Consumer medicine information

Aubagio

Teriflunomide

BRAND INFORMATION

Brand name

Aubagio

Active ingredient

Teriflunomide

Schedule

SUMMARY CMI

Aubagio^®

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 Aubagio?

Aubagio contains the active ingredient teriflunomide. Aubagio is used to treat relapsing forms of multiple sclerosis (MS). For more information, see Section 1. Why am I using Aubagio? in the full CMI.

2. What should I know before I use Aubagio?

Do not use if you have ever had an allergic reaction to teriflunomide, leflunomide 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.

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

3. What if I am taking other medicines?

Some medicines may interfere with Aubagio 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 Aubagio?

Follow all directions given to you by your doctor and pharmacist carefully. The usual dose for this medicine is one 14 mg tablet per day. Swallow the tablet whole with a glass of water.

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

5. What should I know while using Aubagio?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using Aubagio. If you become pregnant while you are taking this medicine, stop taking it and tell your doctor or pharmacist immediately.
Things you should not do	Do not stop taking Aubagio, or lower the dose, without checking with your doctor.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how Aubagio affects you.
Drinking alcohol	Tell your doctor if you drink alcohol. The effects of alcohol could be made worse while taking Aubagio. It is recommended that you minimise your alcohol intake while taking Aubagio.
Looking after your medicine	Keep the medicine in a cool dry place where the temperature stays below 30°C. Keep your tablets in the container until it is time to take them.

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

6. Are there any side effects?

Less serious side effects include diarrhoea; rashes, itchy skin; hair loss; weight loss; unusual tiredness or weakness; numbness or tingling of hands or feet; thickened, inflamed, red patches on the skin, which may be accompanied with whitish scaly skin, or accompanied by white pus-filled bumps. More serious side effects include signs and symptoms of severe infection e.g fever; severe upper stomach pain, often with nausea and vomiting; severe skin rash or sores in your mouth; skin becoming pale, you start to feel tired, you become prone to infections or bruising; new or worsening symptoms such as cough or trouble breathing, with or without a fever; allergic reaction such as swelling of the face, lips, mouth or throat, which may cause difficulty in swallowing or breathing, hives, fainting, yellowing of the skin and eyes (jaundice), thickened patches of red 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

Aubagio^®

Active ingredient(s): Teriflunomide

Consumer Medicine Information (CMI)

This leaflet provides important information about using Aubagio. 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 Aubagio.

Where to find information in this leaflet:

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

1. Why am I using Aubagio?

Aubagio contains the active ingredient teriflunomide.

Aubagio is used to treat relapsing forms of multiple sclerosis (MS).

The cause of MS is not yet known. MS affects the central nervous system (CNS) - the brain and spinal cord.

In MS, the body's immune system reacts against its own myelin (the 'insulation' or the protective sheath surrounding nerve fibres). With relapsing forms of MS, people can have repeated attacks or relapses of inflammation of the CNS from time to time.

Symptoms vary from patient to patient and may include blurred vision, weakness in the legs or arms, or loss of control of bowel or bladder function. These are followed by periods of recovery.

Aubagio works by selectively interfering with the ability of white blood cells (lymphocytes) to produce the disease response and nerve damage that ultimately leads to relapses.

Aubagio has been shown to reduce or decrease the number of relapses and slow down the progression of physical disability in patients with relapsing forms of MS. Although it is not a cure, patients treated with Aubagio generally find they will have fewer relapses.

Your doctor, however, may have prescribed Aubagio for another purpose.

Ask your doctor if you have any questions about why it has been prescribed for you.

2. What should I know before I use Aubagio?

Warnings

Do not use Aubagio if:

you are allergic to teriflunomide, leflunomide or any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can use this medicine.

have any diseases which reduce your body's natural defences
have any diseases of the blood
have, or have had any serious skin disorders such as rash with blisters and peeling of the skin or extended rashes with the liver, blood and other body organs involvement
have severe liver disease
have a condition called hypoproteinaemia (when you do not have enough protein in your blood)
are pregnant or plan to become pregnant
are not using reliable birth control
are breastfeeding

Check with your doctor if you:

intend to become pregnant or father a child.
have any other medical conditions especially the following: Liver problems, high blood pressure, chronic or serious infection, a decrease in the number of white blood cells or an illness which lowered your body's resistance to disease, tuberculosis, lung problems, such as interstitial lung disease (an inflammation of lung tissue) which is a serious and potentially fatal disease, or kidney disease

Before you start Aubagio, your doctor will need to take blood samples to check the health of your liver and blood cells. This must be done in the last 6 months before starting this medicine.

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

You must not become pregnant while taking Aubagio and for a certain period of time after stopping Aubagio.

Aubagio may increase the risk of birth defects. To reduce any risk to the developing baby, you will need to stop taking Aubagio and may need to undergo a wash-out procedure. Your doctor will discuss the wash-out procedure with you.

Women of childbearing potential must use reliable contraception while taking Aubagio.

Tell your doctor immediately if you think you could be pregnant while taking Aubagio.

Tell your doctor if you intend to become pregnant or father a child.

Do not take it if you are breastfeeding or planning to breastfeed

Aubagio passes into breast milk and there is a serious risk to the baby. You and your doctor will decide what is best for you and your baby.

Children and adolescents

Do not give Aubagio to a child or adolescent

Aubagio is not approved for use in children or adolescents under 18 years old.

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 Aubagio and affect how it works or be affected by Aubagio.

Interactions between Aubagio and other medications include:

Some antibiotics such as rifampicin, cefaclor, penicillin G and ciprofloxacin
Some medicines used to treat epilepsy such as carbamazepine and phenytoin
Some medicines used for diabetes such as repaglinide or pioglitazone
Some medicines to treat cancer such as paclitaxel, doxorubicin, methotrexate
Some medicines used to treat depression such as duloxetine
Ondansetron, a medicine used to prevent and treat nausea
Theophylline, a medicine used to prevent asthma
Warfarin, a medicine used to prevent blood clots
Some medicines used to lower cholesterol such as “statins” - rosuvastatin
St John's Wort

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

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

In certain situations, for example, if you experience a serious side effect, you change your medication or you want to fall pregnant, your doctor will ask you to take medication that will help your body get rid of Aubagio faster.

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

4. How do I use Aubagio?

How much to take

The usual dose for this medicine is one 14 mg tablet per day.
Your doctor may have prescribed a different dose.
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. These directions may differ from the information contained in this leaflet. If you take the wrong dose, Aubagio may not work as well.
Continue taking your medicine for as long as your doctor or pharmacist tells you.

The medicine helps control your condition, but it does not cure it. Therefore, you must take it every day.

When to take Aubagio

Aubagio should be taken at about the same time every day. Taking your tablets at the same time each day will have the best effect. It will also help you to remember when to take the tablets.
It does not matter if you take Aubagio before or after food

How to take Aubagio

Swallow the tablet whole with a full glass of water.

If you forget to use Aubagio

Aubagio should be used 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.

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

If there is still a long time to go before your next dose, take it as soon as you remember, and then go back to taking it as you would normally.

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

If you use too much Aubagio

If you think that you or anyone else may have used too much Aubagio, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26 in Australia), or
(by calling 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 Aubagio?

Things you should do

If you become pregnant while you are taking this medicine, stop taking it and tell your doctor or pharmacist immediately.

If you need to stop treatment, the levels of Aubagio in your blood can be lowered rapidly using a special wash-out procedure.

If you are female talk to your doctor about birth control that you must use during treatment. You must use reliable methods of birth control while taking Aubagio.

Talk to your doctor if you plan to become pregnant or before you stop taking this medicine.

Tell your doctor if you need to have a vaccination during treatment with this medicine or for 6 months after stopping treatment.

Call your doctor straight away if you:

have an infection or notice chills or a fever or signs of an infection while taking this medicine
your skin becomes itchy or yellow, the whites of your eyes become yellow, you start to bleed or bruise easily, or your urine becomes very dark or you have stomach pain, nausea or vomiting, stop taking it immediately. You may be developing a liver problem
experience numbness or tingling in the hands or feet or numbness or weakness of the arms and legs

Remind any doctor, dentist or pharmacist you visit that you are using Aubagio.

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

Things you should not do

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.
Do not stop taking Aubagio, or lower the dose, without checking with your doctor.

Driving or using machines

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

Drinking alcohol

Tell your doctor if you drink alcohol.

The effects of alcohol could be made worse while taking Aubagio. It is recommended that you minimise your alcohol intake while taking Aubagio.

Looking after your medicine

Keep the medicine in a cool dry place where the temperature stays below 30°C.
Keep your tablets in the container until it is time to take them.

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

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.

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 effects	What to do
Diarrhoea Rashes, itchy skin Hair loss Weight loss Unusual tiredness or weakness Numbness or tingling of hands or feet Thickened, inflamed, red patches on the skin, which may be accompanied with whitish scaly skin, or accompanied by white pus-filled bumps Nail disorders	Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Signs and symptoms of severe infection e.g fever
Severe upper stomach pain, often with nausea and vomiting
Severe skin rash or sores in your mouth
Your skin becomes pale, you start to feel tired, you become prone to infections or bruising
If you develop new or worsening symptoms such as cough or trouble breathing, with or without a fever
Feeling short of breath, tired, experiencing dizziness or fainting, have a blue tinge to your lips or skin, feeling pressure in your chest, have swelling around your ankles and legs, weight gain over a short period of time or abdominal bloating
Inflammation of the colon, symptoms include diarrhea usually with blood and mucus

Allergic reaction:

Swelling of the face, lips, mouth or throat, which may cause difficulty in swallowing or breathing
Hives
Fainting
Yellowing of the skin and eyes (jaundice)
Thickened patches of red skin

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.

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.

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 (Australia) or the Centre for Adverse Reactions Monitoring (CARM) within the New Zealand Pharmacovigilance Centre nzphvc.otago.ac.nz/reporting (New Zealand).

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 Aubagio contains

Active ingredient (main ingredient)	Teriflunomide 14 mg
Other ingredients (inactive ingredients)	Lactose monohydrate Maize starch Hyprolose Microcrystalline cellulose Sodium starch glycollate Magnesium stearate Hypromellose Macrogol 8000 Purified talc and titanium dioxide Indigo carmine aluminium lake OPADRY complete film coating system 03F20651 BLUE
Potential allergens	Lactose monohydrate

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

What Aubagio looks like

Aubagio 14 mg tablets are pale blue to pastel blue pentagonal film coated tablets with "14" imprinted on one side and engraved with a logo on the other. Aubagio 14 mg tablets are supplied in blister packs of 10 and 28 tablets.

(AUST R 192672)

Who distributes Aubagio

Aubagio is supplied in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113
Freecall No: 1800 818 806

Aubagio is supplied in New Zealand by:

sanofi-aventis new zealand limited
Level 8, 56 Cawley Street
Ellerslie
Auckland
Freecall No: 0800 283 684

This leaflet was prepared in February 2022

aubagio-ccdsv9-cmiv8-07feb22

Published by MIMS March 2022

BRAND INFORMATION

Brand name

Aubagio

Active ingredient

Teriflunomide

Schedule

1 Name of Medicine

Teriflunomide.

2 Qualitative and Quantitative Composition

Each Aubagio tablet contains 14 mg teriflunomide.

Excipient with known effect.

Lactose monohydrate.
For full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Teriflunomide is formulated as film-coated tablets for oral administration.
Aubagio is available as pale blue to pastel blue, pentagonal film-coated tablets with "14" imprinted on one side and engraved with a logo on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Aubagio is indicated for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical relapses and to delay the progression of physical disability.

4.2 Dose and Method of Administration

The recommended dose of Aubagio is 14 mg orally once daily. Aubagio can be taken with or without food.

Special populations.

Children.

The safety and efficacy of Aubagio in paediatric patients with MS below the age of 18 years has not yet been established.

Elderly.

Clinical studies of Aubagio did not include patients over 65 years old. Aubagio should be used with caution in patients aged over 65 years.

Hepatic impairment.

No dosage adjustment is necessary for patients with mild or moderate hepatic impairment. Teriflunomide is contraindicated in patients with severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

Renal impairment.

No dosage adjustment is necessary for patients with severe renal impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Switching patients from or to other disease modifying therapies.

For recommendations related to switching patients from other disease modifying therapies to Aubagio (see Section 4.4 Special Warnings and Precautions for Use, Switching to or from Aubagio and Plasma monitoring).

4.3 Contraindications

Aubagio must not be given to:
patients with hypersensitivity to leflunomide, teriflunomide or to any of the excipients in the tablets;
patients with severe immunodeficiency states, e.g. AIDS;
patients with significantly impaired bone marrow function or significant anaemia, leukopenia or thrombocytopenia;
patients with severe, uncontrolled infections;
patients with severe impairment of liver function;
pregnant women (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy);
women of childbearing potential who are not using reliable contraception during treatment with teriflunomide and for a certain period of time thereafter, as long as the plasma levels are above 0.02 mg/L, unless undergoing washout treatment (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy);
women who are breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation);
patients with severe hypoproteinaemia;
patients who have or have had Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), or erythema multiforme.

4.4 Special Warnings and Precautions for Use

Hepatotoxicity.

Clinically significant and potentially life-threatening liver injury, including acute liver failure requiring transplant, has been reported in patients treated with teriflunomide in the post-marketing setting. Patients with pre-existing liver disease and patients taking other hepatotoxic drugs may be at increased risk for developing liver injury when taking teriflunomide. Clinically significant liver injury can occur at any time during treatment with teriflunomide.
Elevations of liver enzymes have been observed in patients receiving Aubagio. During placebo controlled trials, 3-fold the upper limit of normal (ULN) or greater elevation in liver transaminases (ALT) occurred in 6.1% of patients treated with teriflunomide 14 mg, as compared to 6.2% of patients on placebo. Elevations of 5-fold the ULN (ALT) or greater occurred in 2.6% of patients on Aubagio and 2.2% of patients on placebo. These elevations occurred mostly within the first year of treatment. In clinical trials, teriflunomide was discontinued if the ALT elevation exceeded 3 times the ULN twice. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of Aubagio.
Very rare cases of severe liver injury, with fatal outcome in isolated cases, have been reported during treatment with leflunomide, the parent compound of teriflunomide. Most of the cases occurred within the first 6 months of treatment. Although confounding factors were present in many cases, a causal relationship to leflunomide and hence teriflunomide cannot be excluded. It is considered essential that monitoring recommendations are strictly adhered to (see Liver function monitoring).

Liver function monitoring.

ALT, AST and bilirubin levels must be checked within 6 months before the start of Aubagio treatment. Monitor ALT and AST at monthly or more frequent intervals for at least the first 6 months and then, if stable, every 6-8 weeks thereafter. For minor elevations in ALT or AST (< 2-fold ULN), repeat testing in 2-4 weeks. For moderate elevations in ALT or AST (> 2-fold but < 3-fold ULN), closely monitor, with LFTs every 2-4 weeks. If ALT or AST elevations of more than 3-fold ULN are present, Aubagio should be discontinued. Cholestyramine or activated charcoal should be administered to more rapidly lower teriflunomide levels, with close monitoring including retreatment with cholestyramine or activated charcoal as indicated. Monitor serum transaminase and bilirubin on Aubagio therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be teriflunomide-induced, discontinue Aubagio, start an accelerated elimination procedure and monitor liver tests weekly until normalized.

Blood pressure.

In placebo controlled studies, mean change from baseline for diastolic blood pressure was 1.3 mmHg and for systolic blood pressure was 2.7 mmHg for teriflunomide 14 mg. Check blood pressure before start of Aubagio treatment and periodically thereafter. Blood pressure elevation should be appropriately managed during treatment with Aubagio.

Infections.

In placebo controlled studies, no significant increase in serious infections was observed with teriflunomide 14 mg (2.2%) as compared to placebo (2.1%). Serious opportunistic infections occurred in 0.2% in each group.
However, based on the immunomodulatory effect of Aubagio, if a patient develops a serious infection, consider suspending treatment with Aubagio, and reassess the benefits and risks prior to re-initiation of therapy. Due to the prolonged elimination half-life of teriflunomide, accelerated elimination with cholestyramine or charcoal may be considered (see Section 4.9 Overdose). Instruct patients receiving Aubagio to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment with Aubagio until the infection(s) is resolved. Aubagio is not recommended with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections.
For patients testing positive in tuberculosis screening, manage by standard medical practice prior to therapy with Aubagio.

Respiratory effects.

Interstitial lung disease, (ILD) including acute interstitial pneumonitis, as well as rare cases of pulmonary hypertension have been reported with Aubagio in the post-marketing setting. The risk may be increased in patients with a history of ILD.
Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide. Interstitial lung disease may occur acutely at any time during therapy with a variable clinical presentation. Interstitial lung disease may be fatal. New onset or worsening pulmonary symptoms, such as cough and dyspnoea, with or without associated fever, may be a reason for discontinuation of the therapy and for further investigation as appropriate. If discontinuation of the drug is necessary, consider initiation of an accelerated elimination procedure.

Haematologic effects.

A mean decrease affecting white blood cells (WBC) count (< 15%, mainly neutrophil and lymphocytes decrease) was observed in placebo controlled trials with Aubagio, although a greater decrease was observed in some patients. The decrease in mean count occurred during the first 6 weeks then stabilized over time while on treatment. The effect on red blood cells (RBC) (< 2%) and platelet counts (< 10%) was less pronounced. A complete blood cell count (including differential white blood cell count and platelets) should be performed in all patients before the start of Aubagio treatment and monthly for the first 6 months, followed by 6-8 weeks thereafter. In patients with pre-existing anaemia, leukopenia and/or thrombocytopenia as well as in patients with impaired bone marrow function or those at risk of bone marrow suppression, the risk for occurrence of haematological reactions is increased.

Leflunomide post-marketing safety information.

The following information has been derived from the Australian prescribing information for Arava (leflunomide) and may be pertinent to understanding the safety profile of teriflunomide. Leflunomide is the parent compound of teriflunomide (Aubagio). Leflunomide is indicated in the treatment of rheumatoid arthritis. Leflunomide has been evaluated in clinical studies in rheumatoid arthritis and has over 2 million patient-years of cumulative exposure globally in the post-marketing setting. The risks associated with use of leflunomide are well characterized in the rheumatoid arthritis population and may provide insight into potential risks of teriflunomide treatment in the MS population. See current Australian PI for Arava (leflunomide) for additional information. The following events have been reported rarely:

Hepatotoxicity.

Reports of severe liver injury, including fatal liver failure.

Haematological effects.

Rare reports of pancytopenia, agranulocytosis and thrombocytopenia in patients receiving leflunomide alone. These events have been reported most frequently in patients who received concomitant treatment with methotrexate or other immunosuppressive agents, or who had recently discontinued these therapies; in some cases, patients had a prior history of a significant hematologic abnormality.

Risk of infection.

Reports of fatal infections especially Pneumocystis jiroveci pneumonia and aspergillosis have been reported in patients receiving leflunomide. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection.

Skin disorders.

Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported in patients treated with leflunomide, the parent compound of Aubagio. As soon as skin and/or mucosal reactions are observed which raise the suspicion of such severe reactions, Aubagio and any other possible associated medication must be discontinued, and cholestyramine or charcoal should be used immediately to reduce the plasma concentration of teriflunomide (see Section 4.9 Overdose). A complete washout is essential in such cases. In such cases re-exposure to teriflunomide is contra-indicated.

Respiratory.

Interstitial lung disease has been reported during treatment with leflunomide and has been associated with fatal outcomes. The risk of its occurrence is increased in patients with a history of interstitial lung disease.

Immunosuppression.

Although there is no clinical experience in the following patient populations, Aubagio is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe uncontrolled infections because of the theoretical potential for immunosuppression. If Aubagio is used in such patients, it should be done with caution and with frequent haematologic monitoring (see Haematological effects). If evidence of bone marrow suppression occurs in a patient taking Aubagio, treatment should be stopped and cholestyramine or charcoal should be used to reduce the plasma concentration of teriflunomide (see Section 4.9 Overdose).

Immunosuppressive or immunomodulating therapies.

As leflunomide is the parent compound of teriflunomide, co-administration of teriflunomide with leflunomide is not recommended.
Co-administration with antineoplastic or immunosuppressive therapies used for treatment of multiple sclerosis has not been evaluated.
Safety studies in which teriflunomide was concomitantly administered with other immune modulating therapies for up to one year (interferon beta, glatiramer acetate) did not reveal any specific safety concerns. The long-term safety of these combinations in the treatment of multiple sclerosis has not been established.

Switching to or from Aubagio.

Based on clinical data, no waiting period is required when initiating teriflunomide after interferon beta or glatiramer acetate or when starting interferon beta or glatiramer acetate, after teriflunomide.
Due to the long half-life of natalizumab, concomitant exposure, and thus concomitant immune effects, could occur for up to 2-3 months following discontinuation of natalizumab if Aubagio was immediately started. Therefore, caution is required when switching patients from natalizumab to Aubagio.
Based on the half-life of fingolimod, a 6 week interval without therapy is needed for clearance from the circulation and a 1 to 2 month period is needed for lymphocytes to return to normal range following discontinuation of fingolimod. Starting Aubagio during this interval will result in concomitant exposure to fingolimod. This may lead to an additive effect on the immune system and caution is, therefore, indicated.
In MS patients, the median terminal half-life (t_1/2z) was approximately 19 days after repeated doses of 14 mg. If a decision is made to stop treatment with Aubagio, during the interval of 5 half-lives (approximately 3.5 months although may be longer in some patients), starting other therapies will result in concomitant exposure to Aubagio. In any situation in which the decision is made to switch from Aubagio to another immunomodifying agent with a known potential for haematologic suppression, it would be prudent to monitor for haematologic toxicity, because there will be overlap of systemic exposure to both compounds. Aubagio washout with cholestyramine or charcoal (accelerated elimination procedure) may decrease this risk but also may induce disease worsening if the patient had been responding to Aubagio treatment.

Use in hepatic impairment.

Mild and moderate hepatic impairment had no impact on the pharmacokinetics of teriflunomide. No dosage adjustment is necessary for patients with mild or moderate hepatic impairment. Teriflunomide is contraindicated in patients with severe hepatic impairment (see Section 4.3 Contraindications).

Use in renal impairment.

Leflunomide, the parent compound of teriflunomide was administered as a single oral 100 mg dose to 3 haemodialysis patients and 3 patients on continuous peritoneal dialysis (CAPD). The pharmacokinetics of teriflunomide in CAPD subjects appeared to be similar to healthy volunteers. A more rapid elimination of teriflunomide was observed in haemodialysis subjects which was not due to extraction of drug in the dialysate but instead to displacement of protein binding. Caution should be used when Aubagio is administered to patients with renal impairment.

Use in the elderly.

Clinical studies of Aubagio did not include patients over 65 years old. Aubagio should be used with caution in patients aged over 65 years.

Paediatric use.

The safety and effectiveness of Aubagio in paediatric patients with MS below the age of 18 years have not yet been established.

Vaccination.

Two clinical studies have shown that vaccinations of inactivated neoantigen (first vaccination), or recall antigen (re-exposure) were safe and effective during Aubagio treatment. The use of live attenuated vaccines may carry a risk of infection and should therefore be avoided. Vaccination with live vaccines is not recommended. A live vaccine should only be given after a period of at least 6 months has elapsed after stopping Aubagio.

Skin reactions.

Severe cutaneous adverse reactions (SCARs).

Cases of serious skins reactions, sometimes fatal, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with teriflunomide.
If skin and/or mucosal reactions (ulcerative stomatitis) are observed which raise the suspicion of severe generalised major skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis-Lyell's syndrome, or drug reaction with eosinophilia and systemic symptoms), teriflunomide and any other possibly associated treatment must be discontinued, and an accelerated elimination procedure initiated immediately. In such cases patients should not be re-exposed to teriflunomide (see Section 4.3 Contraindications).

Peripheral neuropathy.

In placebo-controlled studies, peripheral neuropathy was reported more frequently in patients taking Aubagio than in patients taking placebo. In one 108-week placebo-controlled study in 1086 patients with multiple sclerosis, the incidence of peripheral neuropathy confirmed by nerve conduction studies was 1.9% (6 patients) on 14 mg Aubagio respectively and 0% on placebo. This included polyneuropathy and mononeuropathy (e.g. carpal tunnel syndrome). Treatment was discontinued in one patient with polyneuropathy.
Cases of peripheral neuropathy have been reported in patients receiving Aubagio. However, there was a wide variability in final outcome, i.e. in some patients the neuropathy resolved and some patients had persistent symptoms. If a patient taking Aubagio develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing Aubagio therapy and performing an accelerated elimination procedure.

Accelerated elimination procedure.

Teriflunomide is eliminated slowly from the plasma. When desired, an accelerated elimination procedure can be used.
Teriflunomide concentrations measured during an 11-day procedure to accelerate teriflunomide elimination with either 4 g cholestyramine t.i.d, 8 g cholestyramine t.i.d or 50 g activated charcoal b.i.d following cessation of teriflunomide treatment have shown that these regimens were effective in accelerating teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations, with cholestyramine being faster than charcoal. In association with this procedure a higher incidence among patients taking teriflunomide 14 mg was seen of the AEs nausea (3.3% vs 1.5% placebo), vomiting (2.4% vs 0% placebo), and increased ALT (1.6% vs. 0 placebo). When desired, elimination can be accelerated by any of the following procedures. (See Section 4.9 Overdose, Accelerated elimination procedure: cholestyramine and activated charcoal).
Administration of cholestyramine 4 g or 8 g every 8 hours for 11 days or by 50 g oral activated charcoal powder administered every 12 hours for 11 days (days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly). Following discontinuation of teriflunomide and the administration of cholestyramine 8 g three times a day, the plasma concentration of teriflunomide is reduced 99% at the completion of day 11. If cholestyramine 8 g three times a day is not well tolerated, cholestyramine 4 g three times a day can be used.
Both cholestyramine and activated charcoal may influence the absorption of oestrogens and progestogens such that reliable contraception with oral contraceptives may not be guaranteed during the washout procedure with cholestyramine and activated charcoal. Use of alternative contraceptive methods is recommended.

Plasma monitoring.

After the wash-out procedure has been performed, teriflunomide plasma levels of < 0.02 mg/L must be verified by 2 separate tests at least 14 days apart. Human teriflunomide plasma concentrations less than or equal to 0.02 mg/L are expected to have minimal risk based on available data. Without the drug elimination procedure, it may take up to 2 years to reach teriflunomide concentrations < 0.02 mg/L (after stopping treatment with Aubagio), due to individual variation in drug clearance. However, verification of teriflunomide levels < 0.02 mg/L by 2 separate tests at an interval of at least 14 days is required.
In pregnant women and women currently attempting to become pregnant, plasma concentrations should be verified to be equal or less than 0.02 mg/L. If plasma concentrations are higher than 0.02 mg/L, additional elimination should be considered.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The primary biotransformation pathway for teriflunomide is hydrolysis, with oxidation being a minor pathway. The extensive protein binding of teriflunomide could lead to displacement of other highly bound drugs.

Potential for other drugs to affect teriflunomide.

Potent CYP and transport inducers.

Co-administration of repeated doses (600 mg once daily for 22 days) of rifampicin (a CYP2B6, 2C8, 2C9, 2C19, 3A inducer, as well as an inducer of the efflux transporters P-gp and BCRP) and teriflunomide (70 mg single dose) resulted in an approximately 40% decrease in teriflunomide exposure. Rifampicin and other known potent CYP and transporter inducers such as carbamazepine, phenobarbital, phenytoin and St John's wort should be used with caution during the treatment with teriflunomide.

Potential for teriflunomide to affect other drugs.

Repeated administration of teriflunomide was used to assess the effect of teriflunomide on the exposure of other drugs. The regimen used resulted in teriflunomide plasma concentrations which were in the range of the ones observed in patients after repeated doses of 14 mg teriflunomide.

CYP2C8 substrates.

There was an increase in mean repaglinide C_max and AUC (1.7- and 2.4-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. Therefore, monitoring patients with concomitant use of drugs metabolized by CYP2C8, such as repaglinide, paclitaxel, pioglitazone, or rosiglitazone is recommended as they may have higher exposure.

Oral contraceptives.

There was an increase in mean ethinyloestradiol C_max and AUC_0-24 (1.58- and 1.54-fold, respectively) and levonorgestrel C_max and AUC_0-24 (1.33- and 1.41-fold, respectively) following repeated doses of teriflunomide. While this interaction of teriflunomide is not expected to adversely impact the efficacy of oral contraceptives, consideration should be given to the type of oral contraceptive treatment used in combination with teriflunomide.

CYP1A2 substrates.

Repeated doses of teriflunomide decreased mean C_max and AUC of caffeine (CYP1A2 substrate) by 18% and 55%, respectively, suggesting that in vivo teriflunomide is a weak inducer of CYP1A2. Therefore, drugs metabolised by CYP1A2 (such as duloxetine, ondansetron, theophylline and agomelatine) should be used with caution during treatment with teriflunomide, as it could lead to the reduction of efficacy of these drugs.

Warfarin.

A 25% decrease in peak international normalized ratio (INR) was observed when teriflunomide was coadministered with warfarin as compared with warfarin alone. Therefore, when warfarin is coadministered with teriflunomide, close INR follow-up and monitoring is recommended.

Effect of teriflunomide on organic anion transporter 3 (OAT3) substrates.

There was an increase in mean cefaclor C_max and AUC (1.43- and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of OAT3 in vivo. Therefore, when teriflunomide is coadministered with substrates of OAT3, such as cefaclor, penicillin G, ciprofloxacin, indomethacin, ketoprofen, furosemide, cimetidine, methotrexate, zidovudine, caution should be observed.

Effect of teriflunomide on BCRP and/or organic anion transporting polypeptide B1 and B3 (OATP1B1/B3) substrates.

There was an increase in mean rosuvastatin C_max and AUC (2.65- and 2.51-fold, respectively), following repeated doses of teriflunomide. However there was no apparent impact of this increase in plasma rosuvastatin exposure on the HMG-CoA reductase activity. If used together, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g. methotrexate, topotecan, sulfasalazine, daunorubicin, doxorubicin) and the OATP family especially HMG-Co reductase inhibitors (e.g. simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, repaglinide, rifampicin) concomitant administration of teriflunomide should also be undertaken with caution. Monitor patients closely for signs and symptoms of excessive exposure to the drugs and consider reduction of the dose of these drugs.

CYP2B6, CYP3A, CYP2C9, CYP2C19 and CYP2D6 substrates.

Teriflunomide did not affect the pharmacokinetics of bupropion (a CYP2B6 substrate), midazolam (a CYP3A substrate), S-warfarin (a CYP2C9 substrate), omeprazole (a CYP2C19 substrate) and metoprolol (a CYP2D6 substrate) at the anticipated therapeutic dose.

Nonsteroidal anti-inflammatory drugs (NSAIDs).

NSAIDs (including COX-2 inhibitors) are known to cause hepatotoxicity, therefore caution is advised when Aubagio is used concomitantly. Studies showed that ibuprofen and diclofenac did not displace teriflunomide. Teriflunomide displaced ibuprofen and diclofenac and the unbound fraction of these drugs was increased by 10-50%. In clinical trials, no safety problems were observed when leflunomide, the parent compound of teriflunomide and NSAlDs metabolised by CYP2C9 were co-administered.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Oral administration of teriflunomide 10 mg/kg/day (about 6 times the RHD based on mg/m²) to male rats impaired spermatogenesis but had no effect on fertility; the no-effect dose was 3 mg/kg/day. Oral treatment of female rats with teriflunomide from two weeks prior to mating through to implantation (gestation day 6) caused almost complete embryofoetal death and isolated malformations in surviving fetuses at doses of 2.6 mg/kg/day and above (about twice the RHD based on mg/m²; the no-effect dose was 0.84 mg/kg/day. Estimated systemic exposure (plasma AUC) in these studies was less than anticipated clinical exposure.
(Category X)
As teriflunomide is teratogenic in rats and rabbits, it may cause foetal harm in humans. Aubagio must not be given to pregnant women, or women of childbearing potential who are not using reliable contraception during treatment with Aubagio and for a certain period of time thereafter as long as the plasma levels are above 0.02 mg/L, unless undergoing washout treatment (waiting period or accelerated elimination procedure; see below). Pregnancy must be excluded before the start of treatment with Aubagio.
It is recommended that women of childbearing potential only receive Aubagio after it has been confirmed that they are using a reliable form of contraception. In a study in which leflunomide, the parent compound of teriflunomide, was given to healthy female volunteers concomitantly with a triphasic oral contraceptive pill containing 30 microgram ethinyloestradiol, there was no reduction in contraceptive activity of the pill, and teriflunomide pharmacokinetics were within predicted ranges.
Patients must be advised that if there is any delay in the onset of menses or any other reason to suspect pregnancy, they must notify their physician immediately to test for pregnancy. If the test is positive, the physician and patient must discuss the risk to the foetus. It is possible that by rapidly lowering the blood level of the active metabolite at the first delay of menses, using the drug elimination procedure described below, the risk to the foetus may be decreased.

Human experience.

There is limited human experience from clinical studies with Aubagio. A total of 31 patients became pregnant during clinical studies while using teriflunomide. A total of 7 patients were reported having pregnancy with live birth outcome. All of these patients underwent an accelerated elimination procedure. Maternal exposure to teriflunomide was between 5 weeks and 489 weeks. The foetal exposure was from a few days to 11 weeks prior to the accelerated elimination procedure. All seven patients exposed to teriflunomide gave birth to normal healthy newborns, without evidence of structural or functional defects. Of the remaining pregnancies, 13 were electively terminated, 8 resulted in miscarriages and three were ongoing. Due to the limited nature of these data no firm conclusions can be drawn regarding the use of teriflunomide in pregnant women. Aubagio is contraindicated in women who are pregnant or currently attempting to become pregnant (see Section 4.3 Contraindications).
Available human data from pregnancy registries, clinical trials, pharmacovigilance cases, and published literature are too limited to draw any conclusions, but they do not clearly indicate increased birth defects or miscarriage associated with inadvertent teriflunomide exposure in the early first trimester when followed by an accelerated elimination procedure. There are no human data pertaining to exposures later in the first trimester or beyond.
Prospectively reported data (from clinical trials and postmarketing reports) from > 150 pregnancies in patients treated with teriflunomide and > 300 pregnancies in patients treated with leflunomide have not demonstrated an increased rate of congenital malformations or miscarriage following teriflunomide exposure in the early first trimester when followed by an accelerated elimination procedure. Specific patterns of major congenital malformations in humans have not been observed. Limitations of these data include an insufficient number of reported pregnancies, the short duration of drug exposure in reported pregnancies, incomplete reporting, and the inability to control for confounders (such as underlying maternal disease and use of concomitant medications).

Pregnancy registry.

A pregnancy registry has been established to collect information about the effect of Aubagio use during pregnancy. If physicians or patients become aware of pregnancy during treatment with Aubagio, they are encouraged to enrol the patient in the Aubagio pregnancy registry.

Labour and delivery.

There is no adequate information regarding the effects of Aubagio on labour and delivery in pregnant women.
Animal studies indicate that teriflunomide passes into milk and can cause harm to the developing neonate at subclinical maternal exposures. Up to 23% of a maternal dose was ingested by suckling rat pups. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Aubagio, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Use in males.

The risk of male-mediated embryo-foetal toxicity through teriflunomide treatment is considered low. The estimated female plasma exposure via the semen of a treated patient is expected to be 100 times lower than the plasma exposure observed at steady state after 14 mg of oral teriflunomide. There were no external malformations in the offspring of male rats administered teriflunomide for at least 10 weeks prior to mating with untreated female rats at oral doses up to 10 mg/kg/day (about 6 times the RHD based on mg/m²).

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The most frequent adverse reactions for Aubagio (incidence ≥ 10% and ≥ 2% greater than placebo) in the placebo-controlled studies were diarrhoea, nausea, alopecia, ALT increased.
If desired, teriflunomide can be rapidly cleared from the body by the use of the accelerated elimination procedure (see Section 4.9 Overdose).

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 (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

Clinical trial experience.

A total of 2047 patients on teriflunomide (7 or 14 mg once daily) and 997 on placebo constituted the safety population in the pooled analysis of placebo controlled studies in patients with relapsing forms of MS (RMS). See Table 1.

Headache, palpitations, arthralgia, myalgia, increased blood creatine phosphokinase and decreased white blood cell count were also observed.
Clinically relevant adverse reactions in the placebo controlled studies, listed in CIOMS format by system organ class are shown in Table 2.
The following CIOMS frequency rating is used, when applicable:
Very common ≥ 10%; common ≥ 1 and < 10%; uncommon ≥ 0.1 and < 1%; rare ≥ 0.01 and < 0.1%; very rare < 0.01%; unknown (cannot be estimated from available data).

Polyneuropathy.

In the pivotal, placebo controlled studies, the incidence of peripheral neuropathy confirmed by nerve conduction studies was 1.8% (17 patients) on 14 mg of Aubagio, compared with 0.4% on placebo (4 patients). Treatment was discontinued in 8 patients with confirmed peripheral neuropathy (3 on teriflunomide 7 mg and 5 on teriflunomide 14 mg). Four of them recovered following treatment discontinuation. Not all cases of peripheral neuropathy resolved with continued treatment.

Post-marketing experience.

In post-marketing experience with Aubagio, the following adverse reactions have been identified:

Immune system disorders.

Hypersensitivity reactions (immediate or delayed) some of which were severe, such as anaphylaxis, and angioedema.

Skin and subcutaneous tissue disorders.

Severe skin reactions including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS).
Psoriasis (including pustular psoriasis and nail psoriasis).
Nail disorders.

Respiratory, thoracic and mediastinal disorders.

Interstitial lung disease (ILD).
Not known: pulmonary hypertension.

Gastrointestinal disorders.

Stomatitis (such as aphthous or ulcerative), pancreatitis.
Colitis.

Hepatobiliary disorders.

Drug-induced liver injury (DILI).
Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency.

4.9 Overdose

There is no experience regarding teriflunomide overdose or intoxication in humans. Teriflunomide 70 mg daily up to 14 days was well tolerated by healthy subjects.
In the event of relevant overdose or toxicity, cholestyramine or activated charcoal is recommended to accelerate elimination (see Section 4.4 Special Warnings and Precautions for Use).

Accelerated elimination procedure: cholestyramine and activated charcoal.

The elimination of teriflunomide from the circulation can be accelerated by administration of cholestyramine or activated charcoal, presumably by interrupting the reabsorption processes at the intestinal level. Teriflunomide concentrations measured during an 11-day procedure to accelerate teriflunomide elimination with either 4 g cholestyramine t.i.d, 8 g cholestyramine t.i.d or 50 g activated charcoal b.i.d following cessation of teriflunomide treatment have shown that these regimens were effective in accelerating teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations, with cholestyramine being faster than charcoal. In association with this procedure a higher incidence among patients taking teriflunomide 14 mg was seen of the AEs nausea (3.3 vs 1.5% placebo), vomiting (2.4% vs 0% placebo), increased ALT (1.6% vs. 0 placebo). The choice between the 3 elimination procedures should depend on the patient's tolerability. If cholestyramine 8 g three times a day is not well tolerated, cholestyramine 4 g three times a day can be used. Alternatively, activated charcoal may also be used (the 11 days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly).
Use of the accelerated elimination procedure may potentially result in return of disease activity if the patient had been responding to Aubagio treatment.
For information on the management of overdose, contact the Poisons Information Centre, on 13 11 26 (Australia) or the National Poisons Centre, 0800 POISON or 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Teriflunomide is an immunomodulatory agent with anti-inflammatory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), required for the de novo pyrimidine synthesis. As a consequence teriflunomide blocks the activation and proliferation of stimulated lymphocytes which need de novo synthesis of pyrimidine to expand. Slowly dividing or resting cells which rely on the salvage pathway for pyrimidine synthesis are unaffected by teriflunomide. The exact mechanism by which teriflunomide exerts its therapeutic effect in MS is not fully understood, but may include reduced number of activated lymphocytes in CNS. It is likely that teriflunomide diminishes in periphery the numbers of activated lymphocytes available to migrate into the CNS.

Immune system.

Effects on immune cell numbers in the blood.

In the placebo controlled studies, teriflunomide 14 mg once a day led to a mild mean reduction in lymphocyte count, of 0.3 x 10⁹/L, most of which occurred over the first 3 months of treatment following which levels were maintained until the end of the treatment.

Potential to prolong the QT interval.

In a placebo controlled thorough QT study performed in healthy subjects, teriflunomide at mean steady-state concentrations did not show any potential for prolonging the QTcF interval compared with placebo: the largest time matched mean difference between teriflunomide and placebo was 3.46 ms with the upper bound of the 90% CI being 6.45 ms. In addition, no QTcF values were ≥ 480 ms and no changes from baseline were > 60 ms.

Effect on renal tubular functions.

In the placebo controlled studies, mean decreases in serum uric acid at a range of 20 to 30% were observed in patients treated with teriflunomide compared to placebo. Mean decrease in serum phosphorus was 10% in the teriflunomide group compared to placebo. These effects are considered to be related to increase in renal tubular excretion and not related to changes in glomerular functions.

Clinical trials.

The efficacy of Aubagio was established by one phase 2 and two phase 3, placebo-controlled studies in patients with relapsing forms of RMS, one phase 3 active comparator study and one phase 3, placebo-controlled study in patients with early MS (i.e. with a first clinical episode).
Study 1 (EFC6049/TEMSO) was a double-blind, placebo-controlled study that evaluated once daily doses of teriflunomide 7 mg and 14 mg in patients with relapsing forms of multiple sclerosis (RMS) over 108 weeks.
One thousand eighty-eight patients with RMS were randomised to receive 7 mg (n = 366) or 14 mg (n = 359) of Aubagio or placebo (n = 363) for 108 weeks duration. All patients had a definite diagnosis (based on MacDonald criteria) of MS exhibiting a relapsing clinical course, with or without progression, and experienced at least 1 relapse over the year preceding the trial or at least 2 relapses over the 2 years preceding the trial. At entry, patients had an Expanded Disability Status Scale (EDSS) score ≤ 5.5. The mean age of the study population was 37.9 years.
The primary endpoint was the annualised relapse rate (ARR). The annualised relapse rate was significantly lower in patients treated with Aubagio than in patients who received placebo. The key secondary endpoint was the time to disability progression, sustained for 12 weeks. Risk of disability progression was statistically significantly reduced in the teriflunomide 14 mg group compared to placebo. A statistically significant difference in disability progression sustained for 24 weeks was not demonstrated. The estimated proportion of patients free of relapses at week 108 was 45.6% in the placebo group and 56.5% in the teriflunomide 14 mg group. Aubagio effects on magnetic resonance imaging (MRI) variables (burden of disease defined as the total volume of all abnormal brain tissue lesions, and other MRI variables) were assessed. The results indicated that Aubagio 14 mg is more efficacious in disability progression and MRI parameters than Aubagio 7 mg. The results for this study are shown in Table 3 and Figure 1.

The probability of disability progression at 108 weeks (with 90% CIs) was 0.273 (0.223, 0.323) for placebo and 0.202 (0.156, 0.247) for teriflunomide 14 mg.
Study 2 (EFC10531/TOWER) was a double-blind, placebo-controlled study that evaluated once daily doses of teriflunomide 7 mg and 14 mg in patients with relapsing forms of multiple sclerosis (RMS) with a variable treatment duration (mean approximately 18 months). All patients had a definite diagnosis of MS exhibiting a relapsing clinical course, with or without progression, and experienced at least 1 relapse over the year preceding the trial or at least 2 relapses over the 2 years preceding the trial. Subjects had not received interferon-beta or any other preventive MS medications for at least 3 months before entering the study nor were these medications permitted during the study. Neurological evaluations were performed at screening, at every 12 weeks until completion, and at unscheduled visits for suspected relapse. The primary endpoint was the annualized relapse rate (ARR).
A total of 1169 patients were randomized to receive 7 mg (n = 408) or 14 mg (n = 372) of teriflunomide or placebo (n = 389). The mean age was 37.9 years the mean disease duration was 5.16 years, and the mean EDSS at baseline was 2.69 for placebo and 2.71 for 14 mg. A majority of the patients had relapsing remitting MS (97.5%). The mean time on placebo was 571 days and on 14 mg Aubagio 567 days.
The ARR was significantly reduced in patients treated with 14 mg of Aubagio compared to patients who received placebo (see Table 4).
The risk of disability progression sustained for 12 weeks (as measured by at least a 1 point increase from baseline EDSS ≤ 5.5 or a 0.5 point increase for those with a baseline EDSS > 5.5) was statistically significantly reduced only in the teriflunomide 14 mg group compared to placebo (Table 4 and Figure 2).

Study 3 (EFC6260/TOPIC) was a double-blind, placebo-controlled study that evaluated once daily doses of teriflunomide 7 mg and 14 mg for up to 108 weeks in patients with early MS (i.e. a first clinical episode). Patients had a first neurological event occurring within 90 days of randomization, with 2 or more T2 lesions at least 3 mm in diameter that were characteristic of MS. The primary endpoint was time to a second clinical episode (relapse).
A total of 618 patients were randomized to receive 7 mg (n = 205) or 14 mg (n = 216) of teriflunomide or placebo (n = 197). The mean age of the study population was 32.1 years and the mean time since first neurological event was 1.85 months, 59.1% of the patients entered the study with monofocal episode, and 40.9% with a multifocal episode. The mean time on placebo was 464 days, and on 14 mg Aubagio 493 days.
The risk of a second clinical episode was statistically significantly reduced in the teriflunomide 14 mg group compared to placebo (Table 5).

The Aubagio MRI activity was also shown in a phase 2 study (study 4 (study 2001)). A total of 179 patients received 7 mg (n = 61) or 14 mg (n = 57) of Augabio or placebo (n = 61) for 36 weeks duration. Baseline demographics were consistent across treatment groups. The mean number of unique active lesions per brain MRI scan during the 36-week treatment period was lower in patients treated with Aubagio 14 mg (0.98) as compared to placebo (2.69), the difference being statistically significant (p = 0.0052).
Study 5 (EFC10891/TENERE) was a multi-centre, randomized, parallel-group, rater blinded study comparing the effectiveness and safety of teriflunomide and interferon beta-1a in patients with relapsing multiple sclerosis plus a long-term extension period. Teriflunomide effectiveness was compared to that of a subcutaneous interferon beta-1a (at the recommended dose of 44 microgram three times a week) in 324 randomized patients in a study with minimum treatment duration of 48 weeks (maximum 114 weeks). The risk of failure (confirmed relapse or permanent treatment discontinuation whichever came first) was the primary endpoint. Teriflunomide 14 mg/day was not statistically superior to interferon beta-1a on the primary end point: the estimated percentage of patients with treatment failure at 96 weeks using the Kaplan-Meier method was 41.1% versus 44.4% (teriflunomide 14 mg versus interferon beta-1a group, p = 0.595).

5.2 Pharmacokinetic Properties

Absorption.

Median time to reach maximum plasma concentrations occurs between 1 to 4 hours post-dose following repeated oral administration of teriflunomide, with high bioavailability (~ 100%) determined by cross study comparison. Food produced a statistically significant decrease in C_max (18%) and an increase in t_max (~ 3 hours), that does not have a clinically relevant effect on teriflunomide pharmacokinetics.
Based on individual prediction of pharmacokinetic parameters using the population pharmacokinetic (PopPK) model of teriflunomide in healthy volunteers and MS patients, dose was not a significant covariate of teriflunomide pharmacokinetics.
There is a slow approach to steady-state concentration (i.e. ~ 100 days [3.5 months] to attain 95% of steady-state concentrations, based on a median terminal half-life (t_1/2z) of ~ 19 days calculated from the population pharmacokinetic (PopPK) analysis using data from healthy volunteers and MS patients), and the estimated AUC accumulation ratio is ~ 34-fold for 14 mg teriflunomide.

Distribution.

Teriflunomide is extensively bound to plasma protein (> 99%), probably albumin and is mainly distributed in plasma, rather than red blood cells. The volume of distribution is low (11 L) after a single intravenous (IV) administration.

Metabolism.

Teriflunomide is moderately metabolised and is the only component detected in plasma. The primary biotransformation pathway for teriflunomide is hydrolysis, with oxidation being a minor pathway. Other pathways involve N-acetylation and sulfate conjugation.

Excretion.

Teriflunomide is excreted in the gastrointestinal tract mainly through the bile as unchanged drug and possibly by direct secretion. Teriflunomide is a substrate of the efflux transporter breast cancer resistant protein (BCRP), which could be involved in direct secretion. Over 21 days, 60.1% of the administered dose is excreted via faeces (37.5%) and also via urine (22.6%). After the accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in faeces). Based on individual prediction of pharmacokinetic parameters using the PopPK model of teriflunomide in healthy volunteers and MS patients, median terminal exponential half-life (t_1/2z) was ~ 19 days after repeated doses of 14 mg. After a single IV administration, the total body clearance of teriflunomide is 30.5 mL/h. Biliary recycling is a major contributor to the long elimination half-life of teriflunomide. After a single IV administration, the total body clearance of teriflunomide is 30.5 mL/h. Studies with both haemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that teriflunomide is not dialysable.