4.1. Therapeutic indications

TEGLUTIK is indicated to extend life or the time to mechanical ventilation for patients with amyotrophic lateral sclerosis (ALS).

Clinical trials have demonstrated that riluzole extends survival for patients with ALS (see section 5.1). Survival was defined as patients who were alive, not intubated for mechanical ventilation and tracheotomy-free.

There is no evidence that TEGLUTIK exerts a therapeutic effect on motor function, lung function, fasciculations, muscle strength and motor symptoms. TEGLUTIK has not been shown to be effective in the late stages of ALS.

Safety and efficacy of TEGLUTIK has only been studied in ALS. Therefore, TEGLUTIK should not be used in patients with any other form of motor neurone disease.

4.2. Posology and method of administration

Treatment with TEGLUTIK should only be initiated by specialist physicians with experience in the management of motor neurone diseases.

Posology

The recommended daily dose in adults or elderly is 100 mg (50 mg every 12 hours). No significant increased benefit can be expected from higher daily doses.

It is recommended to assume 10 ml two times a day of the suspension (i.e. 10 ml corresponds to 50 mg of Riluzole).

Special populations

Paediatric population:

TEGLUTIK is not recommended for use in paediatric population, due to a lack of data on the safety and efficacy of riluzole in any neurodegenerative diseases occurring in children or adolescents.

Patients with impaired renal function:

TEGLUTIK is not recommended for use in patients with impaired renal function, as studies at repeated doses have not been conducted in this population (see section 4.4).

Older people:

based on pharmacokinetic data, there are no special instructions for the use of TEGLUTIK in this population.

Patients with impaired hepatic function:

see section 4.3, section 4.4, and section 5.2.

Method of administration

The suspension can be given per oral administration and alternatively it is also suitable for administration via enteral feeding tubes.

Dilution with liquids is not necessary.

The suspension is administered by means of graduated dosing syringe.

For instructions on handling of the product before administration, see section 6.6.

4.3. Contraindications

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

Hepatic disease or baseline transaminases greater than 3 times the upper limit of normal.

Patients who are pregnant or breast-feeding.

4.4. Special warnings and precautions for use

Liver impairment:

Riluzole should be prescribed with care in patients with a history of abnormal liver function, or in patients with slightly elevated serum transaminases (ALT/SGPT; AST/SGOT up to 3 times the upper limit of the normal range (ULN)), bilirubin and/or gamma-glutamyl transferase (GGT) levels. Baseline elevations of several liver function tests (especially elevated bilirubin) should preclude the use of riluzole (see section 4.8).

Because of the risk of hepatitis, serum transaminases, including ALT, should be measured before and during therapy with riluzole. ALT should be measured every month during the first 3 months of treatment, every 3 months during the remainder of the first year, and periodically thereafter. ALT levels should be measured more frequently in patients who develop elevated ALT levels.

Riluzole should be discontinued if the ALT levels increase to 5 times the ULN. There is no experience with dose reduction or rechallenge in patients who have developed an increase of ALT to 5 times ULN. Readministration of riluzole to patients in this situation cannot be recommended.

Neutropenia:

Patients should be warned to report any febrile illness to their physicians. The report of a febrile illness should prompt physicians to check white blood cell counts and to discontinue riluzole in case of neutropenia (see section 4.8).

Interstitial lung disease

Cases of interstitial lung disease have been reported in patients treated with riluzole, some of them were severe (see section 4.8). If respiratory symptoms develop such as dry cough and/or dysponea, chest radiography should be performed, and in case of findings suggestive of interstitial lung disease (e.g. bilateral diffuse lung opacities), riluzole should be discontinued immediately. In the majority of the reported cases, symptoms resolved after drug discontinuation and symptomatic treatment.

Renal impairment:

Studies at repeated doses have not been conducted in patients with impaired renal function (see section 4.2).

The product contains liquid sorbitol (E420) therefore patients with rare hereditary problems of fructose intolerance should not take this medicine.

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

There have been no clinical studies to evaluate the interactions of riluzole with other medicinal products.

In vitro studies using human liver microsomal preparations suggest that CYP 1A2 is the principal isozyme involved in the initial oxidative metabolism of riluzole. Inhibitors of CYP 1A2 (e.g. caffeine, diclofenac, diazepam, nicergoline, clomipramine, imipramine, fluvoxamine, phenacetin, theophylline, amitriptyline and quinolones) could potentially decrease the rate of riluzole elimination, while inducers of CYP 1A2 (e.g. cigarette smoke, charcoal-broiled food, rifampicin and omeprazole) could increase the rate of riluzole elimination.

4.6. Fertility, pregnancy and lactation

Pregnancy

TEGLUTIK is contraindicated in pregnancy (see section 4.3 and 5.3). Clinical experience with riluzole in pregnant women is lacking.

Breast-feeding

TEGLUTIK is contraindicated in breast-feeding women (see section 4.3 and 5.3). It is not known whether riluzole is excreted in human milk.

Fertility

Fertility studies in rats revealed slight impairment of reproductive performance and fertility at doses of 15 mg/kg/day (which is higher than the therapeutic dose), probably due to sedation and lethargy.

4.7. Effects on ability to drive and use machines

Patients should be warned about the potential for dizziness or vertigo, and advised not to drive or operate machinery if these symptoms occur.

No studies on the effects on the ability to drive and use machines have been performed.

4.8. Undesirable effects

Summary of safety profile

In phase III clinical studies conducted in ALS patients treated with riluzole, the most commonly reported adverse reactions were asthenia, nausea and abnormal liver function tests.

Tabulated summary of adverse reactions

Undesirable effects ranked under headings of frequency are listed below, using the following convention: 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), very rare (<1/10,000), not known (cannot be estimated from the available data).

Very common

Common

Uncommon

Not known

Blood and lymphatic system disorders

Anaemia

Severe neutropenia (see section 4.4)

Immune system disorders

Anaphylactoid reaction, angioedema

Nervous system disorders

Headache, dizziness, oral paraesthesia, somnolence

Cardiac disorders

Tachycardia

Respiratory, thoracic and mediastinal disorders

Interstitial lung disease (see section 4.4)

Gastrointestinal disorders

Nausea

Diarrhoea, abdominal pain, vomiting

Pancreatitis

Hepato-biliary disorders

Abnormal liver function tests

Hepatitis

General disorders and administration site conditions

Asthenia

Pain

Description of selected adverse reactions

Hepato-biliary disorders

Increased alanine aminotransferase usually appeared within 3 months after the start of therapy with riluzole; they were usually transient and levels returned to below twice the ULN after 2 to 6 months while treatment was continued. These increases could be associated with jaundice. In patients (n=20) from clinical studies with increases in ALT to more than 5 times the ULN, treatment was discontinued and the levels returned to less than 2 times the ULN within 2 to 4 months in most cases (see section 4.4).

Study data indicate that Asian patients may be more susceptible to liver function test abnormalities - 3.2% (194/5995) of Asian patients and 1.8% (100/5641) of Caucasian patients.

Riluzole oral suspension and riluzole tablets total exposure was bioequivalent, while Cmax of riluzole oral suspension was approximately 20% higher (see section 5.2).

A slightly higher risk of the adverse events considered related to either dose or exposure of riluzole (e.g. dizziness, diarrhoea, asthenia and ALT increase) cannot be excluded.

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 Yellow Card Scheme at Website: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma, and methemoglobinemia have been observed in isolated cases.

In case of overdose, treatment is symptomatic and supportive.