ on the other side.
4.
Vimpat is indicated as adjunctive therapy in the treatment of partial-onset seizures with or without
secondary generalisation in patients with epilepsy aged 16 years and older.
Vimpat must be taken twice a day. The recommended starting dose is 50 mg twice a day which should
be increased to an initial therapeutic dose of 100 mg twice a day after one week.
Depending on response and tolerability, the maintenance dose can be further increased by 50 mg twice
a day every week, to a maximum recommended daily dose of 400 mg (200 mg twice a day). Vimpat
may be taken with or without food.
In accordance with current clinical practice, if Vimpat has to be discontinued, it is recommended this
be done gradually (e.g. taper the daily dose by 200 mg/week).
Use in patients with renal impairment
No dose adjustment is necessary in mildly and moderately renally impaired patients (CL
CR
>30 ml/min). A maximum dose of 250 mg/day is recommended for patients with severe renal
impairment (CL
CR
≤30 ml/min) and in patients with endstage renal disease. For patients requiring
haemodialysis a supplement of up to 50% of the divided daily dose directly after the end of
haemodialysis is recommended. Treatment of patients with end-stage renal disease should be made
with caution as there is little clinical experience and accumulation of a metabolite (with no known
pharmacological activity). In all patients with renal impairment, the dose titration should be performed
with caution (see section 5.2).
Use in patients with hepatic impairment
No dose adjustment is needed for patients with mild to moderate hepatic impairment.
The dose titration in these patients should be performed with caution considering co-existing renal
impairment. The pharmacokinetics of lacosamide has not been evaluated in severely hepatic impaired
patients (see section 5.2).
Use in elderly (over 65 years of age
)
No dose reduction is necessary in elderly patients. The experience with lacosamide in elderly patients
with epilepsy is limited. Age associated decreased renal clearance with an increase in AUC levels
should be considered in elderly patients (see ‘Use in patients with renal impairment’ above and section
5.2).
2
Paediatric patients
Vimpat is not recommended for use in children and adolescents below the age of 16 as there is no data
on safety and efficacy in these age groups.
Hypersensitivity to the active substance or to any of the excipients.
Known second- or third-degree atrioventricular (AV) block.
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).
Prolongations in PR interval with lacosamide have been observed in clinical studies. Lacosamide
should be used with caution in patients with known conduction problems or severe cardiac disease
such as a history of myocardial infarction or heart failure. Caution should especially be exerted when
treating elderly patients as they may be at an increased risk of cardiac disorders or when lacosamide is
used in combination with products known to be associated with PR prolongation.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in
several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs 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.
Lacosamide should be used with caution in patients treated with medicinal products known to be
associated with PR prolongation (e.g. carbamazepine, lamotrigine, pregabalin) and in patients treated
with class I antiarrhythmic drugs. 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, 2B6, and 2C9 are not induced and that CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6,
and 2E1 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 3A4 to a clinically relevant extent. Lacosamide
did not affect the AUC of midazolam (metabolised by CYP3A4, lacosamide given 200 mg b.i.d.) but
C
max
of midazolam was slightly increased (30%). Lacosamide did not affect the pharmacokinetics of
omeprazole (metabolised by CYP2C19 and 3A4, lacosamide given 300 mg b.i.d.).
The CYP2C19 inhibitor omeprazole (40 mg q.d.) 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.
3
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 drugs
In interaction trials lacosamide did not significantly affect the plasma concentrations of carbamazepine
and valproic acid. Lacosamide plasma concentrations were not affected by carbamazepine and by
valproic acid. A population PK analysis estimated that concomitant treatment with other anti-epileptic
drugs known to be enzyme inducers (carbamazepine, phenytoin, phenobarbital, in various doses)
decreased the overall systemic exposure of lacosamide by 25%.
Oral contraceptives
In an interaction trial there was no 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.
No data on the interaction of lacosamide with alcohol are available.
Lacosamide has a low protein binding of less than 15%. Therefore, clinically relevant interactions with
other drugs through competition for protein binding sites are considered unlikely.
Pregnancy
Risk related to epilepsy and antiepileptic medicinal products in general
For all anti-epileptic drugs, it has been shown that in the offspring of women treated with epilepsy, the
prevalence of malformations is two to three times greater than the rate of approximately 3% in the
general population. In the treated population, an increase in malformations has been noted with
polytherapy, however, the extent to which the treatment and/or the illness is responsible has not been
elucidated.
Moreover, effective anti-epileptic therapy must not be interrupted, since the aggravation of the illness
is detrimental to both the mother and the foetus.
Risk related to lacosamide
There are no adequate data from the use of lacosamide in pregnant women. Studies in animals did not
indicate any teratogenic effects in rats or rabbits, but embryotoxicity was observed in rats and rabbits
at maternal toxic doses (see section 5.3). The potential risk for humans is unknown.
Lacosamide should not be used during pregnancy unless clearly necessary (if the benefit to the mother
clearly outweighs the potential risk to the foetus). If women decide to become pregnant, the use of this
product should be carefully re-evaluated.
Lactation
It is unknown whether lacosamide is excreted in human breast milk. Animal studies have shown
excretion of lacosamide in breast milk. For precautionary measures, breast-feeding should be
discontinued during treatment with lacosamide.
Vimpat may have minor to moderate influence on the ability to drive and use machines. Vimpat
treatment has been associated with dizziness or blurred vision.
4
Accordingly, patients should be advised not to drive a car or to operate other potentially hazardous
machinery until they are familiar with the effects of Vimpat on their ability to perform such activities.
Based on the analysis of pooled placebo-controlled clinical trials in 1,308 patients with partial-onset
seizures, a total of 61.9% of patients randomized to lacosamide and 35.2% of patients randomized to
placebo reported at least 1 adverse reaction. The most frequently reported adverse reactions with
lacosamide treatment were dizziness, headache, nausea and diplopia. They were usually mild to
moderate in intensity. Some were dose-related and could be alleviated by reducing the dose. Incidence
and severity of CNS and gastrointestinal (GI) adverse reactions usually decreased over time.
Over all controlled studies, the discontinuation rate due to adverse reactions was 12.2% for patients
randomized to lacosamide and 1.6% for patients randomized to placebo. The most common adverse
reaction resulting in discontinuation of lacosamide therapy was dizziness.
The table below shows the frequencies of adverse reactions which have been reported in pooled
placebo-controlled clinical trials (with an incidence rate ≥1% in the lacosamide group and which are
>1% more than placebo) 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). Within each
frequency grouping, undesirable effects are presented in order of decreasing seriousness.
System organ class
Very common Common
Uncommon
Immune system
disorders
Drug hypersensitivity
(2)
Psychiatric disorders
Depression
Confusional state
(1)
Euphoric mood
(2)
Nervous system
disorders
Dizziness
Headache
Balance disorder
Coordination abnormal
Memory impairment
Cognitive disorder
Somnolence
Tremor
Nystagmus
Hypoesthesia
(1)
Dysarthria
(1)
Disturbance in attention
(1)
Eye disorders
Diplopia
Vision blurred
Ear and labyrinth
disorders
Vertigo
Tinnitus
(1)
Cardiac disorders
Atrioventricular block
(2)
Bradycardia
(2)
Gastrointestinal
disorders
Nausea
Vomiting
Constipation
Flatulence
Dyspepsia
(1)
Dry mouth
(1)
Hepatobiliary disorders
Liver function test
abnormal
(2)
Skin and subcutaneous
tissue disorders
Pruritus
Rash
(2)
Musculoskeletal and
connective tissue
disorders
Muscle spasms
(1)
General disorders and
administration site
conditions
Gait disturbance
Asthenia
Fatigue
Irritability
(1)
5
(1)
potentially important adverse drug reactions identified as being reported in pooled clinical trials
with an incidence rate not meeting the criteria used above.
(2)
adverse reactions reported in post marketing experience.
Fall
Skin laceration
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 clinical trials in epilepsy patients the incidence rate of reported first degree AV Block is
uncommon, 0.7%, 0%, 0.5% and 0%
for lacosamide 200 mg, 400 mg, 600 mg or placebo,
respectively. No second or higher degree AV Block was seen in these studies. However, cases with
second and third degree AV Block associated with lacosamide treatment have been reported in post-
marketing experience.
In clinical trials, the incidence rate for syncope is uncommon and did not differ between lacosamide
treated epilepsy patients (0.1%) and placebo treated epilepsy patients (0.3%).
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 anti-epileptic drugs. Elevations
of ALT to ≥3XULN occurred in 0.7% (7/935) of Vimpat patients and 0% (0/356) of placebo patients.
Multiorgan Hypersensitivity Reactions
Multiorgan hypersensitivity reactions have been reported in patients treated with some antiepileptic
agents. These reactions are variable in expression but typically present with fever and rash and can be
associated with involvement of different organ systems. Potential cases have been reported rarely with
lacosamide and if multiorgan hypersensitivity reaction is suspected, lacosamide should be
discontinued
.
There is limited clinical experience with lacosamide overdose in humans. Clinical symptoms
(dizziness and nausea) following doses of 1200 mg/day were mainly related to the central nervous
system and the gastrointestinal system and resolved with dose adjustments.
The highest reported overdose in the clinical development program for lacosamide was 12 g taken in
conjunction with toxic doses of multiple other antiepileptic drugs. The subject was initially comatose
and then fully recovered without permanent sequelae.
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other antiepileptics, ATC code: N03AX18
The active substance, lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide) is a
functionalised amino acid.
Mechanism of action
The precise mechanism by which lacosamide exerts its antiepileptic effect in humans remains to be
fully elucidated.
In vitro
electrophysiological studies have shown that lacosamide selectively enhances
slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable
neuronal membranes.
Pharmacodynamic effects
Lacosamide protected against seizures in a broad range of animal models of partial and primary
generalized seizures and delayed kindling development.
6
Injury, poisoning and
procedural complications
In non-clinical experiments lacosamide in combination with levetiracetam, carbamazepine, phenytoin,
valproate, lamotrigine, topiramate or gabapentin showed synergistic or additive anticonvulsant effects.
Clinical experience
The efficacy of Vimpat as adjunctive therapy at recommended doses (200 mg/day, 400 mg/day) was
established in 3 multicenter, randomized, placebo-controlled clinical trials with a 12-week
maintenance period. Vimpat 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 1308
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 drugs 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.
There are insufficient data regarding the withdrawal of concomitant antiepileptic medicinal products to
achieve monotherapy with lacosamide.
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
max
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.
Metabolism
95% of the dose is excreted in the urine as drug and metabolites. The metabolism of lacosamide has
not been completely characterised.
The major compounds excreted in urine are unchanged lacosamide (approximately 40% of the dose)
and its O-desmethyl metabolite less than 30%.
A polar fraction proposed to be serine derivatives accounted for approximately 20% in urine, but was
detected only in small amounts (0-2%) in human plasma of some subjects. Small amounts (0.5-2%) of
additional metabolites were found in the urine.
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 an interaction trial with omeprazole (CYP2C19-inhibitor)
demonstrated no clinically relevant changes in lacosamide plasma concentrations indicating that the
importance of this pathway is minor. The plasma concentration of O-desmethyl-lacosamide is
approximately 15% of the concentration of lacosamide in plasma. This major metabolite has no known
pharmacological activity.
Elimination
Lacosamide is primarily eliminated from the systemic circulation by renal excretion and
biotransformation. After oral and intravenous administration of radiolabeled lacosamide,
approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the
feces. The elimination half-life of the unchanged drug is approximately 13 hours. The
pharmacokinetics is dose-proportional and constant over time, with low intra- and inter-subject
variability. Following twice daily dosing, steady state plasma concentrations are achieved after a 3 day
period. The plasma concentration increases with an accumulation factor of approximately 2.
7
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 endstage renal disease requiring hemodialysis
compared to healthy subjects, whereas c
max
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 endstage renal disease, the levels were increased and
continuously rising during the 24-hour sampling. It is unknown whether the increased metabolite
exposure in endstage 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).
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 anesthetized 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 anesthetized 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.
8
Studies in rats revealed that lacosamide and/or its metabolites readily crossed the placental barrier.
6.
6.1 List of excipients
Tablet core:
microcrystalline cellulose
hydroxypropylcellulose
hydroxypropylcellulose (low substituted)
silica, colloidal, anhydrous
crospovidone
magnesium stearate
Tablet coat:
polyvinyl alcohol
polyethylene glycol 3350
talc
titanium dioxide (E171)
red iron oxide (E172), black iron oxide (E172), indigo carmine aluminium lake (E132)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/PVDC blister sealed with an aluminium foil.
Packs of 14, 56 and 168 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
UCB Pharma SA
Allée de la Recherche 60
B-1070 Bruxelles
Belgium
8.
EU/1/08/470/001-003
9
9.
Date of first authorisation: 29 August 2008
{MM/YYYY}
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu/.
10
1.
Vimpat 100 mg film-coated tablets
2.
Each film-coated tablet contains 100 mg lacosamide.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Dark yellow, oval film-coated tablet debossed with ‘SP’ on one side and ‘100’ on the other side.
4.
Vimpat is indicated as adjunctive therapy in the treatment of partial-onset seizures with or without
secondary generalisation in patients with epilepsy aged 16 years and older.
Vimpat must be taken twice a day. The recommended starting dose is 50 mg twice a day which should
be increased to an initial therapeutic dose of 100 mg twice a day after one week.
Depending on response and tolerability, the maintenance dose can be further increased by 50 mg twice
a day every week, to a maximum recommended daily dose of 400 mg (200 mg twice a day). Vimpat
may be taken with or without food.
In accordance with current clinical practice, if Vimpat has to be discontinued, it is recommended this
be done gradually (e.g. taper the daily dose by 200 mg/week).
Use in patients with renal impairment
No dose adjustment is necessary in mildly and moderately renally impaired patients (CL
CR
>30 ml/min). A maximum dose of 250 mg/day is recommended for patients with severe renal
impairment (CL
CR
≤30 ml/min) and in patients with endstage renal disease. For patients requiring
haemodialysis a supplement of up to 50% of the divided daily dose directly after the end of
haemodialysis is recommended. Treatment of patients with end-stage renal disease should be made
with caution as there is little clinical experience and accumulation of a metabolite (with no known
pharmacological activity). In all patients with renal impairment, the dose titration should be performed
with caution (see section 5.2).
Use in patients with hepatic impairment
No dose adjustment is needed for patients with mild to moderate hepatic impairment.
The dose titration in these patients should be performed with caution considering co-existing renal
impairment. The pharmacokinetics of lacosamide has not been evaluated in severely hepatic impaired
patients (see section 5.2).
Use in elderly (over 65 years of age
)
No dose reduction is necessary in elderly patients. The experience with lacosamide in elderly patients
with epilepsy is limited. Age associated decreased renal clearance with an increase in AUC levels
should be considered in elderly patients (see ‘Use in patients with renal impairment’ above and section
5.2).
11
Paediatric patients
Vimpat is not recommended for use in children and adolescents below the age of 16 as there is no data
on safety and efficacy in these age groups.
Hypersensitivity to the active substance or to any of the excipients.
Known second- or third-degree atrioventricular (AV) block.
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).
Prolongations in PR interval with lacosamide have been observed in clinical studies. Lacosamide
should be used with caution in patients with known conduction problems or severe cardiac disease
such as a history of myocardial infarction or heart failure. Caution should especially be exerted when
treating elderly patients as they may be at an increased risk of cardiac disorders or when lacosamide is
used in combination with products known to be associated with PR prolongation.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in
several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs 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.
Lacosamide should be used with caution in patients treated with medicinal products known to be
associated with PR prolongation (e.g. carbamazepine, lamotrigine, pregabalin) and in patients treated
with class I antiarrhythmic drugs. 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, 2B6, and 2C9 are not induced and that CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6,
and 2E1 are not inhibited by lacosamide at plasma concentrations observed in clinical trials. An
in
vitro
study indicated that lacosamide is not transported by P-glycoprotein in the intestine.
In vitro
data
show that CYP2C9, CYP2C19 and CYP3A4 are capable of catalysing the formation of the O-
desmethyl metabolite.
In vivo
data
Lacosomide does not inhibit or induce CYP2C19 and CYP3A4 to a clinically relevant extent.
Lacosamide did not affect the AUC of midazolam (metabolised by CYP3A4, lacosamide given 200
mg b.i.d.) but C
max
of midazolam was slightly increased (30%). Lacosamide did not affect the
pharmacokinetics of omeprazole (metabolised by CYP2C19 and 3A4, lacosamide given 300 mg
b.i.d.).
The CYP2C19 inhibitor omeprazole (40 mg q.d.) 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.
12
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 drugs
In interaction trials lacosamide did not significantly affect the plasma concentrations of carbamazepine
and valproic acid. Lacosamide plasma concentrations were not affected by carbamazepine and by
valproic acid. A population PK analysis estimated that concomitant treatment with other anti-epileptic
drugs known to be enzyme inducers (carbamazepine, phenytoin, phenobarbital, in various doses)
decreased the overall systemic exposure of lacosamide by 25%.
Oral contraceptives
In an interaction trial there was no 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.
No data on the interaction of lacosamide with alcohol are available.
Lacosamide has a low protein binding of less than 15%. Therefore, clinically relevant interactions with
other drugs through competition for protein binding sites are considered unlikely.
Pregnancy
Risk related to epilepsy and antiepileptic medicinal products in general
For all anti-epileptic drugs, it has been shown that in the offspring of women treated with epilepsy, the
prevalence of malformations is two to three times greater than the rate of approximately 3% in the
general population. In the treated population, an increase in malformations has been noted with
polytherapy, however, the extent to which the treatment and/or the illness is responsible has not been
elucidated.
Moreover, effective anti-epileptic therapy must not be interrupted, since the aggravation of the illness
is detrimental to both the mother and the foetus.
Risk related to lacosamide
There are no adequate data from the use of lacosamide in pregnant women. Studies in animals did not
indicate any teratogenic effects in rats or rabbits, but embryotoxicity was observed in rats and rabbits
at maternal toxic doses (see section 5.3). The potential risk for humans is unknown.
Lacosamide should not be used during pregnancy unless clearly necessary (if the benefit to the mother
clearly outweighs the potential risk to the foetus). If women decide to become pregnant, the use of this
product should be carefully re-evaluated.
Lactation
It is unknown whether lacosamide is excreted in human breast milk. Animal studies have shown
excretion of lacosamide in breast milk. For precautionary measures, breast-feeding should be
discontinued during treatment with lacosamide.
Vimpat may have minor to moderate influence on the ability to drive and use machines. Vimpat
13
treatment has been associated with dizziness or blurred vision.
Accordingly, patients should be advised not to drive a car or to operate other potentially hazardous
machinery until they are familiar with the effects of Vimpat on their ability to perform such activities.
Based on the analysis of pooled placebo-controlled clinical trials in 1,308 patients with partial-onset
seizures, a total of 61.9% of patients randomized to lacosamide and 35.2% of patients randomized to
placebo reported at least 1 adverse reaction. The most frequently reported adverse reactions with
lacosamide treatment were dizziness, headache, nausea and diplopia. They were usually mild to
moderate in intensity. Some were dose-related and could be alleviated by reducing the dose. Incidence
and severity of CNS and gastrointestinal (GI) adverse reactions usually decreased over time.
Over all controlled studies, the discontinuation rate due to adverse reactions was 12.2% for patients
randomized to lacosamide and 1.6% for patients randomized to placebo. The most common adverse
reaction resulting in discontinuation of lacosamide therapy was dizziness.
The table below shows the frequencies of adverse reactions which have been reported in pooled
placebo-controlled clinical trials (with an incidence rate ≥1% in the lacosamide group and which are
>1% more than placebo) 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). Within each
frequency grouping, undesirable effects are presented in order of decreasing seriousness.
System organ class
Very common Common
Uncommon
Immune system
disorders
Drug hypersensitivity
(2)
Psychiatric disorders
Depression
Confusional state
(1)
Euphoric mood
(2)
Nervous system
disorders
Dizziness
Headache
Balance disorder
Coordination abnormal
Memory impairment
Cognitive disorder
Somnolence
Tremor
Nystagmus
Hypoesthesia
(1)
Dysarthria
(1)
Disturbance in attention
(1)
Eye disorders
Diplopia
Vision blurred
Ear and labyrinth
disorders
Vertigo
Tinnitus
(1)
Cardiac disorders
Atrioventricular block
(2)
Bradycardia
(2)
Gastrointestinal
disorders
Nausea
Vomiting
Constipation
Flatulence
Dyspepsia
(1)
Dry mouth
(1)
Hepatobiliary disorders
Liver function test
abnormal
(2)
Skin and subcutaneous
tissue disorders
Pruritus
Rash
(2)
Musculoskeletal and
connective tissue
disorders
Muscle spasms
(1)
General disorders and
administration site
conditions
Gait disturbance
Asthenia
Fatigue
14
Irritability
(1)
(1)
potentially important adverse drug reactions identified as being reported in pooled clinical trials
with an incidence rate not meeting the criteria used above.
(2)
adverse reactions reported in post marketing experience
Fall
Skin laceration
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 clinical trials in epilepsy patients the incidence rate of reported first degree AV Block is
uncommon, 0.7%, 0%, 0.5% and 0%
for lacosamide 200 mg, 400 mg, 600 mg or placebo,
respectively. No second or higher degree AV Block was seen in these studies. However, cases with
second and third degree AV Block associated with lacosamide treatment have been reported in post-
marketing experience.
In clinical trials, the incidence rate for syncope is uncommon and did not differ between lacosamide
treated epilepsy patients (0.1%) and placebo treated epilepsy patients (0.3%).
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 anti-epileptic drugs. Elevations
of ALT to ≥3XULN occurred in 0.7% (7/935) of Vimpat patients and 0% (0/356) of placebo patients.
Multiorgan Hypersensitivity Reactions
Multiorgan hypersensitivity reactions have been reported in patients treated with some antiepileptic
agents. These reactions are variable in expression but typically present with fever and rash and can be
associated with involvement of different organ systems. Potential cases have been reported rarely with
lacosamide and if multiorgan hypersensitivity reaction is suspected, lacosamide should be
discontinued
.
There is limited clinical experience with lacosamide overdose in humans. Clinical symptoms
(dizziness and nausea) following doses of 1200 mg/day were mainly related to the central nervous
system and the gastrointestinal system and resolved with dose adjustments.
The highest reported overdose in the clinical development program for lacosamide was 12 g taken in
conjunction with toxic doses of multiple other antiepileptic drugs. The subject was initially comatose
and then fully recovered without permanent sequelae.
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other antiepileptics, ATC code: N03AX18
The active substance, lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide) is a
functionalised amino acid.
Mechanism of action
The precise mechanism by which lacosamide exerts its antiepileptic effect in humans remains to be
fully elucidated.
In vitro
electrophysiological studies have shown that lacosamide selectively enhances
slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable
neuronal membranes.
Pharmacodynamic effects
Lacosamide protected against seizures in a broad range of animal models of partial and primary
15
Injury, poisoning and
procedural complications
generalized 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 experience
The efficacy of Vimpat as adjunctive therapy at recommended doses (200 mg/day, 400 mg/day) was
established in 3 multicenter, randomized, placebo-controlled clinical trials with a 12-week
maintenance period. Vimpat 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 1308
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 drugs 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.
There are insufficient data regarding the withdrawal of concomitant antiepileptic medicinal products to
achieve monotherapy with lacosamide.
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
max
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.
Metabolism
95% of the dose is excreted in the urine as drug and metabolites. The metabolism of lacosamide has
not been completely characterised.
The major compounds excreted in urine are unchanged lacosamide (approximately 40% of the dose)
and its O-desmethyl metabolite less than 30%.
A polar fraction proposed to be serine derivatives accounted for approximately 20% in urine, but was
detected only in small amounts (0-2%) in human plasma of some subjects. Small amounts (0.5-2%) of
additional metabolites were found in the urine.
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 an interaction trial with omeprazole (CYP2C19-inhibitor)
demonstrated no clinically relevant changes in lacosamide plasma concentrations indicating that the
importance of this pathway is minor.
The plasma concentration of O-desmethyl-lacosamide is approximately 15% of the concentration of
lacosamide in plasma. This major metabolite has no known pharmacological activity.
Elimination
Lacosamide is primarily eliminated from the systemic circulation by renal excretion and
biotransformation. After oral and intravenous administration of radiolabeled lacosamide,
approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the
feces. The elimination half-life of the unchanged drug is approximately 13 hours. The
pharmacokinetics is dose-proportional and constant over time, with low intra- and inter-subject
variability. Following twice daily dosing, steady state plasma concentrations are achieved after a 3 day
period. The plasma concentration increases with an accumulation factor of approximately 2.
16
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 endstage renal disease requiring hemodialysis
compared to healthy subjects, whereas c
max
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 endstage renal disease, the levels were increased and
continuously rising during the 24-hour sampling. It is unknown whether the increased metabolite
exposure in endstage 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).
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 anesthetized 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 anesthetized 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
17
embryofetotoxic and teratogenic potential of lacosamide.
Studies in rats revealed that lacosamide and/or its metabolites readily crossed the placental barrier.
6.
6.1 List of excipients
Tablet core:
microcrystalline cellulose
hydroxypropylcellulose
hydroxypropylcellulose (low substituted)
silica, colloidal, anhydrous
crospovidone
magnesium stearate
Tablet coat:
polyvinyl alcohol
polyethylene glycol 3350
talc
titanium dioxide (E171)
yellow iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/PVDC blister sealed with an aluminium foil.
Packs of 14, 56 and 168 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
UCB Pharma SA
Allée de la Recherche 60
B-1070 Bruxelles
Belgium
8.
18
EU/1/08/470/004-006
9.
Date of first authorisation: 29 August 2008
{MM/YYYY}
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu/.
19
1.
Vimpat 150 mg film-coated tablets
2.
Each film-coated tablet contains 150 mg lacosamide.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Salmon, oval film-coated tablet debossed with ‘SP’ on one side and ‘150’ on the other side.
4.
Vimpat is indicated as adjunctive therapy in the treatment of partial-onset seizures with or without
secondary generalisation in patients with epilepsy aged 16 years and older.
Vimpat must be taken twice a day. The recommended starting dose is 50 mg twice a day which should
be increased to an initial therapeutic dose of 100 mg twice a day after one week.
Depending on response and tolerability, the maintenance dose can be further increased by 50 mg twice
a day every week, to a maximum recommended daily dose of 400 mg (200 mg twice a day). Vimpat
may be taken with or without food.
In accordance with current clinical practice, if Vimpat has to be discontinued, it is recommended this
be done gradually (e.g. taper the daily dose by 200 mg/week).
Use in patients with renal impairment
No dose adjustment is necessary in mildly and moderately renally impaired patients (CL
CR
>30 ml/min). A maximum dose of 250 mg/day is recommended for patients with severe renal
impairment (CL
CR
≤30 ml/min) and in patients with endstage renal disease. For patients requiring
haemodialysis a supplement of up to 50% of the divided daily dose directly after the end of
haemodialysis is recommended. Treatment of patients with end-stage renal disease should be made
with caution as there is little clinical experience and accumulation of a metabolite (with no known
pharmacological activity). In all patients with renal impairment, the dose titration should be performed
with caution (see section 5.2).
Use in patients with hepatic impairment
No dose adjustment is needed for patients with mild to moderate hepatic impairment.
The dose titration in these patients should be performed with caution considering co-existing renal
impairment. The pharmacokinetics of lacosamide has not been evaluated in severely hepatic impaired
patients (see section 5.2).
Use in elderly (over 65 years of age
)
No dose reduction is necessary in elderly patients. The experience with lacosamide in elderly patients
with epilepsy is limited. Age associated decreased renal clearance with an increase in AUC levels
should be considered in elderly patients (see ‘Use in patients with renal impairment’ above and section
5.2).
20
Paediatric patients
Vimpat is not recommended for use in children and adolescents below the age of 16 as there is no data
on safety and efficacy in these age groups.
Hypersensitivity to the active substance or to any of the excipients.
Known second- or third-degree atrioventricular (AV) block.
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).
Prolongations in PR interval with lacosamide have been observed in clinical studies. Lacosamide
should be used with caution in patients with known conduction problems or severe cardiac disease
such as a history of myocardial infarction or heart failure. Caution should especially be exerted when
treating elderly patients as they may be at an increased risk of cardiac disorders or when lacosamide is
used in combination with products known to be associated with PR prolongation.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in
several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs 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.
Lacosamide should be used with caution in patients treated with medicinal products known to be
associated with PR prolongation (e.g. carbamazepine, lamotrigine, pregabalin) and in patients treated
with class I antiarrhythmic drugs. 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, 2B6, and 2C9 are not induced and that CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6,
and 2E1 are not inhibited by lacosamide at plasma concentrations observed in clinical trials. An
in
vitro
study indicated that lacosamide is not transported by P-glycoprotein in the intestine.
In vitro
data
show that CYP2C9, CYP2C19 and CYP3A4 are capable of catalysing the formation of the O-
desmethyl metabolite.
In vivo
data
Lacosomide does not inhibit or induce CYP2C19 and CYP3A4 to a clinically relevant extent.
Lacosamide did not affect the AUC of midazolam (metabolised by CYP3A4, lacosamide given 200
mg b.i.d.) but C
max
of midazolam was slightly increased (30%). Lacosamide did not affect the
pharmacokinetics of omeprazole (metabolised by CYP2C19 and 3A4, lacosamide given 300 mg
b.i.d.).
The CYP2C19 inhibitor omeprazole (40 mg q.d.) 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.
21
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 drugs
In interaction trials lacosamide did not significantly affect the plasma concentrations of carbamazepine
and valproic acid. Lacosamide plasma concentrations were not affected by carbamazepine and by
valproic acid. A population PK analysis estimated that concomitant treatment with other anti-epileptic
drugs known to be enzyme inducers (carbamazepine, phenytoin, phenobarbital, in various doses)
decreased the overall systemic exposure of lacosamide by 25%.
Oral contraceptives
In an interaction trial there was no 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.
No data on the interaction of lacosamide with alcohol are available.
Lacosamide has a low protein binding of less than 15%. Therefore, clinically relevant interactions with
other drugs through competition for protein binding sites are considered unlikely.
Pregnancy
Risk related to epilepsy and antiepileptic medicinal products in general
For all anti-epileptic drugs, it has been shown that in the offspring of women treated with epilepsy, the
prevalence of malformations is two to three times greater than the rate of approximately 3% in the
general population. In the treated population, an increase in malformations has been noted with
polytherapy, however, the extent to which the treatment and/or the illness is responsible has not been
elucidated.
Moreover, effective anti-epileptic therapy must not be interrupted, since the aggravation of the illness
is detrimental to both the mother and the foetus.
Risk related to lacosamide
There are no adequate data from the use of lacosamide in pregnant women. Studies in animals did not
indicate any teratogenic effects in rats or rabbits, but embryotoxicity was observed in rats and rabbits
at maternal toxic doses (see section 5.3). The potential risk for humans is unknown.
Lacosamide should not be used during pregnancy unless clearly necessary (if the benefit to the mother
clearly outweighs the potential risk to the foetus). If women decide to become pregnant, the use of this
product should be carefully re-evaluated.
Lactation
It is unknown whether lacosamide is excreted in human breast milk. Animal studies have shown
excretion of lacosamide in breast milk. For precautionary measures, breast-feeding should be
discontinued during treatment with lacosamide.
Vimpat may have minor to moderate influence on the ability to drive and use machines. Vimpat
treatment has been associated with dizziness or blurred vision.
22
Accordingly, patients should be advised not to drive a car or to operate other potentially hazardous
machinery until they are familiar with the effects of Vimpat on their ability to perform such activities.
Based on the analysis of pooled placebo-controlled clinical trials in 1,308 patients with partial-onset
seizures, a total of 61.9% of patients randomized to lacosamide and 35.2% of patients randomized to
placebo reported at least 1 adverse reaction. The most frequently reported adverse reactions with
lacosamide treatment were dizziness, headache, nausea and diplopia. They were usually mild to
moderate in intensity. Some were dose-related and could be alleviated by reducing the dose. Incidence
and severity of CNS and gastrointestinal (GI) adverse reactions usually decreased over time.
Over all controlled studies, the discontinuation rate due to adverse reactions was 12.2% for patients
randomized to lacosamide and 1.6% for patients randomized to placebo. The most common adverse
reaction resulting in discontinuation of lacosamide therapy was dizziness.
The table below shows the frequencies of adverse reactions which have been reported in pooled
placebo-controlled clinical trials (with an incidence rate ≥1% in the lacosamide group and which are
>1% more than placebo) 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). Within each
frequency grouping, undesirable effects are presented in order of decreasing seriousness.
System organ class
Very common Common
Uncommon
Immune system
disorders
Drug hypersensitivity
(2)
Psychiatric disorders
Depression
Confusional state
(1)
Euphoric mood
(2)
Nervous system
disorders
Dizziness
Headache
Balance disorder
Coordination abnormal
Memory impairment
Cognitive disorder
Somnolence
Tremor
Nystagmus
Hypoesthesia
(1)
Dysarthria
(1)
Disturbance in attention
(1)
Eye disorders
Diplopia
Vision blurred
Ear and labyrinth
disorders
Vertigo
Tinnitus
(1)
Cardiac disorders
Atrioventricular block
(2)
Bradycardia
(2)
Gastrointestinal
disorders
Nausea
Vomiting
Constipation
Flatulence
Dyspepsia
(1)
Dry mouth
(1)
Hepatobiliary disorders
Liver function test
abnormal
(2)
Skin and subcutaneous
tissue disorders
Pruritus
Rash
(2)
Musculoskeletal and
connective tissue
disorders
Muscle spasms
(1)
General disorders and
administration site
conditions
Gait disturbance
Asthenia
Fatigue
Irritability
(1)
23
(1)
potentially important adverse drug reactions identified as being reported in pooled clinical trials
with an incidence rate not meeting the criteria used above.
(2)
adverse reactions reported in post marketing experience.
Fall
Skin laceration
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 clinical trials in epilepsy patients the incidence rate of reported first degree AV Block is
uncommon, 0.7%, 0%, 0.5% and 0%
for lacosamide 200 mg, 400 mg, 600 mg or placebo,
respectively. No second or higher degree AV Block was seen in.these studies. However, cases with
second and third degree AV Block associated with lacosamide treatment have been reported in post-
marketing experience.
In clinical trials, the incidence rate for syncope is uncommon and did not differ between lacosamide
treated epilepsy patients (0.1%) and placebo treated epilepsy patients (0.3%).
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 anti-epileptic drugs. Elevations
of ALT to ≥3XULN occurred in 0.7% (7/935) of Vimpat patients and 0% (0/356) of placebo patients.
Multiorgan Hypersensitivity Reactions
Multiorgan hypersensitivity reactions have been reported in patients treated with some antiepileptic
agents. These reactions are variable in expression but typically present with fever and rash and can be
associated with involvement of different organ systems. Potential cases have been reported rarely with
lacosamide and if multiorgan hypersensitivity reaction is suspected, lacosamide should be
discontinued
.
There is limited clinical experience with lacosamide overdose in humans. Clinical symptoms
(dizziness and nausea) following doses of 1200 mg/day were mainly related to the central nervous
system and the gastrointestinal system and resolved with dose adjustments.
The highest reported overdose in the clinical development program for lacosamide was 12 g taken in
conjunction with toxic doses of multiple other antiepileptic drugs. The subject was initially comatose
and then fully recovered without permanent sequelae.
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other antiepileptics, ATC code: N03AX18
The active substance, lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide) is a
functionalised amino acid.
Mechanism of action
The precise mechanism by which lacosamide exerts its antiepileptic effect in humans remains to be
fully elucidated.
In vitro
electrophysiological studies have shown that lacosamide selectively enhances
slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable
neuronal membranes.
Pharmacodynamic effects
Lacosamide protected against seizures in a broad range of animal models of partial and primary
generalized seizures and delayed kindling development.
24
Injury, poisoning and
procedural complications
In non-clinical experiments lacosamide in combination with levetiracetam, carbamazepine, phenytoin,
valproate, lamotrigine, topiramate or gabapentin showed synergistic or additive anticonvulsant effects.
Clinical experience
The efficacy of Vimpat as adjunctive therapy at recommended doses (200 mg/day, 400 mg/day) was
established in 3 multicenter, randomized, placebo-controlled clinical trials with a 12-week
maintenance period. Vimpat 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 1308
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 drugs 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.
There are insufficient data regarding the withdrawal of concomitant antiepileptic medicinal products to
achieve monotherapy with lacosamide.
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
max
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.
Metabolism
95% of the dose is excreted in the urine as drug and metabolites. The metabolism of lacosamide has
not been completely characterised.
The major compounds excreted in urine are unchanged lacosamide (approximately 40% of the dose)
and its O-desmethyl metabolite less than 30%.
A polar fraction proposed to be serine derivatives accounted for approximately 20% in urine, but was
detected only in small amounts (0-2%) in human plasma of some subjects. Small amounts (0.5-2%) of
additional metabolites were found in the urine.
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 an interaction trial with omeprazole (CYP2C19-inhibitor)
demonstrated no clinically relevant changes in lacosamide plasma concentrations indicating that the
importance of this pathway is minor.
The plasma concentration of O-desmethyl-lacosamide is approximately 15% of the concentration of
lacosamide in plasma. This major metabolite has no known pharmacological activity.
Elimination
Lacosamide is primarily eliminated from the systemic circulation by renal excretion and
biotransformation. After oral and intravenous administration of radiolabeled lacosamide,
approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the
feces. The elimination half-life of the unchanged drug is approximately 13 hours. The
pharmacokinetics is dose-proportional and constant over time, with low intra- and inter-subject
variability. Following twice daily dosing, steady state plasma concentrations are achieved after a 3 day
period. The plasma concentration increases with an accumulation factor of approximately 2.
25
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 endstage renal disease requiring hemodialysis
compared to healthy subjects, whereas c
max
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 endstage renal disease, the levels were increased and
continuously rising during the 24-hour sampling. It is unknown whether the increased metabolite
exposure in endstage 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).
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 anesthetized 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 anesthetized 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.
26
Studies in rats revealed that lacosamide and/or its metabolites readily crossed the placental barrier.
6.
6.1 List of excipients
Tablet core:
microcrystalline cellulose
hydroxypropylcellulose
hydroxypropylcellulose (low substituted)
silica, colloidal, anhydrous
crospovidone
magnesium stearate
Tablet coat:
polyvinyl alcohol
polyethylene glycol 3350
talc
titanium dioxide (E171)
yellow iron oxide (E172),
red iron oxide (E172), black iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/PVDC blister sealed with an aluminium foil.
Packs of 14, 56 and 168 film-coated tablets (multipacks containing 3 packs of 56 tablets).
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
UCB Pharma SA
Allée de la Recherche 60
B-1070 Bruxelles
Belgium
8.
EU/1/08/470/007-009
27
9.
Date of first authorisation: 29 August 2008
{MM/YYYY}
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu/.
28
1.
FURTHER INFORMATION
What Vimpat contains
The active substance
is lacosamide.
1 ml Vimpat solution for infusion contains 10 mg lacosamide.
1 vial contains 20 ml Vimpat solution for infusion equivalent to 200 mg lacosamide.
The other ingredients
are: sodium chloride, hydrochloric acid, water for injection.
What Vimpat looks like and contents of the pack
Vimpat 10 mg/ml solution for infusion is a clear, colourless solution.
Vimpat solution for infusion is available in packages of 1 vial and 5 vials. Each vial contains 20 ml.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: UCB Pharma SA, Allée de la Recherche 60, B-1070 Bruxelles,
Belgium.
Manufacturer: UCB Pharma GmbH, Alfred-Nobel-Str. 10, 40789 Monheim am Rhein, Germany.
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
UCB Pharma SA/NV
Tel/Tél: + 32 / (0)2 559 92 00
Luxembourg/Luxemburg
UCB Pharma SA/NV
Tél/Tel: + 32 / (0)2 559 92 00
България
Ю СИ БИ България ЕООД
Teл.: + 359 (0) 2 962 99 20
Magyarország
UCB Magyarország Kft.
Tel.: + 36-(1) 391 0060
Česká republika
Malta
131
UCB s.r.o.
Tel: + 420 221 773 411
Pharmasud Ltd.
Tel: + 356 / 21 37 64 36
Danmark
UCB Nordic A/S
Tlf: + 45 / 32 46 24 00
Nederland
UCB Pharma B.V.
Tel.: + 31 / (0)76-573 11 40
Deutschland
UCB GmbH
Tel: + 49 /(0) 2173 48 4847
Norge
UCB Nordic A/S
Tlf: + 45 / 32 46 24 00
Eesti
UCB Pharma Oy Finland
Tel: + 358 10 234 6800 (Soome)
Österreich
UCB Pharma GmbH
Tel: + 43 (1) 291 80 00
Ελλάδα
UCB Α.Ε.
Τηλ: + 30 / 2109974000
Polska
UCB Pharma Sp. z o.o.
Tel.: + 48 (0)22 696 99 20
España
UCB Pharma, S.A.
Tel: + 34 / 91 570 34 44
Portugal
UCB Pharma (Produtos Farmacêuticos), Lda
Tel: + 351 / 21 302 5300
France
UCB Pharma S.A.
Tél: + 33 / (0)1 47 29 44 35
România
UCB Pharma Romania S.R.L.
Tel: + 40 21 300 29 04
Ireland
UCB (Pharma) Ireland Ltd.
Tel: + 353 / (0)1-46 37 395
Slovenija
Medis, d.o.o.
Tel: + 386 1 589 69 00
Ísland
Vistor hf.
Tel: + 354 535 7000
Slovenská republika
UCB s.r.o.
, organizačná zložka
Tel: + 421 (0) 2 5920 2020
Italia
UCB Pharma S.p.A.
Tel: + 39 / 02 300 791
Suomi/Finland
UCB Pharma Oy Finland
Puh/Tel: + 358 10 234 6800
Κύπρος
Lifepharma (Z.A.M.) Ltd
Τηλ: + 357 22 34 74 40
Sverige
UCB Nordic A/S
Tel: + 46 / (0) 40 29 49 00
Latvija
UCB Pharma Oy Finland
Tel: + 358 10 234 6800 (Somija)
United Kingdom
UCB Pharma Ltd.
Tel : + 44 / (0)1753 534 655
Lietuva
UCB Pharma Oy Finland
Tel: + 358 10 234 6800 (Suomija)
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
132
site: http://www.ema.europa.eu/.
The following information is intended for medical or healthcare professionals only
Vimpat solution for infusion can be administered without further dilution, or may be diluted with the
following solutions: 0.9% sodium chloride 9 mg/ml (0.9%), 5% glucose 50 mg/ml or lactated Ringer’s
solution. Each vial of Vimpat solution for infusion must be used only once (single use). Any unused
solution should be discarded (see section 3).
133
Source: European Medicines Agency
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