ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Inovelon 100 mg film-coated tablets
2.
100 mg
Each film-coated tablet contains 100 mg rufinamide.
Excipient: 20 mg lactose monohydrate/film coated tablet.
For a full list of excipients, see Section 6.1.
3.
Film-coated tablet.
100 mg
Pink, ‘ovaloid’, slightly convex, scored on both sides, embossed ‘Є261’ on one side and blank on the
other side.
The tablet can be divided into equal halves.
4.
Inovelon is indicated as adjunctive therapy in the treatment of seizures associated with
Lennox-Gastaut syndrome in patients 4 years and older.
Treatment with Inovelon should be initiated by a physician specialised in paediatrics or neurology
with experience in the treatment of epilepsy.
Inovelon is for oral use. It should be taken twice daily with water in the morning and in the evening,
in two equally divided doses. As a food effect was observed, it will preferable to administer Inovelon
with food (see Section 5.2). If the patient has difficulty with swallowing, tablets can be crushed and
administered in half a glass of water.
Use in children four years of age or older and less than 30 kg
Patients <30 kg not receiving valproate:
Treatment should be initiated at a daily dose of 200 mg. According to clinical response and
tolerability, the dose may be increased by 200 mg/day increments, as frequently as every two days, up
to a maximum recommended dose of 1000 mg/day. Doses of up to 3600 mg/day have been studied in
a limited number of patients.
Patients <30 kg also receiving valproate medication:
As valproate significantly decreases clearance of Inovelon, a lower maximum dose of Inovelon is
recommended for patients <30 kg being co-administered valproate. Treatment should be initiated at a
daily dose of 200 mg. According to clinical response and tolerability, after a minimum of 2 days the
dose may be increased by 200 mg/day, to the maximum recommended dose of 600 mg/day.
2
Use in adults and children four years of age or older of 30 kg or over
Treatment should be initiated at a daily dose of 400 mg. According to clinical response and
tolerability, the dose may be increased by 400 mg/day increments, as frequently as every two days, up
to a maximum recommended dose as indicated in the table below.
Weight range
30.0 – 50.0 kg
50.1 – 70.0 kg ≥70.1 kg
Maximum
recommended dose
(mg/day)
1800
2400
3200
Doses of up to 4000 mg/day (in the 30-50 kg range) or 4800 mg/day (over 50 kg) have been studied in
a limited number of patients.
Elderly
There is limited information on the use of Inovelon in the elderly. Since, the pharmacokinetics of
rufinamide are not altered in the elderly (see Section 5.2), dosage adjustment is not required in patients
over 65 years of age.
Patients with renal impairment
A study in patients with severe renal impairment indicated that no dose adjustments are required for
these patients (see Section 5.2).
Patients with hepatic impairment
Use in patients with hepatic impairment has not been studied. Caution and careful dose titration is
recommended when treating patients with mild to moderate hepatic impairment. Therefore, use in
patients with severe hepatic impairment is not recommended.
Effect of food
Inovelon should preferably be taken with food (see Section 5.2).
Discontinuation of Inovelon
When Inovelon treatment is to be discontinued, it should be withdrawn gradually. In clinical trials
Inovelon discontinuation was achieved by reducing the dose by approximately 25% every two days.
In the case of one or more missed doses, individualised clinical judgement is necessary.
Uncontrolled open-label studies suggest sustained long-term efficacy, although no controlled study
has been conducted for longer than three months.
Hypersensitivity to the active substance, triazole derivatives or to any excipients.
Status epilepticus cases have been observed during clinical development studies, under rufinamide
whereas no such cases have been observed under placebo. These events led to rufinamide
discontinuation in 20 % of the cases. If patients develop new seizure types and/or experience an
increased frequency of status epilepticus that is different from the patient’s baseline condition, then the
benefit risk ratio of the therapy should be reassessed.
Antiepileptic medicinal products, including Inovelon, should be withdrawn gradually to reduce the
possibility of seizures on withdrawal. In clinical studies discontinuation was achieved by reducing the
dose by approximately 25% every two days. There are insufficient data on the withdrawal of
concomitant antiepileptic medicinal products once seizure control has been achieved with the addition
of Inovelon.
3
Rufinamide treatment has been associated with dizziness, somnolence, ataxia and gait disturbances,
which could increase the occurrence of accidental falls in this population (see Section 4.8). Patients
and carers should exercise caution until they are familiar with the potential effects of this medicinal
product.
Serious antiepileptic drug hypersensitivity syndrome has occurred in association with rufinamide
therapy. Signs and symptoms of this disorder were diverse; however, patients typically, although not
exclusively, presented with fever and rash associated with other organ system involvement. Other
associated manifestations included lymphadenopathy, liver function tests abnormalities, and
haematuria. Because the disorder is variable in its expression, other organ system signs and symptoms
not noted here may occur. This syndrome occurred in close temporal association to the initiation of
rufinamide therapy and in the paediatric population. If this reaction is suspected, rufinamide should be
discontinued and alternative treatment started. All patients who develop a rash while taking
rufinamide must be closely monitored.
In a thorough QT study, rufinamide produced a decrease in QTc interval proportional to concentration.
Although the underlying mechanism and safety relevance of this finding is not known, clinicians
should use clinical judgment when assessing whether to prescribe rufinamide to patients at risk from
further shortening their QTc duration (eg. Congenital Short QT Syndrome or patients with a family
history of such a syndrome).
Women of childbearing potential must use contraceptive measures during treatment with Inovelon.
Physicians should try to ensure that appropriate contraception is used, and should use clinical
judgement when assessing whether oral contraceptives, or the doses of the oral contraceptive
components, are adequate based on the individual patients clinical situation (see Section 4.5).
Inovelon contains lactose, therefore patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Potential for other medicinal products to affect Inovelon
Other anti-epileptic medicinal products
Rufinamide concentrations may be decreased by co-administration with carbamazepine, phenobarbital,
phenytoin, vigabatrin or primidone.
For patients on Inovelon treatment who have administration of valproate initiated, significant increases
in rufinamide plasma concentrations may occur. The most pronounced increases were observed in
patients of low body weight (<30 kg). Therefore, consideration should be given to a dose reduction of
Inovelon in patients <30 kg who are initiated on valproate therapy (see Section 4.2).
The addition or withdrawal of these drugs or adjusting of the dose of these drugs during Inovelon
therapy may require an adjustment in dosage of Inovelon.
No significant changes in rufinamide concentration are observed following co-administration with
lamotrigine, topiramate or benzodiazepines.
Potential for Inovelon to affect other medicinal products
Other anti-epileptic medicinal products
The pharmacokinetic interactions between rufinamide and other anti-epileptic drugs have been
evaluated in patients with epilepsy using population pharmacokinetic modelling. Rufinamide appears
not to have clinically relevant effect on carbamazepine, lamotrigine, phenobarbital, topiramate or
valproate steady state concentrations. Since rufinamide may decrease phenytoin clearance and increase
4
average steady state plasma concentrations of co-administered phenytoin, consideration should be
given to reducing the dose of phenytoin.
Oral contraceptives
Co-administration of rufinamide 800 mg b.i.d. and a combined oral contraceptive (ethinyloestradiol 35
μg and norethindrone 1 mg) for 14 days resulted in a mean decrease in the ethinyl estradiol AUC
0-24
of
22% and in norethindrone AUC
0-24
of 14%. Studies with other oral or implant contraceptives have not
been conducted. Women of child-bearing potential using hormonal contraceptives are advised to use
an additional safe and effective contraceptive method (see Section 4.4 and 4.6).
Cytochrome P450 enzymes
Rufinamide is metabolised by hydrolysis, and is not metabolised to any notable degree by cytochrome
P450 enzymes. Furthermore, rufinamide does not inhibit the activity of cytochrome P450 enzymes
(see Section 5.2). Thus, clinically significant interactions mediated through inhibition of cytochrome
P450 system by rufinamide are unlikely to occur.
Rufinamide has been shown to induce the
cytochrome P450 enzyme CYP3A4 and may therefore reduce the plasma concentrations of drugs
which are metabolised by this enzyme. The effect was modest to moderate. The mean CYP3A activity,
assessed as clearance of triazolam, was increased by 55% after 11 days of treatment with rufinamide
400 mg b.i.d. The exposure of triazolam was reduced by 36%. Higher rufinamide doses may result in a
more pronounced induction.
It may not be excluded that rufinamide may decrease the exposure also of
drugs metabolized by other enzymes, or transported by transport proteins such as P-glycoprotein.
It is recommended that patients treated with drugs that are metabolised by the CYP3A enzyme system
are to be carefully monitored for two weeks at the start of, or after the end of treatment with Inovelon,
or after any marked change in the dose. A dose adjustment of the concomitantly administered drug
may need to be considered. These recommendations should also be considered when rufinamide is
used concomitantly with drugs with a narrow therapeutic window such as warfarin and digoxin.
A specific interaction study in healthy subjects revealed no influence of rufinamide at a dose of
400 mg bid on the pharmacokinetics of olanzapine, a CYP1A2 substrate.
No data on the interaction of rufinamide with alcohol are available.
Risk related to epilepsy and antiepileptic medicinal products in general:
It has been shown that in the offspring of women with epilepsy, the prevalence of malformations is
two to three times greater than the rate of approximately 3% in the general population. In the treated
population, an increase in malformations has been noted with polytherapy; however, the extent to
which the treatment and/or the illness is responsible has not been elucidated.
Moreover, effective 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 rufinamide:
Studies in animals revealed no teratogenic effect but foetotoxicity in presence of maternal toxicity (see
Section 5.3). The potential risk for humans is unknown.
For rufinamide, no clinical data on exposed pregnancies are available
Taking these data into consideration, rufinamide should not be used during pregnancy unless clearly
necessary and in women of childbearing age not using contraceptive measures.
Women of childbearing potential must use contraceptive measures during treatment with Inovelon.
Physicians should try to ensure that appropriate contraception is used, and should use clinical
5
judgement when assessing whether oral contraceptives, or the doses of the oral contraceptive
components, are adequate based on the individual patients clinical situation (see Section 4.5).
If women treated with rufinamide plan to become pregnant, the indication of this product should be
carefully weighed. During pregnancy, an effective antiepileptic rufinamide treatment must not be
interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.
Is not known if rufinamide is excreted in human breast milk. Due to the potential harmful effects for
the breast fed infant, the lactation should be avoided during maternal treatment with rufinamide.
Inovelon may cause dizziness, somnolence and blurred vision. Depending on the individual
sensitivity, Inovelon may have a mild to severe influence on the ability to drive or use machines.
Patients must be advised to exercise caution during activities requiring a high degree of alertness, e.g.,
driving or operating machinery.
The clinical development program has included over 1,900 patients, with different types of epilepsy,
exposed to rufinamide. The most commonly reported adverse reactions overall were headache,
dizziness, fatigue, and somnolence. The most common adverse reactions observed at a higher
incidence than placebo in patients with Lennox-Gastaut syndrome were somnolence and vomiting.
Adverse reactions were usually mild to moderate in severity. The discontinuation rate in
Lennox-Gastaut syndrome due to adverse reactions was 8.2% for patients receiving Inovelon and 0%
for patients receiving placebo. The most common adverse reactions resulting in discontinuation from
the Inovelon treatment group were rash and vomiting.
Adverse reactions reported with an incidence greater than placebo, during the Lennox-Gastaut
syndrome double-blind studies or in the overall rufinamide-exposed population, are listed in the table
below by MedDRA preferred term, system organ class and by frequency.
Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 < 1/10),
uncommon (≥ 1/1,000 < 1/100).
System Organ
Class
Very Common Common
Uncommon
Rare
I
nfections and
I
nfestations
P
neumonia
I
nfluenza
Nasopharyngitis
E
ar infection
S
inusitis
Rhinitis
Immune system
disorders
Hypersensitivity*
Metabolism and
Nutrition
disorders
Anorexia
Eating disorder
Decreased appetite
P
sychiatric
d
isorders
Anxiety
I
nsomnia
Nervous system
d
isorders
S
omnolence*
S
tatus epilepticus*
Headache
C
onvulsion
Dizziness*
Coordination Abnormal*
6
System Organ
Class
Very Common Common
Uncommon
Rare
Nystagmus
P
sychomotor hyperactivity
Eye Disorders
Tremor
Diplopia
V
ision blurred
Ear and
Labyrinth
disorders
Vertigo
Respiratory,
thoracic and
mediastinal
disorders
Epistaxis
G
astrointestinal
d
isorders
Nausea
Abdominal pain upper
V
omiting
C
onstipation
Dyspepsia
Diarrhoea
Hepato-biliary
d
isorders
Hepatic enzyme
i
ncrease
S
kin and
s
ubcutaneous
tissue disorders
R
ash*
Acne
Musculoskeletal
and connective
tissue and bone
disorders
Back pain
Reproductive
system and
breast disorders
Oligomenorrhoea
General disorders
and
administration
site conditions
Fatigue
Gait disturbance*
I
nvestigations
Weight decrease
I
njury, poisoning
Head injury
Contusion
*Cross refer to Section 4.4.
After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis.
There is no specific antidote for Inovelon. Treatment should be supportive and may include
haemodialysis (see Section 5.2).
Multiple dosing of 7,200 mg/day was associated with no major signs or symptoms.
5.
5.1 Pharmacodynamic properties
7
Pharmacotherapeutic group: anti-epileptics, carboxamide derivatives; ATC-code: N03AF03.
Mechanism of action
Rufinamide modulates the activity of sodium channels, prolonging their inactive state. Rufinamide is
active in a range of animal models of epilepsy.
Clinical experience
Inovelon was administered in a double blind, placebo-controlled study, at doses of up to 45 mg/kg/day
for 84 days, to 139 patients with inadequately controlled seizures associated with Lennox-Gastaut
Syndrome (including both atypical absence seizures and drop attacks).Male or female patients
(between 4 and 30 years of age) were included if they were being treated with 1 to 3 concomitant
fixed-dose antiepileptic drugs. Each patient had to have at least 90 seizures in the month prior to study
entry. A significant improvement was observed for all three primary variables: the percentage change
in total seizure frequency per 28 days during the maintenance phase relative to baseline (-35.8% on
Inovelon vs. –1.6% on placebo, p= 0.0006), the number of tonic-atonic seizures (-42.9% on Inovelon
vs. 2.2% on placebo, p = 0.0002), and the seizure severity rating from the Global Evaluation
performed by the parent/guardian at the end of the double-blind phase (much or very much improved
in 32.2% on Inovelon vs. 14.5% on the placebo arm, p=0.0041).
Population pharmacokinetic/pharmacodynamic modelling demonstrated that the reduction of total and
tonic-atonic seizure frequencies, the improvement of the global evaluation of seizure severity and the
increase in probability of reduction of seizure frequency were dependent on rufinamide
concentrations.
5.2 Pharmacokinetic properties
Absorption
Maximum plasma levels are reached approximately 6 hours after administration. Peak concentration
(C
max
) and plasma AUC of rufinamide increase less than proportionally with doses in both fasted and
fed healthy subjects and in patients, probably due to dose-limited absorption behaviour. After single
doses food increases the bioavailability (AUC) of rufinamide by approximately 34% and the peak
plasma concentration by 56%.
Distribution
In
in-vitro
studies, only a small fraction of rufinamide (34%) was bound to human serum proteins with
albumin accounting for approximately 80% of this binding. This indicates minimal risk of drug-drug
interactions by displacement from binding sites during concomitant administration of other drugs.
Rufinamide was evenly distributed between erythrocytes and plasma.
Biotransformation
Rufinamide is almost exclusively eliminated by metabolism. The main pathway of metabolism is
hydrolysis of the carboxylamide group to the pharmacologically inactive acid derivative CGP 47292.
Cytochrome P450-mediated metabolism is very minor. The formation of small amounts of glutathione
conjugates cannot be completely excluded.
Rufinamide has demonstrated little or no significant capacity
in-vitro
to act as a competitive or
mechanism-based inhibitor of the following human P450 enzymes: CYP1A2, CYP2A6, CYP2C9,
CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 or CYP4A9/11-2.
Elimination
The plasma elimination half-life is approximately 6-10 hours in healthy subjects and patients with
epilepsy. When given twice daily at 12-hourly intervals, rufinamide accumulates to the extent
predicted by its terminal half-life, indicating that the pharmacokinetics of rufinamide are time-
independent (i.e. no autoinduction of metabolism).
8
In a radiotracer study in three healthy volunteers, the parent compound (rufinamide) was the main
radioactive component in plasma, representing about 80% of the total radioactivity, and the metabolite
CGP 47292 constituting only about 15%. Renal excretion was the predominant route of elimination
for drug related material, accounting for 84.7% of the dose.
Linearity/non-linearity:
The bioavailability of rufinamide is dependent on dose. As dose increases the bioavailability
decreases.
Pharmacokinetics in special patient groups
Sex
Population pharmacokinetic modelling has been used to evaluate the influence of sex on the
pharmacokinetics of rufinamide. Such evaluations indicate that sex does not affect the
pharmacokinetics of rufinamide to a clinically relevant extent.
Renal impairment
The pharmacokinetics of a single 400 mg dose of rufinamide were not altered in subjects with chronic
and severe renal failure compared to healthy volunteers. However, plasma levels were reduced by
approximately 30% when haemodialysis was applied after administration of rufinamide, suggesting
that this may be a useful procedure in case of overdose (see Sections 4.2 and 4.9).
Hepatic impairment
No studies have been performed in patients with hepatic impairment and therefore Inovelon should not
be administered to patients with severe hepatic impairment.
Children (2-12 years)
Children generally have lower clearance of rufinamide than adults, and this difference is related to
body size. Studies in new-born infants or infants and toddlers under 2 years of age have not been
conducted.
Elderly
A pharmacokinetic study in elderly healthy volunteers did not show a significant difference in
pharmacokinetic parameters compared with younger adults.
5.3 Preclinical safety data
Conventional safety pharmacology studies revealed no special hazards at clinically relevant doses.
Toxicities observed in dogs at levels similar to human exposure at the maximum recommended dose
were liver changes, including bile thrombi, cholestasis and liver enzyme elevations thought to be
related to increased bile secretion in this species. No evidence of an associated risk was identified in
the rat and monkey repeat dose toxicity studies.
In reproductive and developmental toxicity studies, there were reductions in foetal growth and
survival, and some stillbirths secondary to maternal toxicity. However, no effects on morphology and
function, including learning or memory, were observed in the offspring. Inovelon was not teratogenic
in mice, rats or rabbits.
Rufinamide was not genotoxic and had no carcinogenic potential. Adverse effects not observed in
clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with
possible relevance to human use was myelofibrosis of the bone marrow in the mouse carcinogenicity
study. Benign bone neoplasms (osteomas) and hyperostosis seen in mice were considered a result of
the activation of a mouse specific virus by fluoride ions released during the oxidative metabolism of
rufinamide.
9
Regarding the immunotoxic potential, small thymus and thymic involution were observed in dogs in a
13 week study with significant response at the high dose in male. In the 13 week study, female bone
marrow and lymphoid changes are reported at the high dose with a weak incidence. In rats decreased
cellularity of the bone marrow and thymic atrophy were observed only in the carcinogenicity study.
6.
6.1 List of excipients
Core:
Lactose monohydrate
Cellulose, microcrystalline
Maize starch
Croscarmellose sodium
Hypromellose
Magnesium stearate
Sodium laurilsulfate
Silica colloidal, anhydrous
Film coating:
Opadry 00F44042 [consists of hypromellose, macrogols (8000), titanium dioxide (E171), talc and
ferric oxide red (E172)].
6.2 Incompatibilities
Not applicable
6.3 Shelf life
4 years.
6.4 Special precautions for storage
Do not store above 30ºC.
6.5
Nature and contents of container
100 mg
Aluminium/aluminium blisters, packs of 10, 30, 50, 60 and 100 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Herts, AL10 9SN, UK
8.
EU/1/06/378/001-005
10
9.
16
th
January 2007
11
1.
Inovelon 200 mg film-coated tablets
2.
200 mg
Each film-coated tablet contains 200 mg rufinamide.
Excipient: 40 mg lactose monohydrate/film coated tablet.
For a full list of excipients, see Section 6.1.
3.
Film-coated tablet.
200 mg
Pink, ‘ovaloid’, slightly convex, scored on both sides, embossed ‘Є262’ on one side and blank on the
other side.
The tablet can be divided into equal halves.
4.
Inovelon is indicated as adjunctive therapy in the treatment of seizures associated with
Lennox-Gastaut syndrome in patients 4 years and older.
Treatment with Inovelon should be initiated by a physician specialised in paediatrics or neurology
with experience in the treatment of epilepsy.
Inovelon is for oral use. It should be taken twice daily with water in the morning and in the evening,
in two equally divided doses. As a food effect was observed, it will preferable to administer Inovelon
with food (see Section 5.2). If the patient has difficulty with swallowing, tablets can be crushed and
administered in half a glass of water.
Use in children four years of age or older and less than 30 kg
Patients <30 kg not receiving valproate:
Treatment should be initiated at a daily dose of 200 mg. According to clinical response and
tolerability, the dose may be increased by 200 mg/day increments, as frequently as every two days, up
to a maximum recommended dose of 1000 mg/day. Doses of up to 3600 mg/day have been studied in
a limited number of patients.
Patients <30 kg also receiving valproate medication:
As valproate significantly decreases clearance of Inovelon, a lower maximum dose of Inovelon is
recommended for patients <30 kg being co-administered valproate. Treatment should be initiated at a
daily dose of 200 mg. According to clinical response and tolerability, after a minimum of 2 days the
dose may be increased by 200 mg/day, to the maximum recommended dose of 600 mg/day.
12
Use in adults and children four years of age or older of 30 kg or over
Treatment should be initiated at a daily dose of 400 mg. According to clinical response and
tolerability, the dose may be increased by 400 mg/day increments, as frequently as every two days, up
to a maximum recommended dose as indicated in the table below.
Weight range
30.0 – 50.0 kg
50.1 – 70.0 kg ≥70.1 kg
Maximum
recommended dose
(mg/day)
1800
2400
3200
Doses of up to 4000 mg/day (in the 30-50 kg range) or 4800 mg/day (over 50 kg) have been studied in
a limited number of patients.
Elderly
There is limited information on the use of Inovelon in the elderly. Since, the pharmacokinetics of
rufinamide are not altered in the elderly (see Section 5.2), dosage adjustment is not required in patients
over 65 years of age.
Patients with renal impairment
A study in patients with severe renal impairment indicated that no dose adjustments are required for
these patients (see Section 5.2).
Patients with hepatic impairment
Use in patients with hepatic impairment has not been studied. Caution and careful dose titration is
recommended when treating patients with mild to moderate hepatic impairment. Therefore, use in
patients with severe hepatic impairment is not recommended.
Effect of food
Inovelon should preferably be taken with food (see Section 5.2).
Discontinuation of Inovelon
When Inovelon treatment is to be discontinued, it should be withdrawn gradually. In clinical trials
Inovelon discontinuation was achieved by reducing the dose by approximately 25% every two days.
In the case of one or more missed doses, individualised clinical judgement is necessary.
Uncontrolled open-label studies suggest sustained long-term efficacy, although no controlled study
has been conducted for longer than three months.
Hypersensitivity to the active substance, triazole derivatives or to any excipients.
Status epilepticus cases have been observed during clinical development studies, under rufinamide
whereas no such cases have been observed under placebo. These events led to rufinamide
discontinuation in 20 % of the cases. If patients develop new seizure types and/or experience an
increased frequency of status epilepticus that is different from the patient’s baseline condition, then the
benefit risk ratio of the therapy should be reassessed.
Antiepileptic medicinal products, including Inovelon, should be withdrawn gradually to reduce the
possibility of seizures on withdrawal. In clinical studies discontinuation was achieved by reducing the
dose by approximately 25% every two days. There are insufficient data on the withdrawal of
13
concomitant antiepileptic medicinal products once seizure control has been achieved with the addition
of Inovelon.
Rufinamide treatment has been associated with dizziness, somnolence, ataxia and gait disturbances,
which could increase the occurrence of accidental falls in this population (see Section 4.8). Patients
and carers should exercise caution until they are familiar with the potential effects of this medicinal
product.
Serious antiepileptic drug hypersensitivity syndrome has occurred in association with rufinamide
therapy. Signs and symptoms of this disorder were diverse; however, patients typically, although not
exclusively, presented with fever and rash associated with other organ system involvement. Other
associated manifestations included lymphadenopathy, liver function tests abnormalities, and
haematuria. Because the disorder is variable in its expression, other organ system signs and symptoms
not noted here may occur. This syndrome occurred in close temporal association to the initiation of
rufinamide therapy and in the paediatric population. If this reaction is suspected, rufinamide should be
discontinued and alternative treatment started. All patients who develop a rash while taking
rufinamide must be closely monitored.
In a thorough QT study, rufinamide produced a decrease in QTc interval proportional to concentration.
Although the underlying mechanism and safety relevance of this finding is not known, clinicians
should use clinical judgment when assessing whether to prescribe rufinamide to patients at risk from
further shortening their QTc duration (eg. Congenital Short QT Syndrome or patients with a family
history of such a syndrome).
Women of childbearing potential must use contraceptive measures during treatment with Inovelon.
Physicians should try to ensure that appropriate contraception is used, and should use clinical
judgement when assessing whether oral contraceptives, or the doses of the oral contraceptive
components, are adequate based on the individual patients clinical situation (see Section 4.5).
Inovelon contains lactose, therefore patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Potential for other medicinal products to affect Inovelon
Other anti-epileptic medicinal products
Rufinamide concentrations may be decreased by co-administration with carbamazepine, phenobarbital,
phenytoin, vigabatrin or primidone.
For patients on Inovelon treatment who have administration of valproate initiated, significant increases
in rufinamide plasma concentrations may occur. The most pronounced increases were observed in
patients of low body weight (<30 kg). Therefore, consideration should be given to a dose reduction of
Inovelon in patients <30 kg who are initiated on valproate therapy (see Section 4.2).
The addition or withdrawal of these drugs or adjusting of the dose of these drugs during Inovelon
therapy may require an adjustment in dosage of Inovelon.
No significant changes in rufinamide concentration are observed following co-administration with
lamotrigine, topiramate or benzodiazepines.
Potential for Inovelon to affect other medicinal products
Other anti-epileptic medicinal products
The pharmacokinetic interactions between rufinamide and other anti-epileptic drugs have been
evaluated in patients with epilepsy using population pharmacokinetic modelling. Rufinamide appears
14
not to have clinically relevant effect on carbamazepine, lamotrigine, phenobarbital, topiramate or
valproate steady state concentrations. Since rufinamide may decrease phenytoin clearance and increase
average steady state plasma concentrations of co-administered phenytoin, consideration should be
given to reducing the dose of phenytoin.
Oral contraceptives
Co-administration of rufinamide 800 mg b.i.d. and a combined oral contraceptive (ethinyloestradiol 35
μg and norethindrone 1 mg) for 14 days resulted in a mean decrease in the ethinyl estradiol AUC
0-24
of
22% and in norethindrone AUC
0-24
of 14%. Studies with other oral or implant contraceptives have not
been conducted. Women of child-bearing potential using hormonal contraceptives are advised to use
an additional safe and effective contraceptive method (see Section 4.4 and 4.6).
Cytochrome P450 enzymes
Rufinamide is metabolised by hydrolysis, and is not metabolised to any notable degree by cytochrome
P450 enzymes. Furthermore, rufinamide does not inhibit the activity of cytochrome P450 enzymes
(see Section 5.2). Thus, clinically significant interactions mediated through inhibition of cytochrome
P450 system by rufinamide are unlikely to occur.
Rufinamide has been shown to induce the
cytochrome P450 enzyme CYP3A4 and may therefore reduce the plasma concentrations of drugs
which are metabolised by this enzyme. The effect was modest to moderate. The mean CYP3A activity,
assessed as clearance of triazolam, was increased by 55% after 11 days of treatment with rufinamide
400 mg b.i.d. The exposure of triazolam was reduced by 36%. Higher rufinamide doses may result in a
more pronounced induction.
It may not be excluded that rufinamide may decrease the exposure also of
drugs metabolized by other enzymes, or transported by transport proteins such as P-glycoprotein.
It is recommended that patients treated with drugs that are metabolised by the CYP3A enzyme system
are to be carefully monitored for two weeks at the start of, or after the end of treatment with Inovelon,
or after any marked change in the dose. A dose adjustment of the concomitantly administered drug
may need to be considered. These recommendations should also be considered when rufinamide is
used concomitantly with drugs with a narrow therapeutic window such as warfarin and digoxin.
A specific interaction study in healthy subjects revealed no influence of rufinamide at a dose of
400 mg bid on the pharmacokinetics of olanzapine, a CYP1A2 substrate.
No data on the interaction of rufinamide with alcohol are available.
Risk related to epilepsy and antiepileptic medicinal products in general:
It has been shown that in the offspring of women with epilepsy, the prevalence of malformations is
two to three times greater than the rate of approximately 3% in the general population. In the treated
population, an increase in malformations has been noted with polytherapy; however, the extent to
which the treatment and/or the illness is responsible has not been elucidated.
Moreover, effective 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 rufinamide:
Studies in animals revealed no teratogenic effect but foetotoxicity in presence of maternal toxicity (see
Section 5.3). The potential risk for humans is unknown.
For rufinamide, no clinical data on exposed pregnancies are available
Taking these data into consideration, rufinamide should not be used during pregnancy unless clearly
necessary and in women of childbearing age not using contraceptive measures.
15
Women of childbearing potential must use contraceptive measures during treatment with Inovelon.
Physicians should try to ensure that appropriate contraception is used, and should use clinical
judgement when assessing whether oral contraceptives, or the doses of the oral contraceptive
components, are adequate based on the individual patients clinical situation (see Section 4.5).
If women treated with rufinamide plan to become pregnant, the indication of this product should be
carefully weighed. During pregnancy, an effective antiepileptic rufinamide treatment must not be
interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.
Is not known if rufinamide is excreted in human breast milk. Due to the potential harmful effects for
the breast fed infant, the lactation should be avoided during maternal treatment with rufinamide.
Inovelon may cause dizziness, somnolence and blurred vision. Depending on the individual
sensitivity, Inovelon may have a mild to severe influence on the ability to drive or use machines.
Patients must be advised to exercise caution during activities requiring a high degree of alertness, e.g.,
driving or operating machinery.
The clinical development program has included over 1,900 patients, with different types of epilepsy,
exposed to rufinamide. The most commonly reported adverse reactions overall were headache,
dizziness, fatigue, and somnolence. The most common adverse reactions observed at a higher
incidence than placebo in patients with Lennox-Gastaut syndrome were somnolence and vomiting.
Adverse reactions were usually mild to moderate in severity. The discontinuation rate in
Lennox-Gastaut syndrome due to adverse reactions was 8.2% for patients receiving Inovelon and 0%
for patients receiving placebo. The most common adverse reactions resulting in discontinuation from
the Inovelon treatment group were rash and vomiting.
Adverse reactions reported with an incidence greater than placebo, during the Lennox-Gastaut
syndrome double-blind studies or in the overall rufinamide-exposed population, are listed in the table
below by MedDRA preferred term, system organ class and by frequency.
Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 < 1/10),
uncommon (≥ 1/1,000 < 1/100).
16
System Organ
Class
Very Common Common
Uncommon
Rare
I
nfections and
I
nfestations
P
neumonia
I
nfluenza
Nasopharyngitis
E
ar infection
S
inusitis
Rhinitis
Immune system
disorders
Hypersensitivity*
Metabolism and
Nutrition
disorders
Anorexia
Eating disorder
Decreased appetite
P
sychiatric
d
isorders
Anxiety
I
nsomnia
Nervous system
d
isorders
S
omnolence*
S
tatus epilepticus*
Headache
C
onvulsion
Dizziness*
C
oordination Abnormal*
Nystagmus
P
sychomotor hyperactivity
Tremor
Eye Disorders
Diplopia
V
ision blurred
Ear and
Labyrinth
d
isorders
Vertigo
Respiratory,
thoracic and
mediastinal
d
isorders
Epistaxis
G
astrointestinal
d
isorders
Nausea
Abdominal pain upper
V
omiting
C
onstipation
Dyspepsia
Diarrhoea
Hepato-biliary
d
isorders
Hepatic enzyme
i
ncrease
S
kin and
s
ubcutaneous
tissue disorders
R
ash*
Acne
Musculoskeletal
and connective
tissue and bone
disorders
Back pain
Reproductive
system and
breast disorders
Oligomenorrhoea
17
System Organ
Class
Very Common Common
Uncommon
Rare
General disorders
and
administration
s
ite conditions
Fatigue
Gait disturbance*
I
nvestigations
Weight decrease
I
njury, poisoning
Head injury
Contusion
*Cross refer to Section 4.4.
After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis.
There is no specific antidote for Inovelon. Treatment should be supportive and may include
haemodialysis (see Section 5.2).
Multiple dosing of 7,200 mg/day was associated with no major signs or symptoms.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-epileptics, carboxamide derivatives; ATC-code: N03AF03.
Mechanism of action
Rufinamide modulates the activity of sodium channels, prolonging their inactive state. Rufinamide is
active in a range of animal models of epilepsy.
Clinical experience
Inovelon was administered in a double blind, placebo-controlled study, at doses of up to 45 mg/kg/day
for 84 days, to 139 patients with inadequately controlled seizures associated with Lennox-Gastaut
Syndrome (including both atypical absence seizures and drop attacks).Male or female patients
(between 4 and 30 years of age) were included if they were being treated with 1 to 3 concomitant
fixed-dose antiepileptic drugs. Each patient had to have at least 90 seizures in the month prior to study
entry. A significant improvement was observed for all three primary variables: the percentage change
in total seizure frequency per 28 days during the maintenance phase relative to baseline (-35.8% on
Inovelon vs. –1.6% on placebo, p= 0.0006), the number of tonic-atonic seizures (-42.9% on Inovelon
vs. 2.2% on placebo, p = 0.0002), and the seizure severity rating from the Global Evaluation
performed by the parent/guardian at the end of the double-blind phase (much or very much improved
in 32.2% on Inovelon vs. 14.5% on the placebo arm, p=0.0041).
Population pharmacokinetic/pharmacodynamic modelling demonstrated that the reduction of total and
tonic-atonic seizure frequencies, the improvement of the global evaluation of seizure severity and the
increase in probability of reduction of seizure frequency were dependent on rufinamide
concentrations.
5.2 Pharmacokinetic properties
Absorption
Maximum plasma levels are reached approximately 6 hours after administration. Peak concentration
(C
max
) and plasma AUC of rufinamide increase less than proportionally with doses in both fasted and
fed healthy subjects and in patients, probably due to dose-limited absorption behaviour. After single
18
doses food increases the bioavailability (AUC) of rufinamide by approximately 34% and the peak
plasma concentration by 56%.
Distribution
In
in-vitro
studies, only a small fraction of rufinamide (34%) was bound to human serum proteins with
albumin accounting for approximately 80% of this binding. This indicates minimal risk of drug-drug
interactions by displacement from binding sites during concomitant administration of other drugs.
Rufinamide was evenly distributed between erythrocytes and plasma.
Biotransformation
Rufinamide is almost exclusively eliminated by metabolism. The main pathway of metabolism is
hydrolysis of the carboxylamide group to the pharmacologically inactive acid derivative CGP 47292.
Cytochrome P450-mediated metabolism is very minor. The formation of small amounts of glutathione
conjugates cannot be completely excluded.
Rufinamide has demonstrated little or no significant capacity
in-vitro
to act as a competitive or
mechanism-based inhibitor of the following human P450 enzymes: CYP1A2, CYP2A6, CYP2C9,
CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 or CYP4A9/11-2.
Elimination
The plasma elimination half-life is approximately 6-10 hours in healthy subjects and patients with
epilepsy. When given twice daily at 12-hourly intervals, rufinamide accumulates to the extent
predicted by its terminal half-life, indicating that the pharmacokinetics of rufinamide are time-
independent (i.e. no autoinduction of metabolism).
In a radiotracer study in three healthy volunteers, the parent compound (rufinamide) was the main
radioactive component in plasma, representing about 80% of the total radioactivity, and the metabolite
CGP 47292 constituting only about 15%. Renal excretion was the predominant route of elimination
for drug related material, accounting for 84.7% of the dose.
Linearity/non-linearity:
The bioavailability of rufinamide is dependent on dose. As dose increases the bioavailability
decreases.
Pharmacokinetics in special patient groups
Sex
Population pharmacokinetic modelling has been used to evaluate the influence of sex on the
pharmacokinetics of rufinamide. Such evaluations indicate that sex does not affect the
pharmacokinetics of rufinamide to a clinically relevant extent.
Renal impairment
The pharmacokinetics of a single 400 mg dose of rufinamide were not altered in subjects with chronic
and severe renal failure compared to healthy volunteers. However, plasma levels were reduced by
approximately 30% when haemodialysis was applied after administration of rufinamide, suggesting
that this may be a useful procedure in case of overdose (see Sections 4.2 and 4.9).
Hepatic impairment
No studies have been performed in patients with hepatic impairment and therefore Inovelon should not
be administered to patients with severe hepatic impairment.
Children (2-12 years)
Children generally have lower clearance of rufinamide than adults, and this difference is related to
body size. Studies in new-born infants or infants and toddlers under 2 years of age have not been
conducted.
19
Elderly
A pharmacokinetic study in elderly healthy volunteers did not show a significant difference in
pharmacokinetic parameters compared with younger adults.
5.3 Preclinical safety data
Conventional safety pharmacology studies revealed no special hazards at clinically relevant doses.
Toxicities observed in dogs at levels similar to human exposure at the maximum recommended dose
were liver changes, including bile thrombi, cholestasis and liver enzyme elevations thought to be
related to increased bile secretion in this species. No evidence of an associated risk was identified in
the rat and monkey repeat dose toxicity studies.
In reproductive and developmental toxicity studies, there were reductions in foetal growth and
survival, and some stillbirths secondary to maternal toxicity. However, no effects on morphology and
function, including learning or memory, were observed in the offspring. Inovelon was not teratogenic
in mice, rats or rabbits.
Rufinamide was not genotoxic and had no carcinogenic potential. Adverse effects not observed in
clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with
possible relevance to human use was myelofibrosis of the bone marrow in the mouse carcinogenicity
study. Benign bone neoplasms (osteomas) and hyperostosis seen in mice were considered a result of
the activation of a mouse specific virus by fluoride ions released during the oxidative metabolism of
rufinamide.
Regarding the immunotoxic potential, small thymus and thymic involution were observed in dogs in a
13 week study with significant response at the high dose in male. In the 13 week study, female bone
marrow and lymphoid changes are reported at the high dose with a weak incidence. In rats decreased
cellularity of the bone marrow and thymic atrophy were observed only in the carcinogenicity study.
6.
6.1 List of excipients
Core:
Lactose monohydrate
Cellulose, microcrystalline
Maize starch
Croscarmellose sodium
Hypromellose
Magnesium stearate
Sodium laurilsulfate
Silica colloidal, anhydrous
Film coating:
Opadry 00F44042 [consists of hypromellose, macrogols (8000), titanium dioxide (E171), talc and
ferric oxide red (E172)].
6.2 Incompatibilities
Not applicable
6.3 Shelf life
4 years.
20
6.4 Special precautions for storage
Do not store above 30ºC.
6.5
Nature and contents of container
200 mg
Aluminium/aluminium blisters, packs of 10, 30, 50, 60 and 100 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Herts, AL10 9SN, UK
8.
EU/1/06/378/006-010
9.
16
th
January 2007
21
1.
Inovelon 400 mg film-coated tablets
2.
400 mg
Each film-coated tablet contains 400 mg rufinamide.
Excipient: 80 mg lactose monohydrate/film coated tablet.
For a full list of excipients, see Section 6.1.
3.
Film-coated tablet.
400 mg
Pink, ‘ovaloid’, slightly convex, scored on both sides, embossed ‘Є263’ on one side and blank on the
other side.
The tablet can be divided into equal halves.
4.
Inovelon is indicated as adjunctive therapy in the treatment of seizures associated with
Lennox-Gastaut syndrome in patients 4 years and older.
Treatment with Inovelon should be initiated by a physician specialised in paediatrics or neurology
with experience in the treatment of epilepsy.
Inovelon is for oral use. It should be taken twice daily with water in the morning and in the evening,
in two equally divided doses. As a food effect was observed, it will preferable to administer Inovelon
with food (see Section 5.2). If the patient has difficulty with swallowing, tablets can be crushed and
administered in half a glass of water.
Use in children four years of age or older and less than 30 kg
Patients <30 kg not receiving valproate:
Treatment should be initiated at a daily dose of 200 mg. According to clinical response and
tolerability, the dose may be increased by 200 mg/day increments, as frequently as every two days, up
to a maximum recommended dose of 1000 mg/day. Doses of up to 3600 mg/day have been studied in
a limited number of patients.
Patients <30 kg also receiving valproate medication:
As valproate significantly decreases clearance of Inovelon, a lower maximum dose of Inovelon is
recommended for patients <30 kg being co-administered valproate. Treatment should be initiated at a
daily dose of 200 mg. According to clinical response and tolerability, after a minimum of 2 days the
dose may be increased by 200 mg/day, to the maximum recommended dose of 600 mg/day.
22
Use in adults and children four years of age or older of 30 kg or over
Treatment should be initiated at a daily dose of 400 mg. According to clinical response and
tolerability, the dose may be increased by 400 mg/day increments, as frequently as every two days, up
to a maximum recommended dose as indicated in the table below.
Weight range
30.0 – 50.0 kg
50.1 – 70.0 kg ≥70.1 kg
Maximum
recommended dose
(mg/day)
1800
2400
3200
Doses of up to 4000 mg/day (in the 30-50 kg range) or 4800 mg/day (over 50 kg) have been studied in
a limited number of patients.
Elderly
There is limited information on the use of Inovelon in the elderly. Since, the pharmacokinetics of
rufinamide are not altered in the elderly (see Section 5.2), dosage adjustment is not required in patients
over 65 years of age.
Patients with renal impairment
A study in patients with severe renal impairment indicated that no dose adjustments are required for
these patients (see Section 5.2).
Patients with hepatic impairment
Use in patients with hepatic impairment has not been studied. Caution and careful dose titration is
recommended when treating patients with mild to moderate hepatic impairment. Therefore, use in
patients with severe hepatic impairment is not recommended.
Effect of food
Inovelon should preferably be taken with food (see Section 5.2).
Discontinuation of Inovelon
When Inovelon treatment is to be discontinued, it should be withdrawn gradually. In clinical trials
Inovelon discontinuation was achieved by reducing the dose by approximately 25% every two days.
In the case of one or more missed doses, individualised clinical judgement is necessary.
Uncontrolled open-label studies suggest sustained long-term efficacy, although no controlled study
has been conducted for longer than three months.
Hypersensitivity to the active substance, triazole derivatives or to any excipients.
Status epilepticus cases have been observed during clinical development studies, under rufinamide
whereas no such cases have been observed under placebo. These events led to rufinamide
discontinuation in 20 % of the cases. If patients develop new seizure types and/or experience an
increased frequency of status epilepticus that is different from the patient’s baseline condition, then the
benefit risk ratio of the therapy should be reassessed.
Antiepileptic medicinal products, including Inovelon, should be withdrawn gradually to reduce the
possibility of seizures on withdrawal. In clinical studies discontinuation was achieved by reducing the
dose by approximately 25% every two days. There are insufficient data on the withdrawal of
concomitant antiepileptic medicinal products once seizure control has been achieved with the addition
of Inovelon.
23
Rufinamide treatment has been associated with dizziness, somnolence, ataxia and gait disturbances,
which could increase the occurrence of accidental falls in this population (see Section 4.8). Patients
and carers should exercise caution until they are familiar with the potential effects of this medicinal
product.
Serious antiepileptic drug hypersensitivity syndrome has occurred in association with rufinamide
therapy. Signs and symptoms of this disorder were diverse; however, patients typically, although not
exclusively, presented with fever and rash associated with other organ system involvement. Other
associated manifestations included lymphadenopathy, liver function tests abnormalities, and
haematuria. Because the disorder is variable in its expression, other organ system signs and symptoms
not noted here may occur. This syndrome occurred in close temporal association to the initiation of
rufinamide therapy and in the paediatric population. If this reaction is suspected, rufinamide should be
discontinued and alternative treatment started. All patients who develop a rash while taking
rufinamide must be closely monitored.
In a thorough QT study, rufinamide produced a decrease in QTc interval proportional to concentration.
Although the underlying mechanism and safety relevance of this finding is not known, clinicians
should use clinical judgment when assessing whether to prescribe rufinamide to patients at risk from
further shortening their QTc duration (eg. Congenital Short QT Syndrome or patients with a family
history of such a syndrome).
Women of childbearing potential must use contraceptive measures during treatment with Inovelon.
Physicians should try to ensure that appropriate contraception is used, and should use clinical
judgement when assessing whether oral contraceptives, or the doses of the oral contraceptive
components, are adequate based on the individual patients clinical situation (see Section 4.5).
Inovelon contains lactose, therefore patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Potential for other medicinal products to affect Inovelon
Other anti-epileptic medicinal products
Rufinamide concentrations may be decreased by co-administration with carbamazepine, phenobarbital,
phenytoin, vigabatrin or primidone.
For patients on Inovelon treatment who have administration of valproate initiated, significant increases
in rufinamide plasma concentrations may occur. The most pronounced increases were observed in
patients of low body weight (<30 kg). Therefore, consideration should be given to a dose reduction of
Inovelon in patients <30 kg who are initiated on valproate therapy (see Section 4.2).
The addition or withdrawal of these drugs or adjusting of the dose of these drugs during Inovelon
therapy may require an adjustment in dosage of Inovelon.
No significant changes in rufinamide concentration are observed following co-administration with
lamotrigine, topiramate or benzodiazepines.
Potential for Inovelon to affect other medicinal products
Other anti-epileptic medicinal products
The pharmacokinetic interactions between rufinamide and other anti-epileptic drugs have been
evaluated in patients with epilepsy using population pharmacokinetic modelling. Rufinamide appears
not to have clinically relevant effect on carbamazepine, lamotrigine, phenobarbital, topiramate or
valproate steady state concentrations. Since rufinamide may decrease phenytoin clearance and increase
24
average steady state plasma concentrations of co-administered phenytoin, consideration should be
given to reducing the dose of phenytoin.
Oral contraceptives
Co-administration of rufinamide 800 mg b.i.d. and a combined oral contraceptive (ethinyloestradiol 35
μg and norethindrone 1 mg) for 14 days resulted in a mean decrease in the ethinyl estradiol AUC
0-24
of
22% and in norethindrone AUC
0-24
of 14%. Studies with other oral or implant contraceptives have not
been conducted. Women of child-bearing potential using hormonal contraceptives are advised to use
an additional safe and effective contraceptive method (see Section 4.4 and 4.6).
Cytochrome P450 enzymes
Rufinamide is metabolised by hydrolysis, and is not metabolised to any notable degree by cytochrome
P450 enzymes. Furthermore, rufinamide does not inhibit the activity of cytochrome P450 enzymes
(see Section 5.2). Thus, clinically significant interactions mediated through inhibition of cytochrome
P450 system by rufinamide are unlikely to occur.
Rufinamide has been shown to induce the
cytochrome P450 enzyme CYP3A4 and may therefore reduce the plasma concentrations of drugs
which are metabolised by this enzyme. The effect was modest to moderate. The mean CYP3A activity,
assessed as clearance of triazolam, was increased by 55% after 11 days of treatment with rufinamide
400 mg b.i.d. The exposure of triazolam was reduced by 36%. Higher rufinamide doses may result in a
more pronounced induction.
It may not be excluded that rufinamide may decrease the exposure also of
drugs metabolized by other enzymes, or transported by transport proteins such as P-glycoprotein.
It is recommended that patients treated with drugs that are metabolised by the CYP3A enzyme system
are to be carefully monitored for two weeks at the start of, or after the end of treatment with Inovelon,
or after any marked change in the dose. A dose adjustment of the concomitantly administered drug
may need to be considered. These recommendations should also be considered when rufinamide is
used concomitantly with drugs with a narrow therapeutic window such as warfarin and digoxin.
A specific interaction study in healthy subjects revealed no influence of rufinamide at a dose of
400 mg bid on the pharmacokinetics of olanzapine, a CYP1A2 substrate.
No data on the interaction of rufinamide with alcohol are available.
Risk related to epilepsy and antiepileptic medicinal products in general:
It has been shown that in the offspring of women with epilepsy, the prevalence of malformations is
two to three times greater than the rate of approximately 3% in the general population. In the treated
population, an increase in malformations has been noted with polytherapy; however, the extent to
which the treatment and/or the illness is responsible has not been elucidated.
Moreover, effective 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 rufinamide:
Studies in animals revealed no teratogenic effect but foetotoxicity in presence of maternal toxicity (see
Section 5.3). The potential risk for humans is unknown.
For rufinamide, no clinical data on exposed pregnancies are available
Taking these data into consideration, rufinamide should not be used during pregnancy unless clearly
necessary and in women of childbearing age not using contraceptive measures.
25
Women of childbearing potential must use contraceptive measures during treatment with Inovelon.
Physicians should try to ensure that appropriate contraception is used, and should use clinical
judgement when assessing whether oral contraceptives, or the doses of the oral contraceptive
components, are adequate based on the individual patients clinical situation (see Section 4.5).
If women treated with rufinamide plan to become pregnant, the indication of this product should be
carefully weighed. During pregnancy, an effective antiepileptic rufinamide treatment must not be
interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.
Is not known if rufinamide is excreted in human breast milk. Due to the potential harmful effects for
the breast fed infant, the lactation should be avoided during maternal treatment with rufinamide.
Inovelon may cause dizziness, somnolence and blurred vision. Depending on the individual
sensitivity, Inovelon may have a mild to severe influence on the ability to drive or use machines.
Patients must be advised to exercise caution during activities requiring a high degree of alertness, e.g.,
driving or operating machinery.
The clinical development program has included over 1,900 patients, with different types of epilepsy,
exposed to rufinamide. The most commonly reported adverse reactions overall were headache,
dizziness, fatigue, and somnolence. The most common adverse reactions observed at a higher
incidence than placebo in patients with Lennox-Gastaut syndrome were somnolence and vomiting.
Adverse reactions were usually mild to moderate in severity. The discontinuation rate in
Lennox-Gastaut syndrome due to adverse reactions was 8.2% for patients receiving Inovelon and 0%
for patients receiving placebo. The most common adverse reactions resulting in discontinuation from
the Inovelon treatment group were rash and vomiting.
Adverse reactions reported with an incidence greater than placebo, during the Lennox-Gastaut
syndrome double-blind studies or in the overall rufinamide-exposed population, are listed in the table
below by MedDRA preferred term, system organ class and by frequency.
Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 < 1/10),
uncommon (≥ 1/1,000 < 1/100).
26
System Organ
Class
Very Common Common
Uncommon
Rare
I
nfections and
I
nfestations
P
neumonia
I
nfluenza
Nasopharyngitis
E
ar infection
S
inusitis
Rhinitis
Immune system
disorders
Hypersensitivity*
Metabolism and
Nutrition
disorders
Anorexia
Eating disorder
Decreased appetite
P
sychiatric
d
isorders
Anxiety
I
nsomnia
Nervous system
d
isorders
S
omnolence*
S
tatus epilepticus*
Headache
C
onvulsion
Dizziness*
C
oordination Abnormal*
Nystagmus
P
sychomotor hyperactivity
Tremor
Eye Disorders
Diplopia
V
ision blurred
Ear and
Labyrinth
d
isorders
Vertigo
Respiratory,
thoracic and
mediastinal
d
isorders
Epistaxis
G
astrointestinal
d
isorders
Nausea
Abdominal pain upper
V
omiting
C
onstipation
Dyspepsia
Diarrhoea
Hepato-biliary
d
isorders
Hepatic enzyme
i
ncrease
S
kin and
s
ubcutaneous
tissue disorders
R
ash*
Acne
Musculoskeletal
and connective
tissue and bone
disorders
Back pain
Reproductive
system and
breast disorders
Oligomenorrhoea
27
System Organ
Class
Very Common Common
Uncommon
Rare
General disorders
and
administration
s
ite conditions
Fatigue
Gait disturbance*
I
nvestigations
Weight decrease
I
njury, poisoning
Head injury
Contusion
*Cross refer to Section 4.4.
After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis.
There is no specific antidote for Inovelon. Treatment should be supportive and may include
haemodialysis (see Section 5.2).
Multiple dosing of 7,200 mg/day was associated with no major signs or symptoms.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-epileptics, carboxamide derivatives; ATC-code: N03AF03.
Mechanism of action
Rufinamide modulates the activity of sodium channels, prolonging their inactive state. Rufinamide is
active in a range of animal models of epilepsy.
Clinical experience
Inovelon was administered in a double blind, placebo-controlled study, at doses of up to 45 mg/kg/day
for 84 days, to 139 patients with inadequately controlled seizures associated with Lennox-Gastaut
Syndrome (including both atypical absence seizures and drop attacks).Male or female patients
(between 4 and 30 years of age) were included if they were being treated with 1 to 3 concomitant
fixed-dose antiepileptic drugs. Each patient had to have at least 90 seizures in the month prior to study
entry. A significant improvement was observed for all three primary variables: the percentage change
in total seizure frequency per 28 days during the maintenance phase relative to baseline (-35.8% on
Inovelon vs. –1.6% on placebo, p= 0.0006), the number of tonic-atonic seizures (-42.9% on Inovelon
vs. 2.2% on placebo, p = 0.0002), and the seizure severity rating from the Global Evaluation
performed by the parent/guardian at the end of the double-blind phase (much or very much improved
in 32.2% on Inovelon vs. 14.5% on the placebo arm, p=0.0041).
Population pharmacokinetic/pharmacodynamic modelling demonstrated that the reduction of total and
tonic-atonic seizure frequencies, the improvement of the global evaluation of seizure severity and the
increase in probability of reduction of seizure frequency were dependent on rufinamide
concentrations.
5.2 Pharmacokinetic properties
Absorption
Maximum plasma levels are reached approximately 6 hours after administration. Peak concentration
(C
max
) and plasma AUC of rufinamide increase less than proportionally with doses in both fasted and
fed healthy subjects and in patients, probably due to dose-limited absorption behaviour. After single
28
doses food increases the bioavailability (AUC) of rufinamide by approximately 34% and the peak
plasma concentration by 56%.
Distribution
In
in-vitro
studies, only a small fraction of rufinamide (34%) was bound to human serum proteins with
albumin accounting for approximately 80% of this binding. This indicates minimal risk of drug-drug
interactions by displacement from binding sites during concomitant administration of other drugs.
Rufinamide was evenly distributed between erythrocytes and plasma.
Biotransformation
Rufinamide is almost exclusively eliminated by metabolism. The main pathway of metabolism is
hydrolysis of the carboxylamide group to the pharmacologically inactive acid derivative CGP 47292.
Cytochrome P450-mediated metabolism is very minor. The formation of small amounts of glutathione
conjugates cannot be completely excluded.
Rufinamide has demonstrated little or no significant capacity
in-vitro
to act as a competitive or
mechanism-based inhibitor of the following human P450 enzymes: CYP1A2, CYP2A6, CYP2C9,
CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 or CYP4A9/11-2.
Elimination
The plasma elimination half-life is approximately 6-10 hours in healthy subjects and patients with
epilepsy. When given twice daily at 12-hourly intervals, rufinamide accumulates to the extent
predicted by its terminal half-life, indicating that the pharmacokinetics of rufinamide are time-
independent (i.e. no autoinduction of metabolism).
In a radiotracer study in three healthy volunteers, the parent compound (rufinamide) was the main
radioactive component in plasma, representing about 80% of the total radioactivity, and the metabolite
CGP 47292 constituting only about 15%. Renal excretion was the predominant route of elimination
for drug related material, accounting for 84.7% of the dose.
Linearity/non-linearity:
The bioavailability of rufinamide is dependent on dose. As dose increases the bioavailability
decreases.
Pharmacokinetics in special patient groups
Sex
Population pharmacokinetic modelling has been used to evaluate the influence of sex on the
pharmacokinetics of rufinamide. Such evaluations indicate that sex does not affect the
pharmacokinetics of rufinamide to a clinically relevant extent.
Renal impairment
The pharmacokinetics of a single 400 mg dose of rufinamide were not altered in subjects with chronic
and severe renal failure compared to healthy volunteers. However, plasma levels were reduced by
approximately 30% when haemodialysis was applied after administration of rufinamide, suggesting
that this may be a useful procedure in case of overdose (see Sections 4.2 and 4.9).
Hepatic impairment
No studies have been performed in patients with hepatic impairment and therefore Inovelon should not
be administered to patients with severe hepatic impairment.
Children (2-12 years)
Children generally have lower clearance of rufinamide than adults, and this difference is related to
body size. Studies in new-born infants or infants and toddlers under 2 years of age have not been
conducted.
29
Elderly
A pharmacokinetic study in elderly healthy volunteers did not show a significant difference in
pharmacokinetic parameters compared with younger adults.
5.3 Preclinical safety data
Conventional safety pharmacology studies revealed no special hazards at clinically relevant doses.
Toxicities observed in dogs at levels similar to human exposure at the maximum recommended dose
were liver changes, including bile thrombi, cholestasis and liver enzyme elevations thought to be
related to increased bile secretion in this species. No evidence of an associated risk was identified in
the rat and monkey repeat dose toxicity studies.
In reproductive and developmental toxicity studies, there were reductions in foetal growth and
survival, and some stillbirths secondary to maternal toxicity. However, no effects on morphology and
function, including learning or memory, were observed in the offspring. Inovelon was not teratogenic
in mice, rats or rabbits.
Rufinamide was not genotoxic and had no carcinogenic potential. Adverse effects not observed in
clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with
possible relevance to human use was myelofibrosis of the bone marrow in the mouse carcinogenicity
study. Benign bone neoplasms (osteomas) and hyperostosis seen in mice were considered a result of
the activation of a mouse specific virus by fluoride ions released during the oxidative metabolism of
rufinamide.
Regarding the immunotoxic potential, small thymus and thymic involution were observed in dogs in a
13 week study with significant response at the high dose in male. In the 13 week study, female bone
marrow and lymphoid changes are reported at the high dose with a weak incidence. In rats decreased
cellularity of the bone marrow and thymic atrophy were observed only in the carcinogenicity study.
6.
6.1 List of excipients
Core:
Lactose monohydrate
Cellulose, microcrystalline
Maize starch
Croscarmellose sodium
Hypromellose
Magnesium stearate
Sodium laurilsulfate
Silica colloidal, anhydrous
Film coating:
Opadry 00F44042 [consists of hypromellose, macrogols (8000), titanium dioxide (E171), talc and
ferric oxide red (E172)].
6.2 Incompatibilities
Not applicable
6.3 Shelf life
4 years.
30
6.4 Special precautions for storage
Do not store above 30ºC.
6.5 Nature and contents of container
400 mg
Aluminium/aluminium blisters, packs of 10, 30, 50, 60, 100 and 200 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Herts, AL10 9SN, UK
8.
EU/1/06/378/011-016
9.
16
th
January 2007
31
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
32
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Eisai Manufacturing Limited
Mosquito Way
Hatfield
Herts
AL10 9SN
United Kingdom
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
The MAH must ensure that the system of pharmacovigilance is in place and functioning before the
product is placed on the market.
The MAH commits to performing a post-marketing safety study (registry) and additional
pharmacovigilance activities detailed in the Pharmacovigilance Plan.
An updated Risk Management Plan should be provided as per the CHMP Guideline on Risk
Management Systems for medicinal products for human use.
33
ANNEX III
LABELLING AND PACKAGE LEAFLET
34
A. LABELLING
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Inovelon 100 mg film-coated tablets
Rufinamide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 100 mg rufinamide
3.
LIST OF EXCIPIENTS
Contains lactose. See leaflet for further information.
4.
10
10 film-coated tablets
30
30 film-coated tablets
50
50 film-coated tablets
60
60 film-coated tablets
100
100 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral Use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP (MM/YYYY)
36
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30ºC
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Eisai Ltd., Mosquito Way, Hatfield, Herts, AL10 9SN, UK
EU/1/06/378/001-005
13. BATCH NUMBER
Lot: {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Inovelon 100 mg tablets
37
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Inovelon 100 mg film-coated tablets
Rufinamide
2.
Eisai Ltd.
3.
EXPIRY DATE
EXP: {MM/YYYY}
4.
BATCH NUMBER
Lot: {number}
5.
OTHER
38
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Inovelon 200 mg film-coated tablets
Rufinamide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 200 mg rufinamide
3.
LIST OF EXCIPIENTS
Contains lactose. See leaflet for further information.
4.
10
10 film-coated tablets
30
30 film-coated tablets
50
50 film-coated tablets
60
60 film-coated tablets
100
100 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Oral use.
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP (MM/YYYY)
39
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30ºC
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Eisai Ltd., Mosquito Way, Hatfield, Herts, AL10 9SN, UK
EU/1/06/378/006-010
13. BATCH NUMBER
Lot: {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Inovelon 200 mg tablets
40
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Inovelon 200 mg film-coated tablets
Rufinamide
2.
Eisai Ltd.
3.
EXPIRY DATE
EXP: {MM/YYYY}
4.
BATCH NUMBER
Lot: {number}
5.
OTHER
41
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Inovelon 400 mg film-coated tablets
Rufinamide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 400 mg rufinamide
3.
LIST OF EXCIPIENTS
Contains lactose. See leaflet for further information.
4.
10
10 film-coated tablets
30
30 film-coated tablets
50
50 film-coated tablets
60
60 film-coated tablets
100
100 film-coated tablets
200
200 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral Use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
42
8.
EXPIRY DATE
EXP (MM/YYYY)
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30ºC
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Eisai Ltd., Mosquito Way, Hatfield, Herts, AL10 9SN, UK
EU/1/06/378/011-016
13. BATCH NUMBER
Lot: {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Inovelon 400 mg tablets
43
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Inovelon 400 mg film-coated tablets
Rufinamide
2.
Eisai Ltd.
3.
EXPIRY DATE
EXP: {MM/YYYY}
4.
BATCH NUMBER
Lot: {number}
5.
OTHER
44
B. PACKAGE LEAFLET
45
PACKAGE LEAFLET: INFORMATION FOR THE USER
Inovelon 100 mg film-coated tablets
Inovelon 200 mg film-coated tablets
Inovelon 400 mg film-coated tablets
Rufinamide
Read all of this leaflet carefully before you start taking this medicine
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Inovelon is and what it is used for
2. Before you take Inovelon
3. How to take Inovelon
4. Possible side effects
5.
How to store Inovelon
6.
Further information
1.
WHAT INOVELON IS AND WHAT IT IS USED FOR
Inovelon contains rufinamide, which is an antiepileptic medicine. It is used to treat seizures associated
with Lennox-Gastaut syndrome.
2.
BEFORE YOU TAKE INOVELON
Do not take Inovelon
- if you are allergic (hypersensitive) to rufinamide or any of the other ingredients of Inovelon and
triazole derivatives.
Take special care with Inovelon
-
if you suffer from liver problems, because there is limited information on the use of Inovelon in
this group and the dose of your medicine may need to be increased more slowly.
-
if you get a skin rash. See your doctor immediately as very occasionally this may become serious.
-
if you suffer an increase in the number or severity or duration of your seizures, you should contact
your doctor immediately.
-
if you experience dizziness or sleepiness inform your doctor.
Please consult your doctor, even if these statements were applicable to you at any time in the past.
46
-
If you have any further questions, ask your doctor or pharmacist.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
If your doctor prescribes or recommends an additional treatment for epilepsy (e.g. valproate) you must
tell him you are taking Inovelon as your dose may need adjusting.
Taking Inovelon with food and drink
Inovelon should preferably be taken with food. As a precaution, do not take Inovelon with alcohol.
Pregnancy and breast-feeding
If you are a woman of childbearing age, you must use contraceptive measures while taking Inovelon.
If you are pregnant, or think you might be pregnant, or are planning to get pregnant, tell your doctor.
You must only take Inovelon during your pregnancy if your doctor tells you to.
You must not breast-feed while taking Inovelon.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Do not drive or operate machinery if you feel drowsy, dizzy or experience blurred vision whilst taking
this medicine. Be particularly careful at the start of treatment or after your dose is increased.
Important information about some of the ingredients of Inovelon
Inovelon contains lactose. If you have been told by your doctor that you have an intolerance to some
sugars, contact your doctor before taking this medicinal product.
3.
HOW TO TAKE INOVELON
Always take Inovelon exactly as your doctor has told you. You must check with your doctor or
pharmacist if you are not sure.
Inovelon tablets must be taken twice daily with water, in the morning and in the evening. Inovelon can
be taken with food. If you have difficulty swallowing, you can crush the tablet. Then mix the powder
in about half a glass (100 ml) of water and drink immediately.
The usual starting dose in children weighing less than 30 kg is 200 mg a day taken in two doses. The
dose will be adjusted for you by your doctor and may be increased by 200 mg at intervals of two days,
to a daily dose of no more than 1000 mg.
The usual starting dose in adults and children weighing 30 kg or over is 400 mg a day taken in two
doses. The dose will be adjusted for you by your doctor and may be increased by 400 mg at intervals
of two days, to a daily dose of no more than 3200 mg, depending upon your weight.
Some patients may respond to lower doses. The dose may be increased more slowly if you experience
side effects.
47
Inovelon is meant to be taken as a long-term medicine. Do not reduce your dose or stop your
medicine unless your doctor tells you to.
If you take more Inovelon than you should
If you may have taken more Inovelon than you should, tell a carer (relative or friend), your doctor or
pharmacist immediately, or contact your nearest hospital casualty department, taking your medicine
with you. You may become sleepy and could lose consciousness. Do not drive at this time.
If you forget to take Inovelon
If you forget to take a dose, continue taking your medicine as normal. Do not take a double dose to
make up for forgotten dose. If you miss more than one dose, seek advice from your doctor.
If you stop taking Inovelon
If your doctor advises you to stop treatment, follow your doctor’s instructions concerning the gradual
reduction of Inovelon in order to lower the risk of an increase in seizures.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Inovelon can cause side effects, although not everybody gets them.
Tell your doctor if you have any of the following and if they are too uncomfortable for you:
Very common (more than 1 in 10 patients) side effects of Inovelon are:
Dizziness, headache, nausea, vomiting, sleepiness, fatigue.
Less commonly reported (more than 1 in a 100 patients) side effects of Inovelon are:
Problems associated with nerves including: difficulty walking, abnormal movement,
convulsions/seizures, unusual eye movements, blurred vision, trembling.
Problems associated with the stomach including: stomach pain, constipation, indigestion,
loose stools (diarrhoea), loss or change in appetite, weight loss.
Infections: Ear infection, flu, nasal congestion, chest infection.
In addition patients have experienced: anxiety, insomnia, nose bleeds, acne, rash, back pain,
infrequent periods, bruising, head injury.
48
Uncommon (between 1 in a 100 and 1 in a 1000 patients) side effects of Inovelon are:
Allergic reactions and an increase in markers of liver function (hepatic enzyme increase).
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE INOVELON
Keep Inovelon out of the reach and sight of children.
Do not use Inovelon after the expiry date which is stated on the blister and carton.
Do not store above 30°C.
Do not use Inovelon if you notice a change in colour of the tablets.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Inovelon contains
-
The active substance is rufinamide.
Each Inovelon 100 mg film-coated tablet contains 100 mg of rufinamide.
Each Inovelon 200 mg film-coated tablet contains 200 mg of rufinamide.
Each Inovelon 400 mg film-coated tablet contains 400 mg of rufinamide.
-
The other ingredients are lactose monohydrate, microcrystalline cellulose, maize starch,
croscarmellose sodium, hypromellose, magnesium stearate, sodium laurilsulfate and colloidal
anhydrous silica. The film-coating consists of Opadry 00F44042 [hypromellose, macrogols
(8000), titanium dioxide (E171), talc and ferric oxide red (E172)].
What Inovelon looks like and contents of the pack
•
Inovelon 100 mg tablets are pink, oval, slightly convex film-coated tablets, scored on both sides,
embossed ‘Є261’ on one side and blank on the other side.
They are available as packs of 10, 30, 50, 60 and 100 film-coated tablets.
•
Inovelon 200 mg tablets are pink, oval, slightly convex film-coated tablets, scored on both sides,
embossed ‘Є262’ on one side and blank on the other side.
They are available as packs of 10, 30, 50, 60 and 100 film-coated tablets.
•
Inovelon 400 mg tablets are pink, oval, slightly convex film-coated tablets, scored on both sides,
embossed ‘Є263’ on one side and blank on the other side.
They are available as packs of 10, 30, 50, 60,100 and 200 film-coated tablets.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Eisai Ltd, Mosquito Way, Hatfield, Herts, AL10 9SN, UK.
49
Manufacturer:
Eisai Manufacturing Ltd, Mosquito Way, Hatfield, Herts, AL10 9SN, United Kingdom
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Eisai Europe Ltd.
Tél/Tel: + 32 (0) 2 735 45 34
Luxembourg/Luxemburg
Eisai Europe Ltd.
Tél/Tel: + 32 (0) 2 735 45 34
(Belgique/Belgien)
България
Eisai Ltd.
Tel: + 44 (0)208 600 1400
(Великобритания (Обединеното кралство)
Magyarország
Eisai GesmbH
Tel.: + 36 1 230 43 20
Česká republika
Eisai GesmbH organizační složka
Tel: + 420 242 485 839
Malta
Associated Drug Company Ltd
Tel: + 356 (0)2277 8000
Danmark
Eisai AB
Tlf: +46 (0)8 501 01 600
(Sverige)
Nederland
Eisai Europe Ltd.
Tel: + 32 (0) 2 735 45 34
(België/Belgique)
Deutschland
Eisai GesmbH
Tel: + 49 (0) 696 65 85-0
Norge
Eisai AB
Tlf: + 46 (0)8 501 01 600
(Sverige)
Eesti
Eisai Ltd.
Tel: + 44 (0)20 8600 1400
(Ühendkuningriik)
Österreich
Eisai GesmbH
Tel: + 43 (0) 1 535 1980-0
Ελλάδα
Arriani Pharmaceuticals S.A.
Τηλ: + 30 210 668 3000
Polska
Eisai Ltd.
Tel.: + 44 (0)208 600 1400
(Wielka Brytania)
España
Eisai Farmacéutica, S.A.
Tel: +(34) 91 455 94 55
Portugal
Eisai Farmacêutica, Unipessoal Lda
Tel: + 351 21 487 55 40
France
Eisai SAS
Tél: + (33) 1 47 67 00 05
Romania
Eisai Ltd.
Tel: + 44 (0)208 600 1400
(Marea Britanie)
Ireland
Eisai Ltd.
Tel: + 44 (0)208 600 1400
(United Kingdom)
Slovenija
Eisai Ltd
Tel: + 44 (0)208 600 1400
(Velika Britanija)
50
Ísland
Eisai AB
Sími: + 46 (0)8 501 01 600
(Svíþjóð)
Slovenská republika
Eisai GesmbH organizační složka
Tel: + 420 242 485 839
(Česká republika)
Italia
Eisai S.r.l.
Tel: + 39 02 5181401
Suomi/Finland
Eisai AB
Puh/Tel: + 46 (0)8 501 01 600
(Ruotsi/Sverige)
Κύπρος
Arriani Pharmaceuticals S.A.
Τηλ: +30 210 668 3000
Sverige
Eisai AB
Tel: + 46 (0)8 501 01 600
Latvija
Eisai Ltd.
Tel: + 44 (0)208 600 1400
(Liebritānija)
United Kingdom
Eisai Ltd.
Tel: + 44 (0)208 600 1400
Lietuva
Eisai Ltd.
Tel: + 44 (0)208 600 1400
(Jungtinė Karalystė)
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this product is available on the European Medicines Agency (EMEA)
website
http://www.emea.europa.eu
51
Source: European Medicines Agency
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