Consumer medicine information

Terimide

Teriflunomide

BRAND INFORMATION

Brand name

Terimide

Active ingredient

Teriflunomide

Schedule

What is in this leaflet

This leaflet answers some common questions about TERIMIDE. 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 TERIMIDE 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 TERIMIDE is used for

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

This medicine belongs to a group of medicines called immunomodulating drugs.

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.

This medicine 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.

TERIMIDE 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 TERIMIDE generally find they will have fewer relapses.

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 available only with a doctor's prescription.

Before you take TERIMIDE

When you must not take it

Do not take TERIMIDE if you have an allergy to:

any medicine containing teriflunomide
any of the ingredients listed at the end of this leaflet
any other similar medicines

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:

any diseases which reduce your body's natural defences
any diseases of the blood
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
severe liver disease
a condition called hypoproteinaemia (when you do not have enough protein in your blood)

Do not take this medicine if you are not using reliable birth control.

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

Do not breast-feed if you are taking this medicine. The active ingredient in TERIMIDE passes into breast milk and there is a possibility that your baby may be affected.

You must not become pregnant while taking TERIMIDE and for a certain period of time after stopping TERIMIDE. TERIMIDE may increase the risk of birth defects.

Do not give this medicine to a child under the age of 18 years. Safety and effectiveness in children younger than 18 years 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 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
kidney disease

Before you start TERIMIDE, 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 are pregnant or plan to become pregnant or are breast-feeding, or if you intend to father a child. TERIMIDE may increase the risk of birth defects. To reduce any risk to the developing baby, you will need to stop taking TERIMIDE and may need to undergo a wash-out procedure. Your doctor will discuss the wash-out procedure with you.

Tell your doctor if you plan to have surgery.

If you have not told your doctor about any of the above, tell them before you start taking TERIMIDE.

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 TERIMIDE may interfere with each other. These include:

antibiotics such as rifampicin, cefaclor, penicillin G and ciprofloxacin
medicines used to treat epilepsy such as carbamazepine and phenytoin
some medicines used for diabetes such as repaglinide or pioglitazone
some medicines used 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 treat asthma
warfarin, a medicine used to prevent blood clots
some medicines used to lower cholesterol such as statins, rosuvastatin
St. John's Wort (Hypericum perforatum)

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

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 TERIMIDE faster.

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

How to take TERIMIDE

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 on the box, ask your doctor or pharmacist for help.

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.

How to take it

Swallow the tablets whole with a full glass of water.

When to take it

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

It does not matter if you take this medicine before or after food.

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

Skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for 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 TERIMIDE. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using TERIMIDE

Things you must do

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

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 taking this medicine, stop taking it and tell your doctor immediately.

If you need to stop treatment, the levels of TERIMIDE 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 TERIMIDE.

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

Tell your doctor immediately if you:

have an infection or notice chills or a fever or signs of an infection while taking this medicine
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

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

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take TERIMIDE 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 when drinking alcohol while you are taking this medicine. The effects of alcohol could be made worse while taking TERIMIDE. It is recommended you minimise your alcohol intake while taking this medicine.

Side effects

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

This medicine helps most people with MS, but it may have unwanted side effects in a few people. 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.

If you are over 65 years of age you may have an increased chance of getting 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:

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

The above list includes the more common side effects of your medicine.

Tell your doctor as soon as possible if you notice any of the following:

signs and symptoms of severe infection, such as fever
severe upper stomach pain, often with nausea and vomiting
severe skin rash or sores in your mouth
pale skin, fatigue, or proneness to bruising
if you develop new or worsening symptoms such as cough or trouble breathing, with or without a fever
inflammation of the colon, symptoms include diarrhoea usually with blood and mucus

The above list includes serious side effects that may require medical attention.

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

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

The above list includes very serious side effects. You may have had a serious allergic reaction to TERIMIDE. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using TERIMIDE

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

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

Do not store TERIMIDE 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

TERIMIDE tablets are pale blue to pastel blue, pentagonal film-coated tablets debossed with "L" on one side and "598" on the other side.

TERIMIDE tablets are available in blister packs of 28 tablets.

Ingredients

TERIMIDE contains 14 mg of teriflunomide as the active ingredient.

The tablets also contain the following inactive ingredients:

colloidal anhydrous silica
hyprolose
lactose monohydrate
magnesium stearate
maize starch
microcrystalline cellulose
OPADRY complete film coating system 03F505071 BLUE
purified water
sodium starch glycollate type A

TERIMIDE contains lactose.

Distributor

TERIMIDE is distributed in Australia by:

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in October 2021.

AUST R 299149

terimide_cmi\Oct21/00

Published by MIMS December 2021

BRAND INFORMATION

Brand name

Terimide

Active ingredient

Teriflunomide

Schedule

1 Name of Medicine

Teriflunomide.

2 Qualitative and Quantitative Composition

Each film coated tablet contains 14 mg of teriflunomide as the active ingredient.

Excipients with known effect.

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

3 Pharmaceutical Form

Film coated tablet. Pale blue to pastel blue, pentagonal film-coated tablet debossed with "L" on one side and "598" on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Terimide is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) 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 Terimide is 14 mg orally once daily. Terimide can be taken with or without food.

Special populations.

Children.

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

Elderly.

Clinical studies of teriflunomide did not include patients over 65 years old. Terimide 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 Terimide (see Section 4.4 Special Warnings and Precautions for Use, Switching to or from teriflunomide and Plasma monitoring).

4.3 Contraindications

Terimide 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 teriflunomide. 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 teriflunomide 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 teriflunomide.
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 teriflunomide 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, teriflunomide should be discontinued. Colestyramine or activated charcoal should be administered to more rapidly lower teriflunomide levels, with close monitoring including retreatment with colestyramine or activated charcoal as indicated. Monitor serum transaminase and bilirubin on teriflunomide 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 teriflunomide, 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 teriflunomide treatment and periodically thereafter. Blood pressure elevation should be appropriately managed during treatment with teriflunomide.

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 teriflunomide, if a patient develops a serious infection, consider suspending treatment with teriflunomide, and reassess the benefits and risks prior to re-initiation of therapy. Due to the prolonged elimination half-life of teriflunomide, accelerated elimination with colestyramine or charcoal may be considered (see Section 4.9 Overdose). Instruct patients receiving teriflunomide to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment with teriflunomide until the infection(s) is resolved. Teriflunomide 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 teriflunomide.
Cases of herpes virus infections, including oral herpes and herpes zoster, have been reported with teriflunomide (see Section 4.8 Adverse Effects (Undesirable Effects)), with some of them being serious, including herpetic meningoencephalitis and herpes dissemination. They may occur at any time during treatment.

Respiratory effects.

Interstitial lung disease (ILD) including acute interstitial pneumonitis as well as rare cases of pulmonary hypertension have been reported with teriflunomide 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 teriflunomide, 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 teriflunomide 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 (Terimide). 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. Please refer to the 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 teriflunomide. As soon as skin and/or mucosal reactions are observed which raise the suspicion of such severe reactions, Terimide and any other possible associated medication must be discontinued, and colestyramine 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, Terimide is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe uncontrolled infections because of the theoretical potential for immunosuppression. If Terimide 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 Terimide, treatment should be stopped and colestyramine 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 teriflunomide.

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 teriflunomide was immediately started. Therefore, caution is required when switching patients from natalizumab to teriflunomide.
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 teriflunomide 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 (t1/2z) was approximately 19 days after repeated doses of 14 mg. If a decision is made to stop treatment with teriflunomide, 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 teriflunomide. In any situation in which the decision is made to switch from teriflunomide 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. Teriflunomide washout with colestyramine or charcoal (accelerated elimination procedure) may decrease this risk but also may induce disease worsening if the patient had been responding to teriflunomide treatment.

Vaccination.

Two clinical studies have shown that vaccinations of inactivated neoantigen (first vaccination), or recall antigen (re-exposure) were safe and effective during teriflunomide 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 teriflunomide.

Skin reactions.

Severe cutaneous adverse reactions (SCARs).

Cases of serious skin 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, or toxic epidermal necrolysis (TEN), Lyell's syndrome or drug reaction with eosinophilia with 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 teriflunomide 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 teriflunomide 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 teriflunomide. 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 teriflunomide develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing teriflunomide 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 colestyramine t.i.d, 8 g colestyramine 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 colestyramine 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: colestyramine and activated charcoal).
Administration of colestyramine 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 colestyramine 8 g three times a day, the plasma concentration of teriflunomide is reduced 99% at the completion of day 11. If colestyramine 8 g three times a day is not well tolerated, colestyramine 4 g three times a day can be used.
Both colestyramine and activated charcoal may influence the absorption of estrogens and progestogens such that reliable contraception with oral contraceptives may not be guaranteed during the washout procedure with colestyramine 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 teriflunomide), 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.

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).

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 Terimide is administered to patients with renal impairment.

Use in the elderly.

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

Paediatric use.

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

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 ethinylestradiol 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, indometacin, 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-CoA 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.

Non-steroidal anti-inflammatory drugs (NSAIDs).

NSAIDs (including COX-2 inhibitors) are known to cause hepatotoxicity, therefore caution is advised when Terimide 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 NSAIDs 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 fetal harm in humans. Terimide must not be given to pregnant women, or women of childbearing potential who are not using reliable contraception during treatment with Terimide 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 Terimide.
It is recommended that women of childbearing potential only receive Terimide 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 ethinylestradiol, 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 fetus. 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 teriflunomide. 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 fetal 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. Terimide is contraindicated in women who are pregnant or currently attempting to become pregnant (see Section 4.3 Contraindications).

Labour and delivery.

There is no adequate information regarding the effects of teriflunomide 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 teriflunomide, 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.

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 teriflunomide (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.

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 teriflunomide, 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 teriflunomide, 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, 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).

Infections and infestations.

Common: herpes infection.
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, colestyramine or activated charcoal is recommended to accelerate elimination (see Section 4.4 Special Warnings and Precautions for Use).

Accelerated elimination procedure: colestyramine and activated charcoal.

The elimination of teriflunomide from the circulation can be accelerated by administration of colestyramine 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 colestyramine t.i.d, 8 g colestyramine 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 colestyramine 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 colestyramine 8 g three times a day is not well tolerated, colestyramine 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 Terimide treatment.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

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 msec with the upper bound of the 90% CI being 6.45 msec. In addition, no QTcF values were ≥ 480 ms and no changes from baseline were > 60 msec.
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 teriflunomide 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 teriflunomide 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 teriflunomide 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. Teriflunomide 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 teriflunomide 14 mg is more efficacious in disability progression and MRI parameters than teriflunomide 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 teriflunomide 567 days.
The ARR was significantly reduced in patients treated with 14 mg of teriflunomide 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 teriflunomide 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 teriflunomide 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 teriflunomide 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 teriflunomide 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 (t1/2z) 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 colestyramine, 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 (t1/2z) 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.