4.1. Therapeutic indications

Rufinamide Tablets are indicated as adjunctive therapy in the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 1 year of age and older.

4.2. 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.

Posology

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 doses separated by approximately 12 hours. According to clinical response and tolerability, the dose may be increased by up to 10 mg/kg/day every third day to a target dose of 45 mg/kg/day administered in two equally divided doses separated by approximately 12 hours. For this patient population, the maximum recommended dose is 45 mg/kg/day.

Patients receiving valproate:

As valproate significantly decreases clearance of rufinamide, a lower maximum dose of Rufinamide is recommended for patients being co-administered valproate. Treatment should be initiated at a dose of 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/day every third day to a target dose of 30 mg/kg/day administered in two equally divided doses separated by approximately 12 hours. For this patient population, the maximum recommended dose is 30 mg/kg/day.

If the recommended calculated dose of Rufinamide is not achievable, the dose should be given to the nearest 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 and tolerability, the dose may be increased by 200 mg/day increments, as frequently as every third day, up to 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 Rufinamide 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 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 200 mg. According to clinical response and tolerability, the dose may be increased by 200 mg/day increments, as frequently as every other day, 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

1,800 mg/day

2,400 mg/day

3,200 mg/day

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.

Patients > 30 kg also receiving valproate:

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 other day, 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

1,200 mg/day

1,600 mg/day

2,200 mg/day

Elderly

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.

Renal impairment

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

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

Discontinuation of rufinamide

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 (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 has been conducted for longer than three months.

Paediatric population

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

Method of administration

Rufinamide is for oral use.

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

The Tablet 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. Alternatively, use the score line to break the tablet into two equal halves.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Status epilepticus

Status epilepticus cases have been observed during treatment with rufinamide in clinical development studies, whereas no such cases were observed with 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.

Withdrawal of rufinamide

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.

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). Patients and carers should exercise caution until they are familiar with the potential effects of this medicinal product.

Hypersensitivity reactions

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. As the disorder is variable in its expression, other organ system signs and symptoms not noted here may occur. The antiepileptic drug (AED) 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.

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, 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

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 sections 4.5 and 4.6).

Lactose

Rufinamide Tablets contains lactose, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium content

This medicine contains less than 1 mmol sodium (23 mg) per daily dose, that is to say essentially 'sodium-free'.

Suicidal ideation

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 rufinamide.

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.

4.5. Interaction with other medicinal products and other forms of interaction

Potential for other medicinal products to affect rufinamide

Other antiepileptic medicinal products

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

For patients on rufinamide treatment who have administration of valproate initiated, significant increases in rufinamide plasma concentrations may occur. Therefore, consideration should be given to a dose reduction of Rufinamide 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 medicinal products during rufinamide therapy may require an adjustment in dosage of rufinamide (see section 4.2).

No significant changes in rufinamide concentration are observed following co-administration with lamotrigine, 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 have been evaluated in patients with epilepsy, using population pharmacokinetic modelling. Rufinamide appears not to have a clinically relevant effect on carbamazepine, lamotrigine, phenobarbital, topiramate, phenytoin or valproate steady state concentrations.

Oral contraceptives

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 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).

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 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 twice daily. 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 metabolised 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 twice daily on the pharmacokinetics of olanzapine, a CYP1A2 substrate.

No data on the interaction of rufinamide with alcohol are available.

4.6. Fertility, pregnancy and lactation

Pregnancy

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

Risk related to rufinamide:

Studies in animals revealed no teratogenic effect, but foetotoxicity in the presence of maternal toxicity was 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 of childbearing 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 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 sections 4.4 and 4.5).

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

Breast-feeding

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.

Fertility

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

4.7. Effects on ability to drive and use machines

Rufinamide 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.

4.8. 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 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 infestations

Pneumonia

Influenza

Nasopharyngits

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

Ear and Labyrinth disorders

Vertigo

Respiratory, thoracic and mediastinal disorders

Epistaxis

Gastrointestinal disorders

Nausea

Vomiting

Abdominal pain upper

Constipation

Dyspepsia

Diarrhoea

Hepatobiliary disorders

Hepatic enzyme increase

Skin and subcutaneous tissue disorders

Rash*

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 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 the investigator's choice to the existing regimen of 1 to 3 AEDs in paediatric patients, 1 to less than 4 years of age with inadequately controlled LGS, 25 patients, of which 10 subjects were aged 1 to 2 years, were exposed to rufinamide as adjunctive therapy for 24 weeks at a dose of up to 45 mg/kg/day, in 2 divided doses. The most frequently reported TEAEs in the rufinamide treatment group (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 in children 4 years of age and older, adolescents and adults. Age characterisation in patients less than 4 years was not identified in the limited safety database due to small number of patients in the study.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play and Apple App store.

4.9. 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.