Consumer medicine information

Rilutek

Riluzole

BRAND INFORMATION

Brand name

Rilutek

Active ingredient

Riluzole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Rilutek.

SUMMARY CMI

Rilutek®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Rilutek?

Rilutek contains the active ingredient riluzole. Rilutek is used in the treatment of amyotrophic lateral sclerosis (ALS), a form of motor neurone disease which can cause muscle degeneration and muscle weakness.

For more information, see Section 1. Why am I using Rilutek? in the full CMI.

2. What should I know before I use Rilutek?

Do not use if you have ever had an allergic reaction to Rilutek or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. Talk to your doctor if you smoke cigarettes or consume caffeine.

For more information, see Section 2. What should I know before I use Rilutek? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Rilutek and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Rilutek?

  • The recommended dose is usually one tablet two times a day.
  • Rilutek may not work as well if it is taken at the same time as your meals. Rilutek should not be taken immediately before or after meals, especially meals which may contain food high in fat.
  • Swallow Rilutek tablets whole with a full glass of water. Do not chew the tablets.

More instructions can be found in Section 4. How do I use Rilutek? in the full CMI.

5. What should I know while using Rilutek?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking Rilutek.
  • Tell your doctor straight away if you are pregnant, or become pregnant, while you are taking Rilutek.
  • Tell your doctor or dentist that you are taking Rilutek if you plan to have surgery that needs a general anaesthetic.
Things you should not do
  • Do not stop using this medicine or lower the dosage without checking with your doctor.
  • Do not take more than the recommended dose unless your doctor tells you to.
Driving or using machines
  • Make sure you know how Rilutek affects you before you drive or use any machines or tools. Rilutek may cause drowsiness or dizziness in some people. If this occurs, do not drive or operate machinery.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep Rilutek in the blister pack until it is time to take them.
  • Keep Rilutek in a cool, dry place, protected from light, where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using Rilutek? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. Tell your doctor or pharmacist if you do not feel well whilst you are taking Rilutek. Most of the side effects from taking Rilutek are minor and temporary, such as headache, nausea and weakness. However, some serious side effects may need urgent medical attention. Examples of serious side effects include severe upper stomach pain and itching or yellowing of the skin.
For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Rilutek®

Active ingredient(s): riluzole

Consumer Medicine Information (CMI)

This leaflet provides important information about using Rilutek. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Rilutek.

Where to find information in this leaflet:

1. Why am I using Rilutek?
2. What should I know before I use Rilutek?
3. What if I am taking other medicines?
4. How do I use Rilutek?
5. What should I know while using Rilutek?
6. Are there any side effects?
7. Product details

1. Why am I using Rilutek?

Rilutek contains the active ingredient riluzole. Rilutek works on how the nerve cells in your central nervous system communicate with each other.

Rilutek is used in the treatment of amyotrophic lateral sclerosis (ALS), a form of motor neuron disease, which can cause muscle degeneration and muscle weakness.

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

  • It is important to remember that you may not feel any different when you take Rilutek. The benefits of using Rilutek may not be noticeable to you. You should not stop taking Rilutek without speaking to your doctor first.

2. What should I know before I use Rilutek?

Warnings

Do not use Rilutek if:

  • you are allergic to riluzole, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • you have liver disease
  • you are pregnant or intend to become pregnant
  • you are breastfeeding or intend to breastfeed
  • the expiry date (EXP) printed on the pack has passed
  • the packaging is damaged or shows signs of tampering.

Check with your doctor if you:

  • have any other medical conditions, especially liver disease, kidney disease or lung disease
  • take any medicines for any other condition
  • are allergic to any of the ingredients listed at the end of this leaflet.

Tell your doctor if you plan to have surgery.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

This medicine should not be used during pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

This medicine should not be used if you are breastfeeding.

Use in children and adolescents

Do not use Rilutek in children or adolescents. There is no experience with the use of this medicine in this age group.

Cigarette smoke and caffeine

Tell your doctor if you smoke cigarettes or consume caffeine. Cigarette smoke and caffeine may affect the amount of Rilutek in your body.

If you have not told your doctor about any of the above, tell them before you take this medicine.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Rilutek and affect how it works. Some medicines may be affected by Rilutek.

You may need to use different amounts of your medicine or you may need to take different medicines. Your doctor will advise you.

Medicines that may increase the effect of Rilutek include:

  • amitriptyline
  • clomipramine
  • diazepam
  • diclofenac
  • fluvoxamine
  • imipramine
  • quinolone antibiotics (e.g. ciprofloxacin, norfloxacin)
  • theophylline

Medicines that may reduce the effect of Rilutek include:

  • omeprazole
  • rifampicin

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Rilutek.

Tell your doctor if you smoke cigarettes or consume caffeine. Cigarette smoke and caffeine may affect the amount of Rilutek in your body.

4. How do I use Rilutek?

How much to take

  • Your doctor will tell you how many tablets you should take, and when to take them.
  • The recommended dose is usually one tablet two times a day.
  • Do not take more than the dose your doctor has directed.
  • Talk to your doctor if you are unsure what dose to take.
  • You should not change the dosage without speaking to your doctor first.
  • Follow the instructions provided and take Rilutek until your doctor tells you to stop.

When to take Rilutek

  • Take your prescribed dose at about the same time each day.
  • Rilutek should not be taken immediately before or after meals, especially meals which may contain food high in fat.
  • Rilutek may not work as well if it is taken at the same time as your meals.

How to take Rilutek

  • Swallow Rilutek tablets whole with a full glass of water.
  • Do not chew the tablets.

If you forget to take Rilutek

Rilutek should be taken regularly at the same time each day.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

  • If you are not sure what to do, ask your doctor.

If you take too much Rilutek

If you think that you have taken too much Rilutek, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26 in Australia or 0800 764 766 in New Zealand), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Rilutek?

Things you should do

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking Rilutek.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking Rilutek.

Call your doctor straight away if you:

  • become pregnant while you are taking this medicine.

Remind any doctor, dentist or pharmacist you visit that you are taking Rilutek.

Things you should not do

  • Do not stop taking this medicine or lower the dosage without checking with your doctor.
  • Do not take more than the recommended dose unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not use this medicine to treat any other complaints unless your doctor tells you to.

Monitoring during treatment

During your treatment with Rilutek, your doctor will do some blood tests from time to time to check for any possible signs of liver damage.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Rilutek affects you.

Rilutek 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.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the box or blister pack, they may not keep well.
  • Keep your tablets in a cool, dry place, protected from light, where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Heat and dampness can destroy some medicines.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

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

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
General:
  • weakness or loss of strength
Gut-related:
  • stomach ache
  • nausea
  • vomiting
Skin-related:
  • rash
  • flaking skin
Joint-related:
  • joint stiffness
Nervous system-related:
  • headache
  • dizziness
  • sleepiness
Speak to your doctor if you have any of these less serious side effects and they worry you.
These are the most common side effects of this medicine.

Serious side effects

Serious side effectsWhat to do
Gut-related:
  • severe upper stomach pain, often with nausea and vomiting
Skin-related:
  • swelling of the hands, feet or legs
  • itching or yellowing of the skin
Blood-related:
  • bruising more easily
Breathing-related:
  • shortness of breath
  • difficulty breathing
Heart-related:
  • irregular or fast heartbeat
Immune system-related:
  • frequent infections, such as fever, severe chills, sore throat or mouth ulcers
Nervous system-related:
  • tingling sensations around the mouth
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
You may need urgent medical attention or hospitalisation.
Serious side effects are rare.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems in Australia or Medsafe in New Zealand at pophealth.my.site.com/carmreportnz/s/. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What Rilutek contains

Active ingredient
(main ingredient)		riluzole 50mg
Other ingredients
(inactive ingredients)		calcium hydrogen phosphate
microcrystalline cellulose
colloidal anhydrous silica
magnesium stearate
croscarmellose sodium
hypromellose
macrogol 6000
titanium dioxide

Do not take this medicine if you are allergic to any of these ingredients.

What Rilutek looks like

Rilutek tablets are white and capsule-shaped. Each tablet is engraved with the text RPR 202 (AUST R 79744).

Each pack contains 56 tablets.

Who distributes Rilutek

Distributed in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113
Freecall: 1800 818 806
Email: [email protected]

Distributed in New Zealand by:

Pharmacy Retailing (NZ) Ltd t/a Healthcare Logistics
PO Box 62027
Sylvia Park Auckland 1644
Freecall: 0800 283 684
Email: [email protected]

This leaflet was prepared in July 2024.

Published by MIMS September 2024

BRAND INFORMATION

Brand name

Rilutek

Active ingredient

Riluzole

Schedule

S4

 

1 Name of Medicine

Riluzole.

2 Qualitative and Quantitative Composition

Rilutek 50 mg riluzole film-coated tablets.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White, capsule shaped, engraved with the text 'RPR 202'.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of 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, Rilutek 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 Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment.

Patients with impaired hepatic function.

See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment.

4.3 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.

4.4 Special Warnings and Precautions for Use

Neutropenia.

There have been three reports (3/5000) of marked neutropenia where absolute neutrophil count was less than 500/mm3. See Section 4.8 Adverse Effects (Undesirable 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 Section 4.8 Adverse Effects (Undesirable 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.

Use in hepatic 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.

Use in renal impairment.

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

Use in the elderly.

No data available.

Paediatric use.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of 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 CYP1A2 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 CYP2D6, CYP2C19, CYP3A4, 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 CYP1A2 (e.g. theophylline, caffeine and tacrine). It is not known 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 CYP1A2 activity. Potential inhibitors of CYP1A2 (e.g. caffeine, diclofenac, diazepam, nicergoline, clomipramine, imipramine, fluvoxamine, phenacetin, theophylline, amitriptyline and quinolones) could decrease the rate of riluzole elimination, while inducers of CYP1A2 (e.g. cigarette smoke, charcoal broiled food, rifampicin and omeprazole) could increase the rate of riluzole elimination.

4.6 Fertility, Pregnancy and Lactation

Effects on 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).
(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.
 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.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable 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 post-marketing 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 Section 4.8 Adverse Effects (Undesirable Effects)).
Rare: Asphyxia, respiratory distress.

Skin and subcutaneous tissue disorders.

Rare: Dermatitis.
Very rare: Angioedema.

Blood and lymphatic system disorders.

Uncommon: Anaemia.
Rare: Erythropenia, leucopenia, 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.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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

Mechanism of action.

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 neurons 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 motor neurons from the excitotoxic effects of glutamic acid and prevents the death of cortical neurons 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 5,000 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).

Clinical trials.

Two multinational, multicenter, double blind, parallel group trials have demonstrated that Rilutek 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 (Chi-square, 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.

5.2 Pharmacokinetic Properties

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 CYP1A2 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 CYP2D6, CYP2C19, CYP3A4 and CYP2E1 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.

Excretion.

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 body weight). 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 Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use.

5.3 Preclinical Safety Data

Genotoxicity.

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).

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Calcium hydrogen phosphate, microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate, croscarmellose sodium, hypromellose, macrogol 6000, titanium dioxide, purified water.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.
Keep out of the reach of children.

6.5 Nature and Contents of Container

Available in a blister pack of 56 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Rilutek is a tablet containing riluzole, a benzothiazole. Chemical name: 2-amino-6 -trifluoromethoxybenzothiazole.
Riluzole is a white to slightly yellow, fine crystalline, non-hygroscopic 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.

Chemical structure.


CAS number.

CAS 1744-22-5.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes