100 mg: Each film-coated tablet contains 100 mg rufinamide. Excipient: 20 mg lactose monohydrate/film coated tablet. 200 mg: Each film-coated tablet contains 200 mg rufinamide. Excipient: 40 mg lactose monohydrate/film coated tablet. 400 mg: Each film-coated tablet contains 400 mg rufinamide. Excipient: 80 mg lactose monohydrate/film coated tablet.

Film-coated tablets. 100 mg: Pink, 'ovaloid', slightly convex, scored on both sides, embossed '?261' on one side and blank on the other side. 200 mg: Pink, 'ovaloid', slightly convex, scored on both sides, embossed '?262' on one side and blank on the other side. 400 mg: Pink, 'ovaloid', slightly convex, scored on both sides, embossed '?263' on one side and blank on the other side. The tablets can be divided into equal halves.

Inovelon is indicated as adjunctive therapy in the treatment of seizures associated with LennoxGastaut 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. If the patient has difficulty with swallowing, tablets can be crushed and administered in half a glass of water.

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.

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.

Patients with renal impairment

A study in patients with severe renal impairment indicated that no dose adjustments are required for these patients.

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.

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When Inovelon treatment is to be discontinued, it should be withdrawn gradually.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.

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.

There is limited information on the use of Inovelon in the elderly. Since, the pharmacokinetics of rufinamide are not altered in the eldery, dosage adjustment is not required in patients over 65 years of age.

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.

Rufinamide treatment has been associated with dizziness, somnolence, ataxia and gait disturbances, which could increase the occurrence of accidental falls in this population. 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.

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.

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 average steady state plasma concentrations of coadministered 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.

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 enzyme. 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 Pglycoprotein.

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.

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 LennoxGastaut 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).

Eisai Limited

POM

21 September 2009