: each film coated tablet contains 20 mg lactose monohydrate For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

Film-coated tablet. Pink, 'ovaloid', slightly convex, scored on both sides, embossed 'Ie261' on one side and blank on the other side. The tablet can be divided into equal doses.

CLINICAL PARTICULARS

Posology and method of administration

Treatment with rufinamide should be initiated by a physician specialised in paediatrics or neurology with 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.

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: As valproate significantly decreases clearance of rufinamide, 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.

Use in adults, adolescents 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.

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 been studied in a limited number of patients.

When rufinamide treatment is to be discontinued, it should be withdrawn gradually. In clinical trials rufinamide 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.

The safety and efficacy of rufinamide of children aged 4 years and less have not yet been established. No data are available.

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

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

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. Use in patients with severe hepatic impairment is not recommended.

Rufinamide 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, Inovelon should be administered 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.

Contraindications

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

Special warnings and precautions for use

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.

Rufinamide 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 rufinamide.

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 medicinal product hypersensitivity syndrome including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) and Stevens-Johnson syndrome have 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. The antiepileptic drug hypersensitivity 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 (e.g. 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.

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic medicinal products has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Inovelon. Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Interaction with other medicinal products and other forms of interaction

Rufinamide concentrations are not subject to clinically relevant changes on co-administration with known enzyme inducing antiepileptic medicinal products. 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 medicinal products or adjusting of the dose of these medicinal products during rufinamide therapy may require an adjustment in dosage of rufinamide. No significant changes in rufinamide concentration are observed following co-administration with lamotrigine, topiramate or benzodiazepines.

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

Co-administration of rufinamide 800 mg b.i.d. and a combined oral contraceptive (ethinyloestradiol 35 mg and norethindrone 1 mg) for 14 days resulted in a mean decrease in the ethinyl estradiol AUC0-24 of 22% and in norethindrone AUC0-24 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 sections 4.4 and 4.6).

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 substances which 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 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 also decrease the exposure of substances metabolized by other enzymes, or transported by transport proteins such as P-glycoprotein. It is recommended that patients treated with substances that are metabolised by the CYP3A4 enzyme system are to be carefully monitored for two weeks at the start of, or after the end of treatment with rufinamide, or after any marked change in the dose. A dose adjustment of the concomitantly administered medicinal product may need to be considered. These recommendations should also be considered when rufinamide is used concomitantly with substances 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.

Fertility, pregnancy and lactation

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 antiepileptic therapy must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.

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 rufinamide. 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.

It is not known if rufinamide is excreted in human breast milk. Due to the potential harmful effects for the 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.

Effects on ability to drive and use machines

Inovelon may cause dizziness, somnolence and blurred vision. Depending on the individual sensitivity, 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.

Undesirable effects

Summary of the safety profile

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 rufinamide and 0% for patients receiving placebo. The most common adverse reactions resulting in discontinuation from the rufinamide treatment group were rash and vomiting.

Tabulated list of adverse reactions

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), rare (>=1/10,000 to <1/1,000).

System Organ Class	Very Common	Common	Uncommon	Rare
Infections and infestations		Pneumonia Influenza Nasopharyngitis Ear infection Sinusitis Rhinitis
Immune system disorders			Hypersensitivity *
Metabolism and nutrition disorders		Anorexia Eating disorder Decreased appetite
Psychiatric disorders		Anxiety Insomnia
Nervous system disorders	Somnolence * Headache Dizziness *	Status epilepticus * Convulsion Coordination Abnormal * Nystagmus Psychomotor hyperactivity Tremor
Eye Disorders		Diplopia Vision blurred
Eye Disorders
Ear and Labyrinth disorders		Vertigo
Respiratory, thoracic and mediastinal disorders		Epistaxis
System Organ Class	Very Common	Common	Uncommon	Rare
Gastrointestinal disorders	Nausea Vomiting	Abdominal pain upper Constipation Dyspepsia Diarrhoea
Hepatobiliary disorders			Hepatic enzyme increase
Skin and subcutaneous tissue disorders		Rash *
Skin and subcutaneous tissue disorders		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 *
Investigations		Weight decrease
Injury, poisoning and procedural complications		Head injury Contusion

*Cross refer to section 4.4.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

the national reporting system

listed in Appendix V.

Overdose

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 include haemodialysis (see section 5.2). Multiple dosing of 7,200 mg/day was associated with no major signs or symptoms.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: antiepileptics, 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.

Inovelon (rufinamide tablets) 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 medicinal products. 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.

Pharmacokinetic properties

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 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%. Inovelon oral suspension and Inovelon film coated tablets have been demonstrated to be bioequivalent.

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 substances. Rufinamide was evenly distributed between erythrocytes and plasma.

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.

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 active substance related material, accounting for 84.7% of the dose.

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

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.

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).

No studies have been performed in patients with hepatic impairment and therefore Inovelon should not be administered to patients with severe hepatic impairment(see section 4.2).

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.

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

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. Rufinamide 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.

PHARMACEUTICAL PARTICULARS

List of excipients

Lactose monohydrate Cellulose, microcrystalline Maize starch Croscarmellose sodium Hypromellose Magnesium stearate Sodium laurilsulfate Silica colloidal, anhydrous

Incompatibilities

Shelf life

Special precautions for storage

Nature and contents of container

Aluminium/aluminium blisters, packs of 10, 30, 50, 60 and 100 film-coated tablets. Not all pack sizes may be marketed.

Special precautions for disposal

MARKETING AUTHORISATION HOLDER

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 16 January 2007 Date of latest renewal: 16 January 2012

DATE OF REVISION OF THE TEXT

{MM/YYYY} Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Weight range	30.0 - 50.0 kg	50.1 - 70.0 kg	>= 70.1 kg
Maximum recommended dose	1,800 mg/day	2,400 mg/day	3,200 mg/day

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION