Consumer medicine information

APO-Riluzole Tablets

Riluzole

BRAND INFORMATION

Brand name

APO-Riluzole Tablets

Active ingredient

Riluzole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Riluzole Tablets.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about riluzole. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

The name of your medicine is APO-Riluzole. It contains the active ingredient Riluzole.

It is used to treat people with amyotrophic lateral sclerosis, which can cause muscle degeneration leading to muscle weakness. It is a form of Motor Neurone Disease.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

It is important to remember that you may not feel any different when you take riluzole. The benefits of using riluzole may not be noticeable to you.

You should not stop taking riluzole without speaking to your doctor first

There is no evidence that this medicine is addictive.

Use in children

This medicine should not be used in children.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You have liver disease
  • You are pregnant.
    Riluzole may affect your developing baby if you take it during pregnancy.
  • You are breastfeeding.
    Riluzole may pass into human breast milk.
  • You are hypersensitive to, or have had an allergic reaction to, riluzole or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • liver disease
  • kidney disease
  • lung disease
  1. You are currently pregnant or you plan to become pregnant. Do not take this medicine whilst pregnant.
  2. You are currently breastfeeding or you plan to breast-feed. Do not take this medicine whilst breastfeeding.
  3. You have recently been vaccinated or plan to get a vaccination.
  4. You are planning to have surgery or an anaesthetic.
  5. You are currently receiving or are planning to receive dental treatment.
  6. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with riluzole. These include:

  • theophylline - a medicine used to treat asthma.
  • amitriptyline - a medicine used to treat depression
  • tacrine - a medicine used in patients with Alzheimer's Disease
  • some types of antibiotics e.g. rifampicin and quinolones
  • omeprazole - a medicine used to treat gastric ulcers.
  • some medicines used to treat depression e.g. Clomipramine and fluvoxamine
  • diazepam - a medicine for sedation.
  • diclofenac - a medicine used to reduce pain and inflammation.

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with riluzole.

Tell your doctor if you smoke and how much coffee you drink.

Nicotine and caffeine may affect the amount of Riluzole in your body.

How to take this medicine

Follow carefully all directions given to you by your doctor or pharmacist. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor or pharmacist will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

How to take it

Swallow tablets with a full glass of water or other liquid.

When to take it

Riluzole should not be taken immediately before or after meals, especially meals which may contain food high in fat.

Riluzole may not work as well if it is taken at the same time as your meals.

Take this medicine at the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

Make sure you have enough to last over weekends and holidays.

Do not stop taking riluzole unless your doctor tells you to, even if you feel better.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time. Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses.

This may increase the chance of you experiencing side effects.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor, or the Poisons Information Centre (Tel: 13 11 26 in Australia or 0800 764 766 in New Zealand).

Alternatively go to the Accident and Emergency department at your nearest hospital, Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you plan to have any vaccinations or immunisations
  • you are pregnant or are planning to become pregnant
  • you are breastfeeding or are planning to breast-feed
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects. Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you.

This medicine may cause drowsiness or dizziness in some people. Make sure you know how you react to it before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking riluzole or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Tell your doctor if you notice any of the following:

  • stomach ache, nausea or vomiting
  • headache
  • joint stiffness
  • skin problems e.g. rash, flaking skin
  • dizziness
  • sleepiness
  • weakness or loss of strength

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and you may need urgent medical attention or hospitalisation:

  • irregular or fast heartbeat
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • swelling of the hands, feet or legs
  • tingling sensations around the mouth
  • shortness of breath or difficulty breathing
  • Severe upper stomach pain, often with nausea and vomiting
  • If your skin becomes itchy or yellow or if you start to bleed or bruise easily. You may be developing a liver problem.

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to riluzole, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Riluzole looks like

The 50 mg tablets are white to off white coloured, film coated, capsule shaped, biconvex tablets "APO" engraved on one side and "RI-50" engraved on other side

APO-Riluzole comes in blister packs of 56 tablets

APO-Riluzole also comes in bottles* of 56, 100 & 500 tablets.

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each tablet contains 50 mg of riluzole as the active ingredient.

It also contains the following inactive ingredients:

  • Calcium hydrogen phosphate
  • microcrystalline cellulose
  • croscarmellose sodium
  • magnesium stearate
  • hypromellose
  • macrogol 8000
  • titanium dioxide
  • purified talc

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

APO-Riluzole 50 mg tablets (blister pack):
AUST R 168091.

APO-Riluzole 50 mg tablets (bottle):
AUST R 168094.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113
Australia

Apotex NZ Ltd
32 Hillside Road
Glenfield
Private Bag 102-995
North Shore Mail Centre
Auckland, New Zealand

Apotex Pty Ltd is the licensee of the registered trademarks APO and APOTEX from the registered proprietor, Apotex Inc.

This leaflet was last updated in:
November 2015

BRAND INFORMATION

Brand name

APO-Riluzole Tablets

Active ingredient

Riluzole

Schedule

S4

 

Name of the medicine

Riluzole.

Excipients.

Calcium hydrogen phosphate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, hypromellose, macrogol 8000, purified talc and titanium dioxide.

Description

Chemical name: 2-amino-6- trifluoromethoxybenzothiazole. Molecular formula: C8H5F3N2OS. MW: 234.2. CAS: 1744-22-5. Riluzole is a white to slightly yellow, fine crystalline, nonhygroscopic powder. It is very slightly soluble in water and 0.1 N sodium hydroxide, sparingly soluble in 0.1 N hydrochloric acid; and very soluble in methanol, acetone, acetonitrile, dichloromethane and dimethyl sulfoxide.

Pharmacology

Pharmacodynamic properties.

The aetiology and pathogenesis of amyotrophic lateral sclerosis (ALS) are not known, although a number of hypotheses have been advanced. One hypothesis is that motor neurones made vulnerable through either genetic predisposition or environmental factors, are injured by glutamate. In some cases of familial ALS, enzyme superoxide dismutase has been found to be defective.
The mechanism of action of riluzole has not been completely elucidated but evidence to date suggests that it may involve inactivation of voltage dependent sodium channels and impairment of glutamatergic neurotransmission.
There are no validated animal models of ALS in which to test riluzole. Riluzole has been shown to cross the blood brain barrier and to possess neuroprotective properties in various in vivo experimental models of neuronal injury known to involve excitotoxic mechanisms, such as cerebral ischemia. In vitro, riluzole protects cultured rat motorneurones from the excitotoxic effects of glutamic acid and prevents the death of cortical neurones induced by anoxia. In healthy volunteers at therapeutic doses, riluzole has been shown to protect to some extent against the hypobaric hypoxia induced at an equivalent altitude of 5000 m. Also, riluzole moderately reduces the cerebral metabolic rate of glucose as shown by PET scan.
Due to its blockade of glutamatergic neurotransmission, riluzole also has myorelaxant and sedative properties in animal studies at doses of 30 mg/kg (about 20 times the human recommended daily dose) and anticonvulsant properties at doses of 2.5 mg/kg (about 2 times the human recommended daily dose).

Pharmacokinetics.

The pharmacokinetics of riluzole have been evaluated in healthy male volunteers after single oral administration 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. Steady-state plasma levels are reached within 3 to 8 days.

Absorption.

Riluzole is rapidly absorbed after oral administration with maximal plasma concentrations occurring within 60 to 90 minutes (Cmax = 173 ± 72 (sd) nanogram/mL). About 90% of the dose is absorbed and the absolute bioavailability is 60 ± 18%. With multiple dose administration (10 day treatment at 50 mg riluzole bid), unchanged riluzole accumulates in plasma by about 2-fold and steady state is reached in less than 5 days.
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%).

Distribution.

Riluzole is extensively distributed throughout the body and has been shown to cross the blood brain barrier. 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.

Metabolism.

Riluzole is extensively metabolized to six major and a number of minor metabolites, not all of which have been identified. Some metabolites appear pharmacologically active in in vitro assays. The metabolism of riluzole is mostly hepatic and consists of cytochrome P450 dependent hydroxylation and glucuronidation.
There is marked interindividual variability in the clearance of riluzole, probably attributable to variability of CYP 1A2 activity, the principal isozyme involved in N-hydroxylation.
In vitro studies using liver microsomes show that hydroxylation of the primary amine group producing N-hydroxyriluzole is the main metabolic pathway in human, monkey, dog and rabbit. In humans, cytochrome P450 1A2 is the principal isozyme involved in N-hydroxylation. In vitro studies predict that CYP 2D6, CYP 2C19, CYP 3A4 and CYP 2E1 are unlikely to contribute significantly to riluzole metabolism in humans. Whereas direct glucuroconjugation of riluzole (involving the glucurotransferase isoform UGT-HP4) is very slow in human liver microsomes, N-hydroxyriluzole is readily conjugated at the hydroxylamine group resulting in the formation of O- (> 90%) and N-glucuronides.

Elimination.

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 more than 85% of the metabolites in the urine. Only 2% of a riluzole dose was recovered unchanged in the urine.

Special populations.

Elderly.

The pharmacokinetics of riluzole in elderly subjects were compared to young healthy subjects and no clinically significant differences were found.

Gender.

No gender effect on the pharmacokinetics of riluzole was found, however CYP1A2 activity has been reported to be lower in women than in men and thus a higher blood concentration of riluzole and its metabolites is possible in women.

Smoking.

Cigarette smoking is known to induce CYP1A2 and thus it is possible that patients who smoke may eliminate riluzole faster. There is no information available on the effect or need for dosage adjustment.

Race.

Clearance of riluzole in native Japanese subjects was found to be 50% lower compared to Caucasian subjects (after normalizing for bodyweight). Although it is not clear if this difference is due to genetic or environmental factors (e.g. smoking, alcohol, coffee and dietary preferences) it is possible that Japanese subjects may possess a lower capacity (oxidative and/or conjugative) for metabolising riluzole. There are no studies, however, of lower doses in Japanese subjects.

Children.

The safety and efficacy of riluzole in children has not been studied.

Renal impairment.

Study results showed that the pharmacokinetic profile of a single dose of riluzole is similar between patients with moderate or severe chronic renal insufficiency (creatinine clearance between 10 and 50 mL/min) and healthy subjects. A multiple dose study in renally impaired patients has not been performed.

Hepatic impairment.

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

Clinical Trials

Two multinational, multicenter, double blind, parallel group trials have demonstrated that riluzole extends survival for patients with ALS regardless of the onset type. It is also concluded that the survival benefit is maintained.
In a first trial, 155 patients were randomised to riluzole 100 mg/day (50 mg twice daily) or placebo and were followed-up for 12 to 21 months. While there was no change from baseline in the functional evaluation, survival was significantly prolonged for patients who received riluzole as compared to patients who received placebo. The median survival time was 17.7 months versus 14.9 months for riluzole and placebo respectively.
Riviere et al. (1998) analysed extended survival in ALS patients treated with riluzole in this study. Post hoc analysis suggested that the patients receiving riluzole remained in the milder health states longer (p < 0.05, Cox model). Patients with advanced disease were less responsive. See Figure 1.
In a second 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 with riluzole 100 mg/day, survival was significantly longer compared to patients who received placebo. The median survival time approached 16.5 months versus 13.5 months for riluzole 100 mg/day and placebo, respectively. There were no changes from baseline observed in the functional evaluation. The effect of 50 mg/day was not statistically significant compared to placebo and the effect of 200 mg/day was essentially comparable to that of 100 mg/day. See Figure 2.
A separate compassionate use study (n = 168), enabling access to treatment for patients excluded from the two pivotal studies, was designed to assess the efficacy and safety of riluzole in patients at a late stage of the disease. In this population with decreased respiratory function (baseline vital capacity less than 60%), survival time and motor function in the riluzole group did not differ significantly from that of placebo. It was anticipated that up to 300 patients would enter this study, but only 168 were enrolled (86 received placebo, 82 received riluzole). Thus the statistical power of the study was diminished.
In a double blind placebo controlled trial designed to assess the efficacy and safety of riluzole in Japanese patients, patients were randomised to riluzole 100 mg/day (50 mg twice daily) or placebo and were followed-up for 18 months. In this study, the efficacy was assessed on inability to walk alone, loss of upper limb function, tracheostomy, need for artificial ventilation, gastric tube feeding or death. Tracheostomy free survival in patients treated with riluzole did not differ significantly from placebo. Due to the low incidence of ALS in Japan, and for practical reasons, the study was limited to 100 patients per treatment group. The small size of this study resulted in a lack of statistical power to detect a significant difference between riluzole and placebo.
Meta-analysis, including this study and those described above, showed a less striking effect of survival for riluzole as compared to placebo although the differences remained statistically significant.
A Cochrane review of data from the two pivotal studies (first trial and dose ranging trial) found that there was a significant difference in percent mortality at 12 months between riluzole 100 mg/day and placebo groups. Results were expressed as odds ratios (OR) and 95% CI for continuous variables. With regards to the primary outcome (mortality at 12 months) the OR for the combined studies was 0.57 (95% CI 0.41 to 0.80, p = 0.001). There was no evidence of heterogeneity (chisquare, p = 0.58). Overall there was a 23% reduction in risk of death in those patients receiving riluzole (p = 0.0509).
A United Kingdom National Institute for Clinical Excellence (NICE) review of the clinical effectiveness of riluzole found that it was effective in the treatment of ALS. In a meta-analysis which included data from the two pivotal studies and the compassionate study, it was found that for tracheostomy free survival over 18 months the hazard ratio was 0.83 (95% CI 0.69-0.99). The report concluded that there was evidence of a modest benefit for patients taking riluzole.

Indications

APO-Riluzole is indicated for the treatment of patients with amyotrophic lateral sclerosis (ALS).

Contraindications

Patients who have a history of severe hypersensitivity reactions to riluzole or any of the tablet components.
Patients who have a hepatic disease or hepatic impairment (baseline transaminases greater than 3 times the upper limit of normal).
Patients who are pregnant or lactating.

Precautions

Liver impairment.

Riluzole is contraindicated in patients with hepatic disease or hepatic impairment (baseline transaminases greater than 3 times the upper limit of normal).
Riluzole should be prescribed with care in patients with a history of abnormal liver function, or in patients with slightly elevated serum transaminase (ALT/ SGPT; AST/ SGOT up to 3 times the 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.
Elevations of alanine aminotransferase (ALT) levels to more than 3 times the upper limit of the normal range (ULN) were observed in about 10% of the patients treated with riluzole compared to 3.7% in the placebo group; levels increased to more than 5 times the ULN in about 3% of the patients treated with riluzole compared to 2% of the placebo treated patients. The increases in ALT usually appeared within 3 months after the start of therapy with riluzole; they were usually transient and levels returned to below 2 times the ULN after 2 to 6 months while treatment was continued. These increases were rarely associated with jaundice. In patients 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.
Because of risks 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 five 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.

Renal insufficiency.

Riluzole should be used with caution in patients with renal insufficiency.

Neutropenia.

There have been three reports (3/5000) of marked neutropenia where absolute neutrophil count was less than 500/mm3. See Adverse Effects. 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.

Interstitial lung disease.

Cases of interstitial lung disease have been reported in patients treated with riluzole, some of them were severe (see Adverse Effects). If respiratory symptoms develop such as dry cough and/or dyspnea, 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 reported cases, symptoms resolved after drug discontinuation and symptomatic treatment.

Carcinogenicity.

Two long-term (2 years) carcinogenicity studies have been completed in rats and mice. Riluzole showed no evidence of carcinogenic potential in rats and mice treated orally for 2 years at doses of 10 and 20 mg/kg/day, respectively. These doses were approximately 0.85 times the recommended maximum dose of 100 mg daily, on a mg/m2 basis.
There was no evidence of a genotoxic potential in standard assays for gene mutations (microbial mutagenicity test, mouse lymphoma assay in L5178Y cells) and chromosomal damage (chromosomal aberrations in human lymphocytes in vitro, rat cytogenetic assay in vivo and mouse micronucleus assay).

Impairment of fertility.

Riluzole impaired fertility when administered to male and female rats prior to mating and during mating at an oral dose of 15 mg/kg (approximately 13 times human exposure at the maximum recommended clinical dose of 100 mg, based on AUC).

Use in pregnancy.

(Category B3)
In the pregnant rat, the transfer of 14C-riluzole across the placenta to the foetus has been detected. There was no evidence of embryotoxicity or teratogenicity in the offspring of rats or rabbits following maternal treatment with riluzole during organogenesis at oral doses of up to 27 and 60 mg/kg/day respectively, corresponding to plasma exposures (based on AUC) 61 and 18 times higher than those anticipated in clinical use. However, foetal growth and development were slightly retarded, possibly as a consequence of maternal toxicity. Foetal growth was not affected following maternal exposure to riluzole at levels approximately 6 to 8-fold higher (based on AUC) than those anticipated in clinical use.
When administered to rats prior to and during mating (males and females) and throughout gestation and lactation (females), riluzole produced adverse effects on pregnancy (decreased implantations) and offspring viability and growth at an oral dose of 15 mg/kg (approximately 13 times human exposure at the maximum recommended clinical dose of 100 mg, based on AUC).
There are no adequate and well controlled studies in pregnant women. Riluzole must not be used in pregnant women.

Use in lactation.

14C-riluzole and/or its metabolites were detected in the milk of lactating rats at levels 2.5-fold higher than those appearing in maternal plasma. There was an increased incidence of postnatal mortality in the offspring of rats treated with riluzole during the perinatal period at oral doses of 15 mg/kg/day, which represents exposure (on the basis of AUC) to levels 13-fold higher than those anticipated in clinical use. It is not known whether riluzole is excreted in human milk; therefore, women should not breastfeed during treatment with riluzole.

Driving and operating machinery.

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

Children.

The safety and effectiveness of riluzole in any neurodegenerative process occurring in children or adolescents have not been established.

Interactions

There have been no clinical studies to evaluate the drug interactions of riluzole with other drugs. Experiments on mice and rats indicated that riluzole potentiated the hypnotic effects of hexobarbitone and chlorpromazine.
The metabolism of riluzole is mostly hepatic and consists of cytochrome P450 dependent hydroxylation and glucuronidation. There is marked interindividual variability in the clearance of riluzole, probably attributable to variability of CYP 1A2 activity, the principal isozyme involved in N-hydroxylation. In vitro studies using liver microsomes show that hydroxylation of the primary amine group producing N-hydroxyriluzole is the main metabolic pathway in humans. In humans, cytochrome P450 1A2 is the principal isozyme involved in N-hydroxylation. In vitro studies predict that CYP 2D6, CYP 2C19, CYP 3A4, and CYP2E1 are unlikely to contribute significantly to riluzole metabolism in humans.

Effect of riluzole on the metabolism of other drugs.

Potential interactions may occur when riluzole is given concurrently with other agents which are also metabolized primarily by CYP 1A2 (e.g. theophylline, caffeine and tacrine). It is not know whether riluzole has any potential for enzyme induction in humans.

Effect of other drugs on riluzole metabolism.

Potential interactions may occur when riluzole is given concurrently with other agents that affect CYP 1A2 activity. Potential inhibitors of CYP 1A2 (e.g. caffeine, diclofenac, diazepam, nicergoline, clomipramine, imipramine, fluvoxamine, phenacetin, theophylline, amitriptyline and quinolones) could 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.

Adverse Effects

Clinical trials.

In phase III studies conducted in North America and Europe, the most frequent side effects related to riluzole were asthenia, nausea, and elevations in liver function tests. Table 1 includes all the adverse events that occurred at a frequency of 1% or more among ALS patients receiving riluzole 100 mg/day.
The following is a list of adverse reactions reported from clinical trials and postmarketing studies with an incidence of less than 1%: uncommon 0.1-1%; rare 0.01-0.1%; very rare < 0.01%; not known (cannot be estimated from the available data).

Cardiac disorders.

Rare: angina unstable, atrial fibrillation, cardiac failure. Very rare: arrhythmia.

Gastrointestinal disorders.

Uncommon: pancreatitis. Rare: gastrointestinal disorder, gastric ulcer, gastrointestinal haemorrhage, gastrointestinal irritation, melaena.

General disorders and administration site conditions.

Rare: condition aggravated, malaise, weakness, pyrexia. Very rare: anaphylactoid reaction.

Hepatobiliary disorders.

Rare: hepatitis, jaundice, hepatocellular damage.

Immune system disorders.

Uncommon: anaphylactoid reaction, angioedema. Rare: hypersensitivity.

Laboratory investigations.

Rare: gamma-glutamyltransferase increased, liver function tests abnormal, transaminase increased, blood bilirubin increased, blood alkaline phosphatase increased, haematocrit decreased, blood creatine phosphokinase increased, glycosuria present, haemoglobin decreased, leukocyte count decreased, platelet count decreased.

Metabolism and nutrition disorders.

Rare: dehydration. Very rare: hyponatraemia.

Nervous system disorders.

Very rare: amnesia.

Psychiatric disorders.

Rare: motor dysfunction, paraesthesia (not elsewhere classified), completed suicide, confusion, delirium, hallucination, personality change due to a general medical condition.

Respiratory, thoracic and mediastinal disorders.

Uncommon: respiratory failure (except neonatal), interstitial lung disease (see Precautions). Rare: asphyxia, respiratory distress.

Skin and subcutaneous tissue disorders.

Rare: dermatitis. Very rare: angioedema.

Blood and lymphatic system disorders.

Uncommon: anaemia. Rare: erythropenia, leucopoenia, thrombocytopenia. Very rare: neutropenia (among approximately 5000 patients given riluzole for ALS, there were three cases of marked neutropenia (absolute neutrophil count less than 500/mm3), all seen within the first 2 months of riluzole treatment. In one case, neutrophil counts rose on continued treatment. In a second case, counts rose after therapy was stopped. A third case was associated with marked anaemia and the aetiology is uncertain).

Dosage and Administration

The recommended daily dose in adults or elderly is 100 mg (50 mg every 12 hours). No significant increase in benefit can be expected from higher daily doses.
Due to the reduction in absorption observed when administered with high fat meals, riluzole should not be taken with a fat containing meal.

Children.

The safety and effectiveness of riluzole in any neurodegenerative process occurring in children or adolescents have not been established.

Patients with impaired renal function.

See Precautions.

Patients with impaired hepatic function.

See Contraindications and Precautions.

Overdosage

Neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma and methemoglobinaemia have been observed in isolated cases. Severe methemoglobinaemia may be rapidly reversible after treatment with methylene blue.
In case of overdose, treatment is symptomatic and supportive.
Contact the Poisons Information Centre on 131 126 (Australia) for advice on the management of overdosage.

Presentation

Tablets, 50 mg (white to off white, capsule shaped, biconvex, film coated, engraved APO on one side and RI-50 on the other side): 56's (blister pack, AUST R 168091); 56's, 100's, 500's (bottle*, AUST R 168094).
*Not currently marketed in Australia.
APO-Riluzole tablets are intended for oral administration.

Storage

Store below 25°C.

Poison Schedule

S4.