Consumer medicine information

Riluzole Sandoz

Riluzole

BRAND INFORMATION

Brand name

Riluzole Sandoz

Active ingredient

Riluzole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Riluzole Sandoz.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Riluzole Sandoz.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

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

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

WHAT RILUZOLE SANDOZ IS USED FOR

This medicine 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.

It contains the active ingredient riluzole.

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

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

BEFORE YOU TAKE RILUZOLE SANDOZ

When you must not take it

Do not take this medicine if you have an allergy to:

  • riluzole, the active ingredient, or to any of the other ingredient(s) listed at the end of this leaflet under Product Description

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine if you have liver disease.

Do not take this medicine if you are pregnant. It may affect your developing baby if you take it during pregnancy.

Do not breastfeed if you are taking this medicine. The active ingredient in Riluzole Sandoz may pass into breast milk and there is a possibility that your baby may be affected.

Do not give this medicine to a child. Safety and effectiveness in children have not been established.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • liver disease
  • kidney disease
  • lung disease.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding.

Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell him/ her before you start taking Riluzole Sandoz.

Taking other medicines

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

Some medicines and Riluzole Sandoz may interfere with each other. These include:

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

These medicines may be affected by Riluzole Sandoz or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

Tell your doctor if you smoke and how much coffee you drink. Nicotine and caffeine may affect the amount of Riluzole Sandoz in your body.

HOW TO TAKE RILUZOLE SANDOZ

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How much to take

The standard dose for this medicine is one tablet two times a day.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you.

If you take the wrong dose, Riluzole Sandoz may not work as well and your problem may not improve.

How to take it

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

Do not chew them. These tablets have a special coating to stop them dissolving until they have gone through the stomach and into the intestines, where they can start to work. If you chew them, the coating is destroyed.

When to take it

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

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

Take your prescribed dose at about the same time each.

How long to take it

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

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

Take your dose as soon as you remember, and continue to take it as you would normally.

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 that you missed. This may increase the chance of you getting an unwanted side effect.

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

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Riluzole Sandoz. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

WHILE YOU ARE TAKING RILUZOLE SANDOZ

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Riluzole Sandoz.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while you are taking this medicine tell your doctor immediately.

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

Things you must not do

Do not take more than the recommended dose unless your doctor tells you to.

Do not take Riluzole Sandoz to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Riluzole Sandoz affects you. This medicine may cause dizziness, and drowsiness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Riluzole Sandoz.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

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

These are common side effects of the medicine.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • irregular or fast heartbeat
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • swelling of the hands, feet or legs
  • tingling sensation around the mouth
  • shortness of breath or difficulty breathing.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

If any of the following happen, stop taking this medicine and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • 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.

These are very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

AFTER TAKING RILUZOLE SANDOZ

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

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

Do not store Riluzole Sandoz 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 it 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 the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

PRODUCT DESCRIPTION

What it looks like

Riluzole Sandoz 50 mg - white, capsule shaped, debossed with the text 'RLZ' on one side.

Available in blisters of 56 film-coated tablets.

Ingredients

Active ingredients:

  • Riluzole Sandoz 50 mg - 50 mg riluzole.

Inactive ingredients:

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

This medicine does not contain lactose, gluten, sucrose, tartrazine or any other azo dyes.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

This leaflet was revised in April 2019.

Australian Register Number(s)

50 mg film-coated tablets: AUST R 167717 (blisters)

Published by MIMS June 2019

BRAND INFORMATION

Brand name

Riluzole Sandoz

Active ingredient

Riluzole

Schedule

S4

 

1 Name of Medicine

Riluzole.

6.7 Physicochemical Properties

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. Riluzole has a pKa of 3.8 and a log P (octanol/0.1 N aq. HCL) of 0.69.
The chemical name of riluzole is 2-amino-6-trifluoromethoxybenzothiazole. Its empirical formula is C8H5F3N2OS (MW: 234.20).

Chemical structure.

Its chemical structure:

CAS number.

1744-22-5.

2 Qualitative and Quantitative Composition

Each Riluzole Sandoz 50 mg film-coated tablet contains 50 mg riluzole, a benzothiazole.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Riluzole Sandoz 50 mg film-coated tablets: white, capsule shaped, debossed with the text 'RLZ' on one side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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 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).

Clinical trials.

Two multinational, multicentre, 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 (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 has 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 twofold 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 was 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 (creatine clearance between 10 and 50 mL/min) and healthy subjects. A multiple dose study in renal 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 threefold 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 an mg/m2 basis.

4 Clinical Particulars

4.1 Therapeutic Indications

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

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.

4.8 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 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 n.e.c., completed suicide, confusion, delirium, hallucination, personality change due to a general medical condition.

Respiratory, thoracic and mediastinal disorders.

Uncommon: respiratory failure (exc neonatal), interstitial lung disease (see Section 4.4 Special Warnings and Precautions for Use).
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.

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 http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

Adults.

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.

Children.

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

Method of administration.

Due to the reduction in absorption observed when administered with high fat meals, Riluzole Sandoz should not be taken with a fat containing meal.

Dosage adjustment.

Renal impairment.

See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use.

Hepatic impairment.

See Section 4.4 Special Warnings and Precautions for Use.

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.

4.9 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 should be supportive and symptomatic.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

The tablet also contains calcium hydrogen phosphate, microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate and croscarmellose sodium as excipients. The tablet coating contains hypromellose, macrogol 6000, titanium dioxide and purified water.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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 and moisture.

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 in accordance with local requirements.

Summary Table of Changes