INOVELON 200mg film-coated tablets medication leaflet

Inovelon 100 mg film-coated tablets

Inovelon 200 mg film-coated tablets

Inovelon 400 mg film-coated tablets

Oral Tablet

Each film-coated tablet contains 100 mg rufinamide.

Each film-coated tablet contains 200 mg rufinamide.

Each film-coated tablet contains 400 mg rufinamide.

Each 100 mg film-coated tablet contains 20 mg lactose (as monohydrate).

Each 200 mg film-coated tablet contains 40 mg lactose (as monohydrate).

Each 400 mg film-coated tablet contains 80 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet.

100 mg: Pink, ‘ovaloid’, slightly convex, approximately 10.2 mm in length, scored on both sides,embossed ‘Є261’ on one side and blank on the other side. The tablet can be divided into equal halves.

200 mg: Pink, ‘ovaloid’, slightly convex, approximately 15.2 mm in length, scored on both sides,embossed ‘Є262’ on one side and blank on the other side. The tablet can be divided into equal halves.

400 mg: Pink, ‘ovaloid’, slightly convex, approximately 18.2 mm in length, scored on both sides,embossed ‘Є263’ on one side and blank on the other side. The tablet can be divided into equal doses.

Inovelon is indicated as adjunctive therapy in the treatment of seizures associated with

Lennox-Gastaut syndrome (LGS) in patients 1 year of age and older.

Treatment with rufinamide should be initiated by a physician specialised in paediatrics or neurologywith experience in the treatment of epilepsy.

Inovelon oral suspension and Inovelon film-coated tablets may be interchanged at equal doses.

Patients should be monitored during the switch over period.

Use in children from 1 year to less than 4 years of age

Patients not receiving valproate:

Treatment should be initiated at a dose of 10 mg/kg/day administered in two equally divided dosesseparated by approximately 12 hours. According to clinical response and tolerability, the dose may beincreased by up to 10 mg/kg/day every third day to a target dose of 45 mg/kg/day administered in twoequally divided doses separated by approximately 12 hours. For this patient population, the maximumrecommended dose is 45 mg/kg/day.

Patients receiving valproate:

As valproate significantly decreases clearance of rufinamide, a lower maximum dose of Inovelon isrecommended for patients being co-administered valproate. Treatment should be initiated at a doseof 10 mg/kg/day administered in two equally divided doses separated by approximately 12 hours.

According to clinical response and tolerability, the dose may be increased by up to 10 mg/kg/dayevery third day to a target dose of 30 mg/kg/day administered in two equally divided doses separatedby approximately 12 hours. For this patient population, the maximum recommended doseis 30 mg/kg/day.

If the recommended calculated dose of Inovelon is not achievable, the dose should be given to thenearest whole 100 mg tablet.

Use in children 4 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 andtolerability, the dose may be increased by 200 mg/day increments, as frequently as every third day, upto a maximum recommended dose of 1,000 mg/day.

Doses of up to 3,600 mg/day have been studied in a limited number of patients.

Patients < 30 kg also receiving valproate:

As valproate significantly decreases clearance of rufinamide, a lower maximum dose of Inovelon isrecommended for patients < 30 kg being co-administered valproate. Treatment should be initiated at adaily dose of 200 mg. According to clinical response and tolerability, after a minimum of 2 days thedose may be increased by 200 mg/day, to the maximum recommended dose of 600 mg/day.

Use in adults, adolescents and children 4 years of age or older of 30 kg or over

Patients > 30 kg not receiving valproate:

Treatment should be initiated at a daily dose of 400 mg. According to clinical response andtolerability, the dose may be increased by 400 mg/day increments, as frequently as every other day, upto 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 1,800 mg/day 2,400 mg/day 3,200 mg/dayrecommended dose

Doses of up to 4,000 mg/day (in the 30 - -50 kg range) or 4,800 mg/day (in the over 50 kg) have beenstudied in a limited number of patients.

Patients > 30 kg also receiving valproate:

Treatment should be initiated at a daily dose of 400 mg. According to clinical response andtolerability, the dose may be increased by 400 mg/day increments, as frequently as every other day, upto 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 1,200 mg/day 1,600 mg/day 2,200 mg/dayrecommended dose

There is limited information on the use of rufinamide in older people. Since the pharmacokinetics ofrufinamide are not altered in older people (see section 5.2), dosage adjustment is not required inpatients over 65 years of age.

A study in patients with severe renal impairment indicated that no dose adjustments are required forthese patients (see section 5.2).

Use in patients with hepatic impairment has not been studied. Caution and careful dose titration isrecommended when treating patients with mild to moderate hepatic impairment. Use in patients withsevere hepatic impairment is not recommended.

Discontinuation of rufinamide

When rufinamide treatment is to be discontinued, it should be withdrawn gradually. In clinical trialsrufinamide discontinuation was achieved by reducing the dose by approximately 25% every two days(see section 4.4).

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 hasbeen conducted for longer than three months.

The safety and efficacy of rufinamide in new-born infants or infants and toddlers aged less than 1 yearhave not been established. No data are available (see section 5.2).

Rufinamide is for oral use.

The tablet should be taken twice daily with water in the morning and in the evening, in two equallydivided doses.

Inovelon should be administered with food (see section 5.2). If the patient has difficulty withswallowing, tablets can be crushed and administered in half a glass of water. Alternatively, use thescore line to break the tablet into two equal halves.

Hypersensitivity to the active substance, triazole derivatives or to any of the excipients listed insection 6.1.

Status epilepticus

Status epilepticus cases have been observed during treatment with rufinamide in clinical developmentstudies, whereas no such cases were observed with placebo. These events led to rufinamidediscontinuation in 20% of the cases. If patients develop new seizure types and/or experience anincreased frequency of status epilepticus that is different from the patient’s baseline condition, then thebenefit-risk ratio of the therapy should be reassessed.

Withdrawal of rufinamide

Rufinamide should be withdrawn gradually to reduce the possibility of seizures on withdrawal. Inclinical studies discontinuation was achieved by reducing the dose by approximately 25% every twodays. There are insufficient data on the withdrawal of concomitant antiepileptic medicinal productsonce seizure control has been achieved with the addition of rufinamide.

Central Nervous System reactions

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). Patientsand carers should exercise caution until they are familiar with the potential effects of this medicinalproduct.

Serious antiepileptic medicinal product hypersensitivity syndrome including DRESS (Drug Reactionwith Eosinophilia and Systemic Symptoms) and Stevens-Johnson syndrome have occurred inassociation 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 organsystem involvement. Other associated manifestations included lymphadenopathy, liver function testsabnormalities, and haematuria. As the disorder is variable in its expression, other organ system signsand symptoms not noted here may occur. The antiepileptic drug (AED) hypersensitivity syndromeoccurred in close temporal association to the initiation of rufinamide therapy and in the paediatricpopulation. If this reaction is suspected, rufinamide should be discontinued and alternative treatmentstarted. All patients who develop a rash while taking rufinamide must be closely monitored.

QT shortening

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, cliniciansshould use clinical judgment when assessing whether to prescribe rufinamide to patients at risk fromfurther shortening their QTc duration (e.g., Congenital Short QT Syndrome or patients with a familyhistory 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 clinicaljudgement when assessing whether oral contraceptives, or the doses of the oral contraceptivecomponents, are adequate, based on the individual patients clinical situation (see sections 4.5 and 4.6).

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.

This medicine contains less than 1 mmol sodium (23 mg) per daily dose, i.e. is essentially ‘sodium-free’.

Suicidal ideation

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents inseveral indications. A meta-analysis of randomised placebo-controlled trials of anti-epilepticmedicinal products has also shown a small increased risk of suicidal ideation and behaviour. Themechanism of this risk is not known and the available data do not exclude the possibility of anincreased risk for Inovelon.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriatetreatment should be considered. Patients (and caregivers of patients) should be advised to seek medicaladvice should signs of suicidal ideation or behaviour emerge.

Potential for other medicinal products to affect rufinamide

Other antiepileptic medicinal products

Rufinamide concentrations are not subject to clinically relevant changes on co-administration withknown enzyme inducing antiepileptic medicinal products.

For patients on Inovelon treatment who have administration of valproate initiated, significant increasesin rufinamide plasma concentrations may occur. Therefore, consideration should be given to a dosereduction of Inovelon in patients who are initiated on valproate therapy (see section 4.2).

The addition or withdrawal of these medicinal products or adjusting of the dose of these medicinalproducts during rufinamide therapy may require an adjustment in dosage of rufinamide (seesection 4.2).

No significant changes in rufinamide concentration are observed following co-administration withlamotrigine, topiramate or benzodiazepines.

Potential for rufinamide to affect other medicinal products

Other antiepileptic medicinal products

The pharmacokinetic interactions between rufinamide and other antiepileptic medicinal products havebeen evaluated in patients with epilepsy, using population pharmacokinetic modelling. Rufinamideappears not to have a clinically relevant effect on carbamazepine, lamotrigine, phenobarbital,topiramate, phenytoin or valproate steady state concentrations.

Co-administration of rufinamide 800 mg twice daily and a combined oral contraceptive(ethinyloestradiol 35 μg and norethindrone 1 mg) for 14 days resulted in a mean decrease in theethinyl estradiol AUC0-24 of 22% and in norethindrone AUC0-24 of 14%. Studies with other oral orimplant contraceptives have not been conducted. Women of child-bearing potential using hormonalcontraceptives are advised to use an additional safe and effective contraceptive method (seesections 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 thecytochrome P450 enzyme CYP3A4 and may therefore reduce the plasma concentrations of substanceswhich are metabolised by this enzyme. The effect was modest to moderate. The mean

CYP3A4 activity, assessed as clearance of triazolam, was increased by 55% after 11 days of treatmentwith rufinamide 400 mg twice daily. The exposure of triazolam was reduced by 36%. Higherrufinamide doses may result in a more pronounced induction. It may not be excluded that rufinamidemay also decrease the exposure of substances metabolised by other enzymes, or transported bytransport proteins such as P-glycoprotein.

It is recommended that patients treated with substances that are metabolised by the CYP3A4 enzymesystem are to be carefully monitored for two weeks at the start of, or after the end of treatment withrufinamide, or after any marked change in the dose. A dose adjustment of the concomitantlyadministered medicinal product may need to be considered. These recommendations should also beconsidered when rufinamide is used concomitantly with substances with a narrow therapeutic windowsuch as warfarin and digoxin.

A specific interaction study in healthy subjects revealed no influence of rufinamide at a doseof 400 mg twice daily 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 istwo to three times greater than the rate of approximately 3% in the general population. In the treatedpopulation, an increase in malformations has been noted with polytherapy; however, the extent towhich the treatment and/or the illness is responsible has not been elucidated.

Moreover, effective antiepileptic therapy should not be interrupted abruptly, since the aggravation ofthe illness is detrimental to both the mother and the foetus. AED treatment during pregnancy should becarefully discussed with the treating physician.

Risk related to rufinamide:

Studies in animals revealed no teratogenic effect, but foetotoxicity in the presence of maternal toxicitywas observed (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, or in women ofchildbearing age not using contraceptive measures, unless clearly necessary.

Women of childbearing potential must use contraceptive measures during treatment with rufinamide.

Physicians should try to ensure that appropriate contraception is used, and should use clinicaljudgement when assessing whether oral contraceptives, or the doses of the oral contraceptivecomponents, are adequate based on the individual patients clinical situation (see sections 4.4 and 4.5).

If women treated with rufinamide plan to become pregnant, the continued use of this product shouldbe carefully weighed. During pregnancy, interruption of an effective antiepileptic can be detrimentalto both the mother and the foetus if it results in aggravation of the illness.

It is not known if rufinamide is excreted in human breast milk. Due to the potential harmful effects forthe breast-fed infant, breast-feeding should be avoided during maternal treatment with rufinamide.

No data are available on the effects on fertility following treatment with rufinamide.

Inovelon may cause dizziness, somnolence and blurred vision. Depending on the individualsensitivity, rufinamide may have a minor to major influence on the ability to drive and 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 higherincidence 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 rufinamideand 0% for patients receiving placebo. The most common adverse reactions resulting indiscontinuation from the rufinamide treatment group were rash and vomiting.

Adverse reactions reported with an incidence greater than placebo, during the Lennox-Gastautsyndrome double-blind studies or in the overall rufinamide-exposed population, are listed in the tablebelow by MedDRA preferred term, system organ class and by frequency.

Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10),uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000).

System Organ

Class Very Common Common Uncommon Rare

Infections and Pneumoniainfestations Influenza

Nasopharyngitis

Ear infection

Sinusitis

Rhinitis

Immune systemdisorders Hypersensitivity*

Metabolism and Anorexianutrition Eating disorderdisorders Decreased appetite

Psychiatric Anxietydisorders Insomnia

Nervous system Somnolence* Status epilepticus*disorders Headache Convulsion

Dizziness* Coordination

Abnormal*

Nystagmus

Psychomotorhyperactivity

Tremor

Eye Disorders Diplopia

Vision blurred

Ear and Vertigo

Labyrinthdisorders

Respiratory, Epistaxisthoracic andmediastinaldisorders

Gastrointestinal Nausea Abdominal paindisorders upper

Vomiting Constipation

Dyspepsia

Hepatobiliary Hepatic enzymedisorders increase

Skin and Rash*subcutaneoustissue disorders Acne

Musculoskeletal Back painand connectivetissue and bonedisorders

Reproductive Oligomenorrhoeasystem andbreast disorders

System Organ

Class Very Common Common Uncommon Rare

General Fatigue Gait disturbance*disorders andadministrationsite conditions

Investigations Weight decrease

Injury, poisoning Head injuryand procedural Contusioncomplications

*Cross reference to section 4.4.

Additional information on special populations

Paediatric Population (age 1 to less than 4 years)

In a multicentre, open-label study comparing the addition of rufinamide to any other AED of theinvestigator’s choice to the existing regimen of 1 to 3 AEDs in paediatric patients, 1 to lessthan 4 years of age with inadequately controlled LGS, 25 patients, of which 10 subjects wereaged 1 to 2 years, were exposed to rufinamide as adjunctive therapy for 24 weeks at a dose of upto 45 mg/kg/day, in 2 divided doses. The most frequently reported TEAEs in the rufinamide treatmentgroup (occurring in ≥ 10% of subjects) were upper respiratory tract infection and vomiting (28.0%each), pneumonia and somnolence (20.0% each), sinusitis, otitis media, diarrhoea, cough and pyrexia(16.0% each), and bronchitis, constipation, nasal congestion, rash, irritability and decreased appetite(12.0% each). The frequency, type and severity of these adverse reactions were similar to that inchildren 4 years of age and older, adolescents and adults. Age characterisation in patients lessthan 4 years was not identified in the limited safety database due to small number of patients in thestudy.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis.

There is no specific antidote for rufinamide. Treatment should be supportive and may includehaemodialysis (see section 5.2).

Multiple dosing of 7,200 mg/day was associated with no major signs or symptoms.

Pharmacotherapeutic group: antiepileptics, carboxamide derivatives; ATC code: N03AF03.

Rufinamide modulates the activity of sodium channels, prolonging their inactive state. Rufinamide isactive in a range of animal models of epilepsy.

Inovelon (rufinamide tablets) was administered in a double blind, placebo-controlled study, at doses ofup 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 andfemale patients (between 4 and 30 years of age) were eligible if they had a history of multiple seizuretypes, which had to include atypical absence seizures and drop attacks (i.e., tonic-atonic or astaticseizures); were being treated with 1 to 3 concomitant fixed dose antiepileptic medicinal products; aminimum of 90 seizures in the month before the 28-day baseline period; an EEG within 6 months ofstudy entry demonstrating a pattern of slow spike-and-wave complexes (2.5 Hz); a weight of atleast 18 kg; and a CT scan or MRI study confirming the absence of a progressive lesion. All seizureswere classified according to the International League Against Epilepsy Revised Classification of

Seizures. As it is difficult for caregivers to precisely separate tonic and atonic seizures, theinternational expert panel of child neurologists agreed to group these seizure types and call themtonic-atonic seizures or “drop attacks”. As such, drop attacks were used as one of the primary endpoints. A significant improvement was observed for all three primary variables: the percentage changein 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 Inovelonvs. 2.2% on placebo, p=0.0002), and the seizure severity rating from the Global Evaluation performedby 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).

Additionally, Inovelon (rufinamide oral suspension) was administered in a multicentre, open-labelstudy comparing the addition of rufinamide to the addition of any other AED of the investigator’schoice to the existing regimen of 1 to 3 AEDs in paediatric patients, 1 to less than 4 years of age withinadequately controlled LGS. In this study, 25 patients were exposed to rufinamide as adjunctivetherapy for 24 weeks at a dose of up to 45 mg/kg/day, in 2 divided doses. A total of 12 patientsreceived any other AED at the investigator’s discretion in the control arm. The study was mainlydesigned for safety and not adequately powered to show a difference with regards to the seizureefficacy variables. The adverse event profile was similar to that in children 4 years of age and older,adolescents, and adults. In addition, the study investigated the cognitive development, behaviour andlanguage development of subjects treated with rufinamide compared to subjects receivingany-other-AED. The Least Square mean change of the Child Behaviour Checklist (CBCL) Total

Problems score after 2 years of treatment were 53.75 for the any other AED group and 56.35 for therufinamide group (LS mean difference [95% CI] +2.60 [-10.5,15.7]; p=0.6928), and the differencebetween treatments was -2.776 (95% CI: -13.3, 7.8, p=0.5939).

Population pharmacokinetic/pharmacodynamic modelling demonstrated that the reduction of total andtonic-atonic seizure frequencies, the improvement of the global evaluation of seizure severity and theincrease in probability of reduction of seizure frequency were dependent on rufinamideconcentrations.

Maximum plasma levels are reached approximately 6 hours after administration. Peak concentration(Cmax) and plasma AUC of rufinamide increase less than proportionally with doses in both fasted andfed healthy subjects and in patients, probably due to dose-limited absorption behaviour. After singledoses, food increases the bioavailability (AUC) of rufinamide by approximately 34% and the peakplasma concentration by 56%.

Inovelon oral suspension and Inovelon film-coated tablets have been demonstrated to bebioequivalent.

In in -vitro studies, only a small fraction of rufinamide (34%) was bound to human serum proteinswith albumin accounting for approximately 80% of this binding. This indicates minimal risk ofdrug-drug interactions by displacement from binding sites during concomitant administration of othersubstances. Rufinamide was evenly distributed between erythrocytes and plasma.

Rufinamide is almost exclusively eliminated by metabolism. The main pathway of metabolism ishydrolysis 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 glutathioneconjugates cannot be completely excluded.

Rufinamide has demonstrated little or no significant capacity in -vitro to act as a competitive ormechanism-based inhibitor of the following human P450 enzymes: CYP1A2, CYP2A6, CYP2C9,

CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 or CYP4A9/11-2.

The plasma elimination half-life is approximately 6-10 hours in healthy subjects and patients withepilepsy. When given twice daily at 12-hourly intervals, rufinamide accumulates to the extentpredicted by its terminal half-life, indicating that the pharmacokinetics of rufinamide aretime-independent (i.e. no autoinduction of metabolism).

In a radiotracer study in three healthy volunteers, the parent compound (rufinamide) was the mainradioactive 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 eliminationfor active substance related material, accounting for 84.7% of the dose.

The bioavailability of rufinamide is dependent on dose. As dose increases, the bioavailabilitydecreases.

Sex

Population pharmacokinetic modelling has been used to evaluate the influence of sex on thepharmacokinetics of rufinamide. Such evaluations indicate that sex does not affect thepharmacokinetics of rufinamide to a clinically relevant extent.

The pharmacokinetics of a single 400 mg dose of rufinamide were not altered in subjects with chronicand severe renal failure compared to healthy volunteers. However, plasma levels were reduced byapproximately 30% when haemodialysis was applied after administration of rufinamide, suggestingthat this may be a useful procedure in case of overdose (see sections 4.2 and 4.9).

No studies have been performed in patients with hepatic impairment and therefore Inovelon should notbe administered to patients with severe hepatic impairment (see section 4.2).

A pharmacokinetic study in older healthy volunteers did not show a significant difference inpharmacokinetic parameters compared with younger adults.

Children (1-12 years)

Children generally have lower clearance of rufinamide than adults, and this difference is related tobody size with rufinamide clearance increasing with body weight.

A recent population PK analysis of rufinamide on data pooled from 139 subjects (115 LGS patientsand 24 healthy subjects), including 83 paediatric LGS patients (10 patientsaged 1 to < 2 years, 14 patients aged 2 to < 4 years, 14 patients aged 4 to < 8 years, 21 patientsaged 8 to < 12 years and 24 patients aged 12 to < 18 years) indicated that when rufinamide is dosed ona mg/kg/day basis in LGS subjects aged 1 to < 4 years, comparable exposure to that in LGS patientsaged ≥ 4 years, in which efficacy has been demostrated, is achieved.

Studies in new-born infants or infants and toddlers under 1 year of age have not been conducted.

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 dosewere liver changes, including bile thrombi, cholestasis and liver enzyme elevations thought to berelated to increased bile secretion in this species. No evidence of an associated risk was identified inthe rat and monkey repeat dose toxicity studies.

In reproductive and developmental toxicity studies, there were reductions in foetal growth andsurvival, and some stillbirths secondary to maternal toxicity. However, no effects on morphology andfunction, including learning or memory, were observed in the offspring. Rufinamide was notteratogenic in mice, rats or rabbits.

The toxicity profile of rufinamide in juvenile animals was similar to that in adult animals. Decreasedbody weight gain was observed in both juvenile and adult rats and dogs. Mild toxicity in the liver wasobserved in juvenile as well as in adult animals at exposure levels lower than or similar to thosereached in patients. Reversibility of all findings was demonstrated after stopping treatment.

Rufinamide was not genotoxic and had no carcinogenic potential. An adverse effect not observed inclinical studies, but seen in animals at exposure levels similar to clinical exposure levels and withpossible relevance to human use, was myelofibrosis of the bone marrow in the mouse carcinogenicitystudy. Benign bone neoplasms (osteomas) and hyperostosis seen in mice were considered a result ofthe activation of a mouse specific virus by fluoride ions released during the oxidative metabolism ofrufinamide.

Regarding the immunotoxic potential, small thymus and thymic involution were observed in dogs ina 13-week study with significant response at the high dose in male. In the 13-week study, female bonemarrow and lymphoid changes are reported at the high dose with a weak incidence. In rats, decreasedcellularity of the bone marrow and thymic atrophy were observed only in the carcinogenicity study.

Environmental Risk Assessment (ERA):

Environmental risk assessment studies have shown that rufinamide is very persistent in theenvironment (see section 6.6).

Core

Lactose monohydrate

Cellulose, microcrystalline (E460)

Maize starch

Croscarmellose sodium (E468)

Hypromellose (E464)

Magnesium stearate (E470b)

Sodium laurilsulfate

Silica colloidal, anhydrous

Hypromellose (E464)

Macrogols (8000)

Titanium dioxide (E171)

Talc

Ferric oxide red (E172)

Not applicable.

4 years.

Do not store above 30ºC.

Aluminium/aluminium blisters, packs of 10, 30, 50, 60 and 100 film-coated tablets.

Not all pack sizes may be marketed.

No special requirements for disposal.

This medicinal product could have potential risk for the environment. Any unused medicinal productor waste material should be disposed of in accordance with local requirements (see section 5.3).

Eisai GmbH

Edmund-Rumpler-Straße 360549 Frankfurt am Main

Germanye-mail: medinfo_de@eisai.net

EU/1/06/378/001-005

EU/1/06/378/006-010

EU/1/06/378/011-016

Date of first authorisation: 16 January 2007

Date of latest renewal: 09 January 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.