RILUTEK 50mg film-coated tablets medication leaflet

RILUTEK 50 mg film-coated tablets

Each film-coated tablet contains 50 mg of riluzole

For the full list of excipients, see section 6.1.

Film-coated tablet

The tablets are capsule-shaped, white and engraved with “RPR 202” on one side.

RILUTEK is indicated to extend life or the time to mechanical ventilation for patients withamyotrophic lateral sclerosis (ALS).

Clinical trials have demonstrated that RILUTEK extends survival for patients with ALS (see section5.1). Survival was defined as patients who were alive, not intubated for mechanical ventilation andtracheotomy-free.

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

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

Treatment with RILUTEK should only be initiated by specialist physicians with experience in themanagement of motor neurone diseases.

The recommended daily dose in adults or older people is 100 mg (50 mg every 12 hours).

No significant increased benefit can be expected from higher daily doses.

RILUTEK is not recommended for use in patients with impaired renal function, as studies at repeateddoses 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 RILUTEK in thispopulation.

See sections pct. 4.3, pct. 4.4 and 5.2.

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

Oral use

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.

Liver impairment

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

Because of the risk of hepatitis, serum transaminases, including ALT, should be measured before andduring therapy with riluzole. ALT should be measured every month during the first 3 months oftreatment, every 3 months during the remainder of the first year, and periodically thereafter. ALTlevels 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 experiencewith 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.

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

Cases of interstitial lung disease have been reported in patients treated with riluzole, some of themwere severe (see section 4.8). If respiratory symptoms develop such as dry cough and/or dyspnoea,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 ofthe reported cases, symptoms resolved after medicinal product discontinuation and symptomatictreatment.

Studies at repeated doses have not been conducted in patients with impaired renal function (see section4.2).

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodiumfree”.

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

In vitro studies using human liver microsomal preparations suggest that CYP 1A2 is the principalisozyme 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, whileinducers of CYP 1A2 (e.g. cigarette smoke, charcoal-broiled food, rifampicin and omeprazole) couldincrease the rate of riluzole elimination.

RILUTEK is contraindicated in pregnancy (see sections 4.3 and 5.3).

Clinical experience with riluzole in pregnant women is lacking.

RILUTEK is contraindicated in breast-feeding women (see sections 4.3 and 5.3).

It is not known whether riluzole is excreted in human milk.

Fertility studies in rats revealed slight impairment of reproductive performance and fertility at doses of15 mg/kg/day (which is higher than the therapeutic dose), probably due to sedation and lethargy.

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

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

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

Undesirable effects ranked under headings of frequency are listed below, using the followingconvention: 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 availabledata).

Very common Common Uncommon Not known

Blood and Anaemia Severelymphatic neutropenia (seesystem disorders section 4.4)

Immune system Anaphylactoiddisorders reaction,angioedema

Nervous system Headache,disorders dizziness,oral paraesthesia,somnolence

Cardiac Tachycardiadisorders

Respiratory, Interstitial lungthoracic and disease (seemediastinal section 4.4)disorders

Gastrointestinal Nausea Diarrhoea, Pancreatitisdisorders abdominal pain,vomiting

Skin and Rashsubcutaneoustissue disorders

Hepato-biliary Abnormal liver Hepatitisdisorders function tests

General Asthenia Paindisorders andadministrationsite conditions

Hepato-biliary disorders

Increased alanine aminotransferase usually appeared within 3 months after the start of therapy withriluzole; they were usually transient and levels returned to below twice the ULN after 2 to 6 monthswhile 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 discontinuedand the levels returned to less than 2 times the ULN within 2 to 4 months in most cases (see section4.4).

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.

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.

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

In case of overdose, treatment is symptomatic and supportive.

Pharmacotherapeutic group: other nervous system drugs, ATC code: N07XX02.

Although the pathogenesis of ALS is not completely elucidated, it is suggested that glutamate (theprimary excitatory neurotransmitter in the central nervous system) plays a role for cell death in thedisease.

Riluzole is proposed to act by inhibiting glutamate processes. The mode of action is unclear.

In a trial, 155 patients were randomised to riluzole 100 mg/day (50 mg twice daily) or placebo andwere followed-up for 12 to 21 months. Survival, as defined in the second paragraph of section 4.1, wassignificantly extended for patients who received riluzole as compared to patients who receivedplacebo. The median survival time was 17.7 months versus 14.9 months for riluzole and placebo,respectively.

In a dose-ranging trial, 959 patients with ALS were randomised to one of four treatment groups:riluzole 50, 100, 200 mg/day, or placebo and were followed-up for 18 months. In patients treated withriluzole 100 mg/day, survival was significantly higher compared to patients who received placebo. Theeffect of riluzole 50 mg/day was not statistically significant compared to placebo and the effect of200 mg/day was essentially comparable to that of 100 mg/day. The median survival time approached16.5 months versus 13.5 months for riluzole 100 mg/day and placebo, respectively.

In a parallel group study designed to assess the efficacy and safety of riluzole in patients at a late stageof the disease, survival time and motor function under riluzole did not differ significantly from that ofplacebo. In this study the majority of patients had a vital capacity less than 60%.

In a double-blind placebo-controlled trial designed to assess the efficacy and safety of riluzole in

Japanese patients, 204 patients were randomised to riluzole 100 mg/day (50 mg twice daily) orplacebo and were followed-up for 18 months. In this study, the efficacy was assessed on inability towalk alone, loss of upper limb function, tracheostomy, need for artificial ventilation, gastric tubefeeding or death. Tracheostomy-free survival in patients treated with riluzole did not differsignificantly from placebo. However, the power of this study to detect differences between treatmentgroups was low. Meta-analysis including this study and those described above showed a less strikingeffect on survival for riluzole as compared to placebo although the differences remained statisticallysignificant.

The pharmacokinetics of riluzole have been evaluated in healthy male volunteers after single oraladministration of 25 to 300 mg and after multiple-dose oral administration of 25 to 100 mg bid.

Plasma levels increase linearly with the dose and the pharmacokinetic profile is dose-independent.

With multiple dose administration (10 day-treatment at 50 mg riluzole bid), unchanged riluzoleaccumulates in plasma by about 2 fold and steady-state is reached in less than 5 days.

Riluzole is rapidly absorbed after oral administration with maximal plasma concentrations occurringwithin 60 to 90 minutes (Cmax=173 ± 72 (sd) ng/ml). About 90% of the dose is absorbed and theabsolute bioavailability is 60 ± 18%.

The rate and extent of absorption is reduced when riluzole is administered with high-fat meals(decrease in Cmax of 44%, decrease in AUC of 17%).

Riluzole is extensively distributed throughout the body and has been shown to cross the blood brainbarrier. The volume of distribution of riluzole is about 245 ± 69 L (3.4 L/kg). Riluzole is about 97%protein bound and it binds mainly to serum albumin and to lipoproteins.

Unchanged riluzole is the main component in plasma and is extensively metabolised by cytochrome

P450 and subsequent glucuronidation. In vitro studies using human liver preparations demonstratedthat cytochrome P450 1A2 is the principal isoenzyme involved in the metabolism of riluzole. Themetabolites identified in urine are three phenolic derivatives, one ureido-derivative and unchangedriluzole.

The primary metabolic pathway for riluzole is initial oxidation by cytochrome P450 1A2 producing

N-hydroxy-riluzole (RPR112512), the major active metabolite of riluzole. This metabolite is rapidlyglucuronoconjugated to O- and N-glucuronides.

The elimination half-life ranges from 9 to 15 hours. Riluzole is eliminated mainly in the urine.

The overall urinary excretion accounts for about 90% of the dose. Glucuronides accounted for morethan 85% of the metabolites in the urine. Only 2% of a riluzole dose was recovered unchanged in theurine.

There is no significant difference in pharmacokinetic parameters between patients with moderate orsevere chronic renal insufficiency (creatinine clearance between 10 and 50 ml.min-1) and healthyvolunteers after a single oral dose of 50 mg riluzole.

Older people

The pharmacokinetic parameters of riluzole after multiple dose administration (4.5 days of treatmentat 50 mg riluzole bid) are not affected in the older people (>70 years).

The AUC of riluzole after a single oral dose of 50 mg increases by about 1.7 fold in patients with mildchronic liver insufficiency and by about 3 fold in patients with moderate chronic liver insufficiency.

A clinical study conducted to evaluate the pharmacokinetics of riluzole and its metabolite

N-hydroxyriluzole following repeated oral administration twice daily for 8 days in 16 healthy Japaneseand 16 Caucasian adult males showed in the Japanese group a lower exposure of riluzole (Cmax 0.85[90% CI 0.68-1.08] and AUC inf. 0.88 [90% CI 0.69-1.13]) and similar exposure to the metabolite. Theclinical significance of these results is not known.

Riluzole did not show any carcinogenicity potential in either rats or mice.

Standard tests for genotoxicity performed with riluzole were negative. Tests on the major activemetabolite of riluzole gave positive results in two in vitro tests. Intensive testing in seven otherstandard in vitro or in vivo assays did not show any genotoxic potential of the metabolite. On the basisof these data, and taking into consideration the negative studies on the carcinogenesis of riluzole in themouse and rat, the genotoxic effect of this metabolite is not considered to be of relevance in humans.

Reductions in red blood cell parameters and/or alterations in liver parameters were notedinconsistently in subacute and chronic toxicity studies in rats and monkeys. In dogs, haemolyticanaemia was observed.

In a single toxicity study, the absence of corpora lutea was noted at a higher incidence in the ovary oftreated compared to control female rats. This isolated finding was not noted in any other study orspecies.

All these findings were noted at doses which were 2-10 times higher than the human dose of100 mg/day.

In the pregnant rat, the transfer of 14C-riluzole across the placenta to the foetus has been detected. Inrats, riluzole decreased the pregnancy rate and the number of implantations at exposure levels at leasttwice the systemic exposure of humans given clinical therapy. No malformations were seen in animalreproductive studies.

In lactating rats, 14C-riluzole was detected in milk.

Core:

Dibasic calcium phosphate, anhydrous

Micro crystalline cellulose

Colloidal silica, anhydrous

Magnesium stearate

Croscarmellose sodium

Hypromellose

Macrogol 6000

Titanium dioxide (E171)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

Tablets are packaged in opaque pvc/aluminium blister cards.

Each package contains 56 tablets.

No special requirements.

Sanofi Winthrop Industrie82 Avenue Raspail94250 Gentilly

France

EU/1/96/010/001

date of first authorisation: 10 June 1996date of last renewal: 10 June 2006