TERIFLUNOMIDE ACCORD 7mg tablets medication leaflet

Teriflunomide Accord 7 mg film-coated tablets

Teriflunomide Accord 14 mg film-coated tablets

Teriflunomide Accord 7 mg film-coated tablets

Each film-coated tablet contains 7 mg of teriflunomide.

Each tablet contains 79 mg of lactose monohydrate.

Teriflunomide Accord 14 mg film-coated tablets

Each film-coated tablet contains 14 mg of teriflunomide.

Each tablet contains 72 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Teriflunomide Accord 7 mg film-coated tablets

Light greenish-bluish grey to pale greenish-blue, hexagonal shaped, approximate 7.3 x 6.9 mm, filmcoated tablet, debossed with “T1” on one side and plain on other side.

Teriflunomide Accord 14 mg film-coated tablets

Blue colored, pentagonal shaped, approximate 7.3 × 7.2 mm, film coated tablet, debossed with “T2”on one side and plain on other side.

Teriflunomide Accord is indicated for the treatment of adult patients and paediatric patients aged10 years and older with relapsing remitting multiple sclerosis (MS) (please refer to section 5.1 forimportant information on the population for which efficacy has been established).

The treatment should be initiated and supervised by a physician experienced in the management ofmultiple sclerosis.

In adults, the recommended dose of teriflunomide is 14 mg once daily.

Paediatric population (10 years and older)

In paediatric patients (10 years of age and above), the recommended dose is dependent on bodyweight:

- Paediatric patients with body weight >40 kg: 14 mg once daily.

- Paediatric patients with body weight ≤40 kg: 7 mg once daily.

Paediatric patients who reach a stable body weight above 40 kg should be switched to 14 mg oncedaily.

Teriflunomide Accord should be used with caution in patients aged 65 years and over due toinsufficient data on safety and efficacy.

No dose adjustment is necessary for patients with mild, moderate or severe renal impairment notundergoing dialysis.

Patients with severe renal impairment undergoing dialysis were not evaluated. Teriflunomide iscontraindicated in this population (see section 4.3).

No dose adjustment is necessary for patients with mild and moderate hepatic impairment.

Teriflunomide is contraindicated in patients with severe hepatic impairment (see section 4.3).

Paediatric population (less than 10 years of age)

The safety and efficacy of teriflunomide in children aged below 10 years have not been established. Nodata are available.

The film-coated tablets are for oral use. The tablets should be swallowed whole with some water.

Film-coated tablets can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with severe hepatic impairment (Child-Pugh class C).

Pregnant women, or women of childbearing potential who are not using reliable contraception duringtreatment with teriflunomide and thereafter as long as its plasma levels are above 0.02 mg/l (seesection 4.6). Pregnancy must be excluded before start of treatment (see section 4.6).

Breast-feeding women (see section 4.6).

Patients with severe immunodeficiency states, e.g. acquired immunodeficiency syndrome (AIDS).

Patients with significantly impaired bone marrow function or significant anaemia, leucopenia,neutropenia or thrombocytopenia.

Patients with severe active infection until resolution (see section 4.4).

Patients with severe renal impairment undergoing dialysis, because insufficient clinical experience isavailable in this patient group.

Patients with severe hypoproteinaemia, e.g. in nephrotic syndrome.

Before starting treatment with teriflunomide the following should be assessed:

- Blood pressure

- Alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT)

- Complete blood cell count including differential white blood cell and platelet count.

During treatment with teriflunomide the following should be monitored:

- Blood pressureo Check periodically

- Alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT)o Liver enzymes should be assessed at least every four weeks during the first 6 monthsof treatment and regularly thereafter.o Consider additional monitoring when teriflunomide is given in patients withpre-existing liver disorders, given with other potentially hepatotoxic drugs or asindicated by clinical signs and symptoms such as unexplained nausea, vomiting,abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. Liver enzymesshould be assessed every two weeks during the first 6 months of treatment, and atleast every 8 weeks thereafter for at least 2 years from initiation of treatmento For ALT (SGPT) elevations between 2- and 3-fold the upper limit of normal,monitoring must be performed weekly.

- Complete blood cell counts should be performed based on clinical signs and symptoms (e.g.infections) during treatment.

Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure,it takes an average of 8 months to reach plasma concentrations less than 0.02 mg/l, although due toindividual variation in substance clearance it may take up to 2 years. An accelerated eliminationprocedure can be used at any time after discontinuation of teriflunomide (see sections 4.6 and 5.2 forprocedural details).

Elevations of liver enzymes have been observed in patients receiving teriflunomide (see section 4.8).

These elevations occurred mostly within the first 6 months of treatment.

Cases of drug-induced liver injury (DILI) have been observed during treatment with teriflunomide,sometimes life-threatening. Most cases of DILI occurred with time to onset of several weeks or severalmonths after treatment initiation of teriflunomide, but DILI can also occur with prolonged use.

The risk for liver enzyme increases and DILI with teriflunomide might be higher in patients withpre-existing liver disorder, concomitant treatment with other hepatotoxic drugs, and/or consumption ofsubstantial quantities of alcohol. Patients should therefore be closely monitored for signs andsymptoms of liver injury.

Teriflunomide therapy should be discontinued and accelerated elimination procedure considered ifliver injury is suspected. If elevated liver enzymes (greater than 3-fold ULN) are confirmed,teriflunomide therapy should be discontinued.

In case of treatment discontinuation, liver tests should be pursued until normalisation of transaminaselevels.

Since teriflunomide is highly protein bound and as the binding is dependent upon the concentrations ofalbumin, unbound plasma teriflunomide concentrations are expected to be increased in patients withhypoproteinaemia, e.g. in nephrotic syndrome. Teriflunomide should not be used in patients withconditions of severe hypoproteinaemia.

Elevation of blood pressure may occur during treatment with teriflunomide (see section 4.8). Bloodpressure must be checked before the start of teriflunomide treatment and periodically thereafter. Bloodpressure elevation should be appropriately managed before and during treatment with teriflunomide.

Initiation of treatment with teriflunomide should be delayed in patients with severe active infectionuntil resolution.

In placebo-controlled studies, no increase in serious infections was observed with teriflunomide (seesection 4.8).

Cases of herpes virus infections, including oral herpes and herpes zoster, have been reported withteriflunomide (see section 4.8), with some of them being serious, including herpeticmeningoencephalitis and herpes dissemination. They may occur at any time during treatment.

Based on the immunomodulatory effect of teriflunomide, if a patient develops any serious infection,suspending treatment with teriflunomide should be considered and the benefits and risks should bereassessed prior to re-initiation of therapy. Due to the prolonged half-life, accelerated elimination withcholestyramine or charcoal may be considered.

Patients receiving teriflunomide should be instructed to report symptoms of infections to a physician.

Patients with active acute or chronic infections should not start treatment with teriflunomide until theinfection(s) is resolved.

The safety of teriflunomide in individuals with latent tuberculosis infection is unknown, astuberculosis screening was not systematically performed in clinical studies. Patients tested positive intuberculosis screening should be treated by standard medical practice prior to therapy.

Interstitial lung disease (ILD) as well as cases of pulmonary hypertension have been reported withteriflunomide in the postmarketing setting.

The risk might be increased in patients with a history of ILD.

ILD may occur acutely at any time during therapy with a variable clinical presentation.

ILD may be fatal. New onset or worsening pulmonary symptoms, such as persistent cough anddyspnoea, may be a reason for discontinuation of the therapy and for further investigation, asappropriate. If discontinuation of the medicinal product is necessary, initiation of an acceleratedelimination procedure should be considered.

A mean decrease less than 15% from baseline affecting white blood cell count has been observed (seesection 4.8). As a precaution, a recent complete blood cell count, including differential white bloodcell count and platelets, should be available before the initiation of treatment and the complete bloodcell count should be assessed during therapy as indicated by clinical signs and symptoms(e.g., infections).

In patients with pre-existing anaemia, leucopenia, and /or thrombocytopenia as well as in patients withimpaired bone marrow function or those at risk of bone marrow suppression, the risk ofhaematological disorders is increased. If such effects occur, the accelerated elimination procedure (seeabove) to reduce plasma levels of teriflunomide should be considered.

In cases of severe haematological reactions, including pancytopenia, teriflunomide and anyconcomitant myelosuppressive treatment must be discontinued and a teriflunomide acceleratedelimination procedure should be considered.

Cases of serious skin reactions, sometimes fatal including Stevens-Johnson syndrome (SJS), toxicepidermal necrolysis (TEN), and drug reaction with eoseinophilia and systemic symptoms (DRESS),have been reported with teriflunomide.

If skin and /or mucosal reactions (ulcerative stomatitis) are observed which raise the suspicion ofsevere generalised major skin reactions (Stevens-Johnson syndrome, toxic epidermalnecrolysis-Lyell’s syndrome, or drug reaction with eosinophilia and systemic symptoms),teriflunomide and any other possibly associated treatment must be discontinued, and an acceleratedelimination procedure initiated immediately. In such cases patients should not be re-exposed toteriflunomide (see section 4.3).

New onset of psoriasis (including pustular psoriasis) and worsening of pre-existing psoriasis have beenreported during the use of teriflunomide. Treatment withdrawal and initiation of an acceleratedelimination procedure may be considered taking into account patient’s disease and medical history.

Cases of peripheral neuropathy have been reported in patients receiving teriflunomide (seesection 4.8). Most patients improved after discontinuation of teriflunomide. However, there was a widevariability in final outcome, i.e. in some patients the neuropathy resolved and some patients hadpersistent symptoms. If a patient taking teriflunomide develops a confirmed peripheral neuropathy,consider discontinuing teriflunomide therapy and performing the accelerated elimination procedureshould be considered.

Two clinical studies have shown that vaccinations to inactivated neoantigen (first vaccination), orrecall antigen (reexposure) were safe and effective during teriflunomide treatment. The use of liveattenuated vaccines may carry a risk of infections and should therefore be avoided.

As leflunomide is the parent compound of teriflunomide, co-administration of teriflunomide withleflunomide is not recommended.

Co-administration with antineoplastic or immunosuppressive therapies used for treatment of MS hasnot been evaluated. Safety studies, in which teriflunomide was concomitantly administered withinterferon beta or with glatiramer acetate for up to one year did not reveal any specific safety concerns,but a higher adverse reaction rate as compared to teriflunomide monotherapy was observed. The longterm safety of these combinations in the treatment of multiple sclerosis has not been established.

Switching to or from teriflunomide

Based on the clinical data related to concomitant administration of teriflunomide with interferon betaor with glatiramer acetate, no waiting period is required when initiating teriflunomide after interferonbeta 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 wasimmediately started. Therefore, caution is required when switching patients from natalizumab toteriflunomide.

Based on the half-life of fingolimod, a 6-week interval without therapy is needed for clearance fromthe circulation and a 1 to 2 month period is needed for lymphocytes to return to normal rangefollowing discontinuation of fingolimod. Starting teriflunomide during this interval will result inconcomitant exposure to fingolimod. This may lead to an additive effect on the immune system andcaution is, therefore, indicated.

In MS patients, the median t1/2z was approximately 19 days after repeated doses of 14 mg. If a decisionis made to stop treatment with teriflunomide, during the interval of 5 half-lives (approximately3.5 months although may be longer in some patients), starting other therapies will result inconcomitant exposure to teriflunomide. This may lead to an additive effect on the immune system andcaution is, therefore, indicated.

The measurement of ionised calcium levels might show falsely decreased values under treatment withleflunomide and/or teriflunomide (the active metabolite of leflunomide) depending on the type ofionised calcium analyser used (e.g. blood gas analyser). Therefore, the plausibility of observeddecreased ionised calcium levels needs to be questioned in patients under treatment with leflunomideor teriflunomide. In case of doubtful measurements, it is recommended to determine the total albuminadjusted serum calcium concentration.

In the paediatric clinical trial, cases of pancreatitis, some acute, have been observed in patientsreceiving teriflunomide (see section 4.8). Clinical symptoms included abdominal pain, nausea and/orvomiting. Serum amylase and lipase were elevated in these patients. The time to onset ranged from afew months up to three years. Patients should be informed of the characteristic symptoms ofpancreatitis. If pancreatitis is suspected, pancreatic enzymes and related laboratory parameters shouldbe obtained. If pancreatitis is confirmed, teriflunomide should be discontinued and an acceleratedelimination procedure should be initiated (see section 5.2).

Since Teriflunomide Accord tablets contain lactose, patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption, should not take this medicinalproduct.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially“sodium free”.

The primary biotransformation pathway for teriflunomide is hydrolysis, with oxidation being a minorpathway.

Potent cytochrome P450 (CYP) and transporter 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-glycoprotein [P-gp] andbreast cancer resistant protein [BCRP] with teriflunomide (70 mg single dose) resulted in anapproximately 40% decrease in teriflunomide exposure. Rifampicin and other known potent CYP andtransporter inducers such as carbamazepine, phenobarbital, phenytoin and St John’s Wort should beused with caution during the treatment with teriflunomide.

It is recommended that patients receiving teriflunomide are not treated with cholestyramine oractivated charcoal because this leads to a rapid and significant decrease in plasma concentration unlessan accelerated elimination is desired. The mechanism is thought to be by interruption of enterohepaticrecycling and/or gastrointestinal dialysis of teriflunomide.

There was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively), followingrepeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo.

Therefore, medicinal products metabolised by CYP2C8, such as repaglinide, paclitaxel, pioglitazoneor rosiglitazone, should be used with caution during treatment with teriflunomide.

Effect of teriflunomide on oral contraceptives: 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel

There was an increase in mean ethinylestradiol Cmax and AUC0-24 (1.58- and 1.54-fold, respectively)and levonorgestrel Cmax and AUC0-24 (1.33- and 1.41-fold, respectively) following repeated doses ofteriflunomide. While this interaction of teriflunomide is not expected to adversely impact the efficacyof oral contraceptives, it should be considered when selecting or adjusting oral contraceptive treatmentused in combination with teriflunomide.

Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine (CYP1A2 substrate) by18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2 in vivo.

Therefore, medicinal products metabolised by CYP1A2 (such as duloxetin, alosetron, theophylline andtizanidine) should be used with caution during treatment with teriflunomide, as it could lead to thereduction of the efficacy of these medicinal products.

Repeated doses of teriflunomide had no effect on the pharmacokinetics of S-warfarin, indicating thatteriflunomide is not an inhibitor or an inducer of CYP2C9. However, a 25% decrease in peakinternational normalised ratio (INR) was observed when teriflunomide was coadministered withwarfarin as compared with warfarin alone. Therefore, when warfarin is co-administered withteriflunomide, close INR follow-up and monitoring is recommended.

There was an increase in mean cefaclor Cmax and AUC (1.43- and 1.54-fold, respectively), followingrepeated 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,benzylpenicillin, ciprofloxacin, indometacin, ketoprofen, furosemide, cimetidine, methotrexate,zidovudine, caution is recommended.

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

There was an increase in mean rosuvastatin Cmax and AUC (2.65- and 2.51-fold, respectively),following repeated doses of teriflunomide. However, there was no apparent impact of this increase inplasma rosuvastatin exposure on the HMG-CoA reductase activity. For rosuvastatin, a dose reductionby 50% is recommended for coadministration with teriflunomide. 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 withcaution. Patients should be closely monitored for signs and symptoms of excessive exposure to themedicinal products and reduction of the dose of these medicinal products should be considered.

The risk of male-mediated embryo-foetal toxicity through teriflunomide treatment is considered low(see section 5.3).

There are limited amount of data from the use of teriflunomide in pregnant women. Studies in animalshave shown reproductive toxicity (see section 5.3).

Teriflunomide may cause serious birth defects when administered during pregnancy. Teriflunomide iscontraindicated in pregnancy (see section 4.3).

Women of childbearing potential have to use effective contraception during treatment and aftertreatment as long as teriflunomide plasma concentration is above 0.02 mg/l. During this period womenshould discuss any plans to stop or change contraception with the treating physician. Female childrenand/or parents/caregivers of female children should be informed about the need to contact the treatingphysician once the female child under teriflunomide treatment experiences menses. Counsellingshould be provided to the new patients of child-bearing potential about contraception and the potentialrisk to the foetus. Referral to a gynaecologist should be considered.

The patient must be advised that if there is any delay in onset of menses or any other reason to suspectpregnancy, they must discontinue teriflunomide and notify the physician immediately for pregnancytesting, and if positive, the physician and patient must discuss the risk to the pregnancy. It is possiblethat rapidly lowering the blood level of teriflunomide, by instituting the accelerated eliminationprocedure described below, at the first delay of menses, may decrease the risk to the foetus.

For women receiving teriflunomide treatment, who wish to become pregnant, the medicinal productshould be stopped and an accelerated elimination procedure is recommended in order to more rapidlyachieve concentration below 0.02 mg/l (see below).

If an accelerated elimination procedure is not used, teriflunomide plasma levels can be expected to beabove 0.02 mg/l for an average of 8 months, however, in some patients it may take up to 2 years toreach plasma concentration below 0.02 mg/l. Therefore, teriflunomide plasma concentrations shouldbe measured before a woman begins to attempt to become pregnant. Once the teriflunomide plasmaconcentration is determined to be below 0.02 mg/l, the plasma concentration must be determined againafter an interval of at least 14 days. If both plasma concentrations are below 0.02 mg/l, no risk to thefoetus is to be expected.

For further information on the sample testing please contact the Marketing Authorisation Holder or itslocal representative (see section 7).

After stopping treatment with teriflunomide:

- cholestyramine 8 g is administered 3 times daily for a period of 11 days, or cholestyramine 4 gthree times a day can be used, if cholestyramine 8 g three times a day is not well tolerated,

- alternatively, 50 g of activated powdered charcoal is administered every 12 hours for a period of11 days.

However, also following either of the accelerated elimination procedures, verification by 2 separatetests at an interval of at least 14 days and a waiting period of one-and-a-half months between the firstoccurrence of a plasma concentration below 0.02 mg/l and fertilisation is required.

Both cholestyramine and activated powdered charcoal may influence the absorption of oestrogens andprogestogens such that reliable contraception with oral contraceptives may not be guaranteed duringthe accelerated elimination procedure with cholestyramine or activated powdered charcoal. Use ofalternative contraceptive methods is recommended.

Animal studies have shown excretion of teriflunomide in milk. Teriflunomide is contraindicatedduring breast-feeding (see section 4.3).

Results of studies in animals have not shown an effect on fertility (see section 5.3). Although humandata are lacking, no effect on male and female fertility is anticipated.

Teriflunomide Accord has no or negligible influence on the ability to drive and use machines.

In the case of adverse reactions such as dizziness, which has been reported with leflunomide, theparent compound, the patient’s ability to concentrate and to react properly may be impaired. In suchcases, patients should refrain from driving cars and using machines.

The most frequently reported adverse reactions in the teriflunomide treated (7 mg and 14 mg)patientswere: headache (17.8%, 15.7%), diarrhoea (13.1%, 13.6%) increased ALT (13%, 15%), nausea (8%,10.7%), and alopecia (9.8%, 13.5%). In general, headache, diarrhoea, nausea and alopecia, were mildto moderate, transient and infrequently led to treatment discontinuation.

Teriflunomide is the main metabolite of leflunomide. The safety profile of leflunomide in patientssuffering from rheumatoid arthritis or psoriatic arthritis may be pertinent when prescribingteriflunomide in MS patients.

Teriflunomide was evaluated in a total of 2,267 patients exposed to teriflunomide (1,155 onteriflunomide 7 mg and 1,112 on teriflunomide 14 mg) once daily for a median duration of about672 days in four placebo-controlled studies (1,045 and 1,002 patients for teriflunomide 7 mg and14 mg, respectively) and one active comparator study (110 patients in each of the teriflunomidetreatment groups) in adult patients with relapsing forms of MS (Relapsing Multiple Sclerosis, RMS).

Listed below are the adverse reactions reported with teriflunomide in placebo-controlled studies inadult patients, reported for teriflunomide 7 mg or 14 mg from clinical studies in adult patients.

Frequencies were defined using the following convention: very common (≥1/10); common (≥1/100 to<1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); notknown (cannot be estimated from the available data). Within each frequency grouping, adversereactions are ranked in order of decreasing seriousness.

System organ Very Common Uncommon Rare Ver Notclass common y knownrare

Infections and Influenza, Severeinfestations Upper infectionsrespiratory tract includinginfection, sepsisa

Urinary tractinfection,

System organ Very Common Uncommon Rare Ver Notclass common y knownrare

Bronchitis,

Sinusitis,

Pharyngitis,

Cystitis,

Gastroenteritisviral,

Herpes virusinfectionsb,

Tooth infection,

Laryngitis,

Tinea pedis

Blood and Neutropeniab, Mildlymphatic Anaemia thrombocytopesystem nia (plateletsdisorders <100G/l)

Immune Mild allergic Hyper-system reactions sensitivitydisorders reactions(immediate ordelayed)includinganaphylaxisandangioedema

Psychiatric Anxietydisorders

Nervous Headache Paraesthesia, Hyperaesthesia,system Sciatica, Neuralgia,disorders Carpal tunnel Peripheralsyndrome neuropathy

Cardiac Palpitationsdisorders

Vascular Hypertensionbdisorders

Respiratory, Interstitial lung Pulmonarythoracic and disease hypertensimediastinal ondisorders

Gastrointestin Diarrhoea, Pancreatitisb’c, Stomatitisal disorders Nausea Abdominal pain Colitisupper,

Vomiting,

Toothache

Hepatobiliary Alanine Gamma- Acute Drug-disorders aminotransfera glutamyltransfer hepatit inducedse (ALT) ase (GGT) is liver injuryincreaseb increaseb, (DILI)

Aspartateaminotransferaseincreaseb

Metabolism Dyslipidaemiaand nutritiondisorders

System organ Very Common Uncommon Rare Ver Notclass common y knownrare

Skin and Alopecia Rash, Acne Nail disorders,subcutaneous Psoriasistissue (includingdisorders pustular)a.b ,

Severe skinreactionsa

Musculoskele Musculoskeletaltal and pain,connective Myalgia,tissue Arthralgiadisorders

Renal and Pollakiuriaurinarydisorders

Reproductive Menorrhagiasystem andbreastdisorders

General Pain, Astheniaadisorders andadministration siteconditions

Investigations Weight decrease,

Neutrophil countdecreaseb,

White blood cellcount decreaseb,

Blood creatinephosphokinaseincreased

Injury, Post-traumaticpoisoning and painproceduralcomplicationsa: please refer to the detailed description sectionb: see section 4.4c: frequency is “common” in children based on a controlled clinical study in paediatrics; frequency is“uncommon” in adults

Alopecia

Alopecia was reported as hair thinning, decreased hair density, hair loss, associated or not with hairtexture change, in 13.9% of patients treated with 14 mg teriflunomide versus 5.1% in patients treatedwith placebo.

Most cases were described as diffuse or generalised over the scalp (no complete hair loss reported) andoccurred most often during the first 6 months and with resolution in 121 of 139 (87.1%) patientstreated with teriflunomide 14 mg. Discontinuation because of alopecia was 1.3% in the teriflunomide14 mg teriflunomide group, versus 0.1% in the placebo group.

During placebo-controlled studies in adult patients the following was detected:

ALT increase (based on laboratory data) according to baseline status - Safety population inplacebo- controlled studies

Placebo Teriflunomide 14 mg(N=997) (N=1002)>3 ULN 66/994 (6.6%) 80/999 (8.0%)>5 ULN 37/994 (3.7%) 31/999 (3.1%)>10 ULN 16/994 (1.6%) 9/999 (0.9%)>20 ULN 4/994 (0.4%) 3/999 (0.3%)

ALT >3 ULN and TBILI >2 ULN 5/994 (0.5%) 3/999 (0.3%)

Mild increases in transaminase, ALT below or equal to 3-fold ULN were more frequently seen interiflunomide-treated groups as compared to placebo. The frequency of elevations above 3-fold ULNand higher was balanced across treatment groups. These elevations in transaminase occurred mostlywithin the first 6 months of treatment and were reversible after treatment cessation. The recovery timevaried between months and years.

In placebo-controlled studies in adult patients the following was established:

- systolic blood pressure was >140 mm Hg in 19.9% of patients receiving 14 mg/dayteriflunomide as compared to 15.5% receiving placebo;

- systolic blood pressure was >160 mm Hg in 3.8% of patients receiving 14 mg/day teriflunomideas compared to 2.0% receiving placebo;

- diastolic blood pressure was >90 mm Hg in 21.4% of patients receiving 14 mg/dayteriflunomide as compared to 13.6% receiving placebo.

In placebo-controlled studies in adult patients, no increase in serious infections was observed withteriflunomide 14 mg (2.7%) as compared to placebo (2.2%). Serious opportunistic infections occurredin 0.2% of each group. Severe infections including sepsis, sometimes fatal have been reportedpostmarketing.

A mean decrease affecting white blood cell (WBC) count (<15% from baseline levels, mainlyneutrophil and lymphocytes decrease) was observed in placebo-controlled trials with teriflunomide inadult patients, although a greater decrease was observed in some patients. The decrease in mean countfrom baseline occurred during the first 6 weeks then stabilised over time while on-treatment but atdecreased levels (less than a 15% decrease from baseline). The effect on red blood cell (RBC) (<2%)and platelet counts (<10%) was less pronounced.

In placebo-controlled studies in adult patients, peripheral neuropathy, including both polyneuropathyand mononeuropathy (e.g., carpal tunnel syndrome), was reported more frequently in patients takingteriflunomide than in patients taking placebo. In the pivotal, placebo-controlled studies, the incidenceof peripheral neuropathy confirmed by nerve conduction studies was 1.9% (17 patients out of 898) on14 mg of teriflunomide, compared with 0.4% (4 patients out of 898) on placebo. Treatment wasdiscontinued in 5 patients with peripheral neuropathy on teriflunomide 14 mg. Recovery followingtreatment discontinuation was reported in 4 of these patients.

There does not appear to be an increased risk of malignancy with teriflunomide in the clinical trialexperience. The risk of malignancy, particularly lymphoproliferative disorders, is increased with use ofsome other agents that affect the immune system (class effect).

Severe skin reactions

Cases of severe skin reactions have been reported with teriflunomide post-marketing (see section 4.4).

Asthenia

In placebo-controlled studies in adult patients, frequencies for asthenia were 2.0%, 1.6% and 2.2% inthe placebo, teriflunomide 7 mg and teriflunomide 14 mg group, respectively.

In placebo-controlled studies, frequencies for psoriasis were 0.3%, 0.3% and 0.4% in the placebo,teriflunomide 7 mg and teriflunomide 14 mg group, respectively.

Pancreatitis has been reported infrequently in the post-marketing setting with teriflunomide in adults,including cases of necrotising pancreatitis and pancreatic pseudocyst. Pancreatic events may occur atany time during treatment with teriflunomide, which may lead to hospitalisation and/or requirecorrective treatment.

The observed safety profile in paediatric patients (from 10 to 17 years-old) receiving teriflunomidedaily was overall similar to that seen in adult patients. However, in the paediatric study (166 patients:109 in the teriflunomide group and 57 in the placebo group), cases of pancreatitis were reported in1.8% (2/109) of the teriflunomide-treated patients compared to none in the placebo group, in thedouble-blind phase. One of these events led to hospitalisation and required corrective treatment. Inpaediatric patients treated with teriflunomide in the open-label phase of the study, 2 additional cases ofpancreatitis (one was reported as a serious event, the other was a nonserious event of mild intensity)and one case of serious acute pancreatitis (with pseudo-papilloma), were reported. In two of these3 patients, pancreatitis led to hospitalisation. Clinical symptoms included abdominal pain, nausea and/or vomiting and serum amylase and lipase were elevated in these patients. All patients recovered aftertreatment discontinuation and accelerated elimination procedure (see section 4.4) and correctivetreatment.

The following adverse reactions were more frequently reported in the paediatric population than in theadult population:

- Alopecia was reported in 22.0% of patients treated with teriflunomide versus 12.3% in patientstreated with placebo.

- Infections were reported in 66.1% of patients treated with teriflunomide versus 45.6% inpatients treated with placebo. Among them, nasopharyngitis and upper respiratory tractinfections were more frequently reported with teriflunomide.

- CPK increase was reported in 5.5% of patients treated with teriflunomide versus 0% in patientstreated with placebo. The majority of the cases were associated with documented physicalexercise.

- Paraesthesia was reported in 11.0% of patients treated with teriflunomide versus 1.8% inpatients treated with placebo.

- Abdominal pain was reported in 11.0% of patients treated with teriflunomide versus 1.8% inpatients treated with placebo.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no experience regarding teriflunomide overdose or intoxication in humans. Teriflunomide70 mg daily was administered up to 14 days in healthy subjects. The adverse reactions were consistentwith the safety profile for teriflunomide in MS patients.

In the event of relevant overdose or toxicity, cholestyramine or activated charcoal is recommended toaccelerate elimination. The recommended elimination procedure is cholestyramine 8 g three times aday for 11 days. If this is not well tolerated, cholestyramine 4 g three times a day for 11 days can beused. Alternatively, when cholestyramine is not available, activated charcoal 50 g twice a day for11 days may also be used. In addition, if required for tolerability reasons, administration ofcholestyramine or activated charcoal does not need to occur on consecutive days (see section 5.2).

Pharmacotherapeutic group: Immunosuppressants, Selective immunosuppressants, ATC Code:

L04AA31.

Teriflunomide is an immunomodulatory agent with anti-inflammatory properties that selectively andreversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), whichfunctionally connects with the respiratory chain. As a consequence of the inhibition, teriflunomidegenerally reduces the proliferation of rapidly dividing cells that depend on de novo synthesis ofpyrimidine to expand. The exact mechanism by which teriflunomide exerts its therapeutic effect in MSis not fully understood, but this is mediated by a reduced number of T-lymphocytes.

Immune system

Effects on immune cell numbers in the blood: In the placebo-controlled studies, teriflunomide 14 mgonce a day led to a mild mean reduction in lymphocyte count, of less than 0.3 x 109/l, which occurredover the first 3 months of treatment and 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 meansteady-state concentrations did not show any potential for prolonging the QTcF interval compared withplacebo: the largest time matched mean difference between teriflunomide and placebo was3.45 ms with the upper bound of the 90% CI being 6.45 ms.

Effect on renal tubular functions

In the placebo-controlled studies, mean decreases in serum uric acid at a range of 20 to 30% wereobserved in patients treated with teriflunomide compared to placebo. Mean decrease in serumphosphorus was around 10% in the teriflunomide group compared to placebo. These effects areconsidered to be related to increase in renal tubular excretion and not related to changes in glomerularfunctions.

The efficacy of teriflunomide was demonstrated in two placebo-controlled studies, the TEMSO andthe TOWER study, that evaluated once daily doses of teriflunomide 7 mg and 14 mg in adult patientswith RMS.

A total of 1,088 patients with RMS were randomised in TEMSO 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 definitediagnosis of MS (based on McDonald criteria (2001)), exhibited a relapsing clinical course, with orwithout progression, and experienced at least 1 relapse over the year preceding the trial or at least2 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 majority of patients had relapsing-remittingmultiple sclerosis (91.5%), but a subgroup of patients had secondary progressive (4.7%) or progressiverelapsing multiple sclerosis (3.9%). The mean number of relapses within the year before studyinclusion was 1.4 with 36.2% of patients having gadolinium-enhancing lesions at baseline. The median

EDSS score at baseline was 2.50; 249 patients (22.9%) had an EDSS score › 3.5 at baseline. The meanduration of disease, since first symptoms, was 8.7 years. A majority of patients (73%) had not receiveddisease-modifying therapy during the 2 years before study entry. The study results are shown in

Table 1.

Long term follow-up results from TEMSO long term extension safety study (overall median treatmentduration approximately 5 years, maximum treatment duration approximately 8.5 years) did not presentany new or unexpected safety findings.

A total of 1,169 patients with RMS were randomised in TOWER to receive 7 mg (n=408) or 14 mg(n=372) of teriflunomide or placebo (n= 389) for a variable treatment duration ending at 48 weeksafter last patient randomised. All patients had a definite diagnosis of MS (based on McDonald criteria(2005)), exhibited a relapsing clinical course, with or without progression, and experienced at least1 relapse over the year preceding the trial or at least 2 relapses over the 2 years preceding the trial. Atentry, patients had an Expanded Disability Status Scale (EDSS) score ≤5.5.

The mean age of the study population was 37.9 years. The majority of patients had relapsing-remittingmultiple sclerosis (97.5%), but a subgroup of patients had secondary progressive (0.8%) or progressiverelapsing multiple sclerosis (1.7%). The mean number of relapses within the year before studyinclusion was 1.4. Gadolinium-enhancing lesions at baseline: no data. The median EDSS score atbaseline was 2.50; 298 patients (25.5%) had an EDSS score › 3.5 at baseline. The mean duration ofdisease, since first symptoms, was 8.0 years. A majority of patients (67.2%) had not receiveddisease-modifying therapy during the 2 years before study entry. The study results are shown in

Table 1.

Table 1 - Main results (for the approved dose, ITT population)

TEMSO-study TOWER-study

Teriflunomide Placebo Teriflunomide Placebo14 mg 14 mg

N 358 363 370 388

Clinical Outcomes

Annualised relapse rate 0.37 0.54 0.32 0.50

Risk difference (CI ) -0.17 (-0.26, -0.08)*** -0.18 (-0.27, -0.09)****95%

Relapse-free week 108 56.5% 45.6% 57.1% 46.8%

Hazard ratio (CI95%) 0.72, (0.58, 0.89)** 0.63, (0.50, 0.79)****3-month Sustained

Disability Progression 20.2% 27.3% 15.8% 19.7%week 108

Hazard ratio (CI95% ) 0.70 (0.51, 0.97)* 0.68 (0.47, 1.00)*6-month Sustained

Disability Progression 13.8% 18.7% 11.7% 11.9%week 108

Hazard ratio (CI95% ) 0.75 (0.50, 1.11) 0.84 (0.53, 1.33)

MRI endpoints

Change in BOD (1)week 108 0.72 2.21 Not measured

Change relative to placebo 67%***

Mean Number of Gd-enhancing lesions at 0.38 1.18week 108

Change relative to placebo

- 0.80 (-1.20, -0.39)****(CI95% )

Number of unique active0.75 2.46lesions /scan

Change relative to placebo69%, (59%; 77%)****(CI95% )

**** p<0.0001 *** p<0.001 ** p<0.01 * p<0.05 compared to placebo(1) BOD: burden of disease: total lesion volume (T2 and T1 hypointense) in ml

Efficacy in patients with high disease activity:

A consistent treatment effect on relapses and time to 3-month sustained disability progression in asubgroup of patients in TEMSO (n= 127) with high disease activity was observed. Due to the design ofthe study, high disease activity was defined as 2 or more relapses in one year, and with one or more

Gd-enhancing lesion on brain MRI. No similar subgroup analysis was performed in TOWER as no

MRI data were obtained.

No data are available in patients who have failed to respond to a full and adequate course (normally atleast one year of treatment) of beta-interferon, having had at least 1 relapse in the previous year whileon therapy, and at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gd-enhancing lesion, orpatients having an unchanged or increased relapse rate in the prior year as compared to the previous2 years.

TOPIC was a double-blind, placebo-controlled study that evaluated once daily doses of teriflunomide7 mg and 14 mg for up to 108 weeks in patients with first clinical demyelinating event (mean age32.1 years). The primary endpoint was time to a second clinical episode (relapse). A total of618 patients were randomised to receive 7 mg (n=205) or 14 mg (n=216) of teriflunomide or placebo(n=197). The risk of a second clinical attack over 2 years was 35.9% in the placebo group and 24.0%in the teriflunomide 14 mg treatment group (hazard ratio: 0.57, 95% confidence interval: 0.38 to 0.87,p=0.0087). The results from the TOPIC study confirmed the efficacy of teriflunomide in RRMS(including early RRMS with first clinical demyelinating event and MRI lesions disseminated in timeand space).

Teriflunomide effectiveness was compared to that of a subcutaneous interferon beta-1a (at therecommended dose of 44 μg three times a week) in 324 randomised patients in a study (TENERE)with minimum treatment duration of 48 weeks (maximum 114 weeks). The risk of failure (confirmedrelapse or permanent treatment discontinuation whichever came first) was the primary endpoint. Thenumber of patients with permanent treatment discontinuation in the teriflunomide 14 mg group was 22out of 111 (19.8%), the reasons being adverse events (10.8%), lack of efficacy (3.6%), other reason(4.5%) and lost to follow-up (0.9%). The number of patients with permanent treatment discontinuationin the subcutaneous interferon beta-1a group was 30 out of 104 (28 .8%), the reasons being adverseevents (21.2%), lack of efficacy (1.9%), other reason (4.8%) and poor compliance to protocol (1%).

Teriflunomide 14 mg/day was not superior to interferon beta- 1a on the primary endpoint: theestimated percentage of patients with treatment failure at 96 weeks using the Kaplan-Meier methodwas 41.1% versus 44.4% (teriflunomide 14 mg versus interferon beta-1a group, p=0.595).

Children and adolescents (10 to 17 years of age)

Study EFC11759/TERIKIDS was an international double-blind, placebo-controlled study in paediatricpatients aged 10 to 17 years with relapsing-remitting MS that evaluated once daily doses ofteriflunomide (adjusted to reach an exposure equivalent to the dose of 14 mg in adults) for up to96 weeks followed by an open-label extension. All patients had experienced at least 1 relapse over1 year or at least 2 relapses over 2 years preceding the study. Neurological evaluations wereperformed at screening and every 24 weeks until the completion, and at unscheduled visits forsuspected relapse. Patients with a clinical relapse or high MRI activity of at least 5 new or enlarging

T2 lesions on 2 consecutive scans were switched prior to 96 weeks to the open-label extension toensure active treatment. The primary endpoint was time to first clinical relapse after randomisation.

Time to first confirmed clinical relapse or high MRI activity, whichever came first, was pre-defined asa sensitivity analysis because it includes both clinical and MRI conditions qualifying for switching intothe open-label period.

A total of 166 patients were randomised at a 2:1 ratio to receive teriflunomide (n=109) or placebo(n=57). At entry, study patients had an EDSS score ≤5.5; the mean age was 14.6 years; the meanweight was 58.1 kg; the mean disease duration since diagnosis was 1.4 years; and the mean T1

Gd-enhancing lesions per MRI scan was 3.9 lesions at baseline. All patients had relapsing remitting

MS with the median EDSS score of 1.5 at baseline. The mean treatment time was 362 days on placeboand 488 days on teriflunomide. Switching from the double-blind period to open-label treatment due tohigh MRI activity was more frequent than anticipated, and more frequent and earlier in the placebogroup than in the teriflunomide group (26% on placebo, 13% on teriflunomide).

Teriflunomide reduced the risk of clinical relapse by 34% relative to placebo, without reachingstatistical significance (p = 0.29) (Table 2). In the pre-defined sensitivity analysis, teriflunomideachieved a statistically significant reduction in the combined risk of clinical relapse or high MRIactivity by 43% relative to placebo (p = 0.04) (Table 2).

Teriflunomide significantly reduced the number of new and enlarging T2 lesions per scan by 55%(p=0.0006) (post-hoc analysis also adjusted for baseline T2 counts: 34%, p=0.0446), and the numberof Gadolinium-enhancing T1 lesions per scan by 75% (p <0.0001) (Table 2).

Table 2 - Clinical and MRI results of EFC11759/TERIKIDS

EFC11759 ITT population Teriflunomide Placebo(N=109) (N=57)

Clinical endpoints

Time to first confirmed clinical relapse,

Probability (95%CI) of confirmed relapse at Week 96 0.39 (0.29, 0.48) 0.53 (0.36, 0.68)

Probability (95%CI) of confirmed relapse at Week 48 0.30 (0.21, 0.39) 0.39 (0.30, 0.52)

Hazard Ratio (95% CI) 0.66 (0.39, 1.11)^

Time to first confirmed clinical relapse or high MRI activity,

Probability (95%CI) of confirmed relapse or high MRI 0.51 (0.41, 0.60) 0.72 (0.58, 0.82)activity at Week 96

Probability (95%CI) of confirmed relapse or high MRI 0.38 (0.29, 0.47) 0.56 (0.42, 0.68)activity at Week 48

Hazard Ratio (95% CI) 0.57 (0.37, 0.87)*

Key MRI endpoints

Adjusted number of new or enlarged T2 lesions,

Estimate (95% CI) 4.74 (2.12, 10.57) 10.52 (4.71, 23.50)

Estimate (95% CI), post-hoc analysis also adjusted for 3.57 (1.97, 6.46) 5.37 (2.84, 10.16)baseline T2 counts

Relative risk (95% CI) 0.45 (0.29, 0.71)∗∗

Relative risk (95% CI), post-hoc analysis also adjusted 0.67 (0.45, 0.99)*for baseline T2 counts

Adjusted number of T1 Gd-enhancing lesions,

Estimate (95% CI) 1.90 (0.66, 5.49) 7.51 (2.48, 22.70)

Relative risk (95% CI) 0.25 (0.13, 0.51)***^p≥0.05 compared to placebo, ∗ p<0.05, ∗∗ p<0.001, ∗∗∗ p<0.0001

Probability was based on Kaplan-Meier estimator and Week 96 was the end of study treatment (EOT).

The European Medicines Agency has waived the obligation to submit the results of studies with thereference medicinal product containing teriflunomide in children from birth to less than 10 years intreatment of multiple sclerosis (see section 4.2 for information on paediatric use).

Median time to reach maximum plasma concentrations occurs between 1 to 4 hours post-dosefollowing repeated oral administration of teriflunomide, with high bioavailability (approximately100%).

Food does not have a clinically relevant effect on teriflunomide pharmacokinetics.

From the mean predicted pharmacokinetic parameters calculated from the population pharmacokinetic(PopPK) analysis using data from healthy volunteers and MS patients, there is a slow approach tosteady-state concentration (i.e., approximately 100 days (3.5 months) to attain 95% of steady-stateconcentrations) and the estimated AUC accumulation ratio is approximately 34-fold.

Teriflunomide is extensively bound to plasma protein (>99%), probably albumin and is mainlydistributed in plasma. The volume of distribution is 11 l after a single intravenous (IV) administration.

However, this is most likely an underestimation since extensive organ distribution was observed inrats.

Teriflunomide is moderately metabolised and is the only component detected in plasma. The primarybiotransformation pathway for teriflunomide is hydrolysis with oxidation being a minor pathway.

Secondary pathways involve oxidation, N-acetylation and sulfate conjugation.

Teriflunomide is excreted in the gastrointestinal tract mainly through the bile as unchanged activesubstance and most likely by direct secretion. Teriflunomide is a substrate of the efflux transporter

BCRP, which could be involved in direct secretion. Over 21 days, 60.1% of the administered dose isexcreted via feces (37.5%) and urine (22.6%). After the rapid elimination procedure withcholestyramine, an additional 23.1% was recovered (mostly in feces). Based on individual predictionof pharmacokinetic parameters using the PopPK model of teriflunomide in healthy volunteers and MSpatients, median t1/2z was approximately 19 days after repeated doses of 14 mg. After a singleintravenous administration, the total body clearance of teriflunomide is 30.5 ml/h.

Accelerated elimination procedure: cholestyramine and activated charcoal

The elimination of teriflunomide from the circulation can be accelerated by administration ofcholestyramine or activated charcoal, presumably by interrupting the reabsorption processes at theintestinal level. Teriflunomide concentrations measured during an 11-day procedure to accelerateteriflunomide elimination with either 8 g cholestyramine three times a day, 4 g cholestyramine threetimes a day or 50 g activated charcoal twice a day following cessation of teriflunomide treatment haveshown that these regimens were effective in accelerating teriflunomide elimination, leading to morethan 98% decrease in teriflunomide plasma concentrations, with cholestyramine being faster thancharcoal. Following discontinuation of teriflunomide and the administration of cholestyramine 8 gthree times a day, the plasma concentration of teriflunomide is reduced 52% at the end of day 1, 91%at the end of day 3, 99.2% at the end of day 7, and 99.9% at the completion of day 11. The choicebetween the 3 elimination procedures should depend on the patient’s tolerability. If cholestyramine 8 gthree 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 needto lower teriflunomide plasma concentration rapidly).

Systemic exposure increases in a dose proportional manner after oral administration teriflunomidefrom 7 to 14 mg.

Characteristics in specific groups of patients

Gender and elderly

Several sources of intrinsic variability were identified in healthy subjects and MS patients based on the

PopPK analysis: age, body weight, gender, race, and albumin and bilirubin levels. Nevertheless, theirimpact remains limited (≤31%).

Mild and moderate hepatic impairment had no impact on the pharmacokinetic of teriflunomide.

Therefore no dose adjustment is anticipated in mild and moderate hepatic-impaired patients. However,teriflunomide is contraindicated in patients with severe hepatic impairment (see sections 4.2 and 4.3).

Severe renal impairment had no impact on the pharmacokinetic of teriflunomide. Therefore no doseadjustment is anticipated in mild, moderate and severe renal-impaired patients.

In paediatric patients with body weight >40 kg treated with 14 mg once daily, steady state exposureswere in the range observed in adult patients treated with the same dosing regimen.

In paediatric patients with body weight ≤40 kg treatment with 7 mg once daily (based on limitedclinical data and simulations) led to steady state exposures in the range observed in adult patientstreated with 14 mg once daily.

Observed steady state trough concentrations were highly variable between individuals, as observed foradult MS patients.

Repeated-dose toxicity

Repeated oral administration of teriflunomide to mice, rats and dogs for up to 3, 6, and 12 months,respectively, revealed that the major targets of toxicity were the bone marrow, lymphoid organs, oralcavity/ gastro intestinal tract, reproductive organs, and pancreas. Evidence of an oxidative effect on redblood cells was also observed. Anemia, decreased platelet counts and effects on the immune system,including leukopenia, lymphopenia and secondary infections, were related to the effects on the bonemarrow and/or lymphoid organs. The majority of effects reflect the basic mode of action of thecompound (inhibition of dividing cells). Animals are more sensitive to the pharmacology, andtherefore toxicity, of teriflunomide than humans. As a result, toxicity in animals was found atexposures equivalent or below human therapeutic levels.

Genotoxic and carcinogenic potential

Teriflunomide was not mutagenic in vitro or clastogenic in vivo. Clastogenicity observed in vitro wasconsidered to be an indirect effect related to nucleotide pool imbalance resulting from thepharmacology of DHO-DH inhibition. The minor metabolite TFMA (4-trifluoromethylaniline) causedmutagenicity and clastogenicity in vitro but not in vivo.

No evidence of carcinogenicity was observed in rats and mice.

Reproduction toxicity

Fertility was unaffected in rats despite adverse effects of teriflunomide on male reproductive organs,including reduced sperm count. There were no external malformations in the offspring of male ratsadministered teriflunomide prior to mating with untreated female rats. Teriflunomide was embryotoxicand teratogenic in rats and rabbits at doses in the human therapeutic range. Adverse effects on theoffspring were also seen when teriflunomide was administered to pregnant rats during gestation andlactation. The risk of male-mediated embryo-fetal toxicity through teriflunomide treatment isconsidered low. The estimated female plasma exposure via the semen of a treated patient is expectedto be 100 times lower than the plasma exposure after 14 mg of oral teriflunomide.

Juvenile toxicity

Juvenile rats receiving oral teriflunomide for 7 weeks from weaning through sexual maturity revealedno adverse effects on growth, physical or neurological development, learning and memory, locomotoractivity, sexual development, or fertility. Adverse effects comprised anaemia, reduction of lymphoidresponsiveness, dose-dependently diminished T cell dependent antibody response and greatlydecreased IgM and IgG concentrations, which generally coincided with observations in repeat-dosetoxicity studies in adult rats. However, the increase in B cells observed in juvenile rats was notobserved in adult rats. The significance of this difference is unknown, but complete reversibility wasdemonstrated as for most of the other findings. Due to the high sensitivity of animals to teriflunomide,juvenile rats were exposed to lower levels than those in children and adolescents at the maximumrecommended human dose (MRHD).

Tablet corelactose monohydratemaize starchmicrocrystalline cellulosesodium starch glycolatecolloidal anhydrous silicahydroxypropylcellulosemagnesium stearate

Tablet coating7 mg film-coated tabletshypromellose (E464)titanium dioxide (E171)talc (E553b)macrogol (E1521)indigo carmine aluminum lake (E132)yellow iron oxide (E172)14 mg film-coated tabletshypromellose (E464)titanium dioxide (E171)talc (E553b)macrogol (E1521)indigo carmine aluminum lake (E132)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

7 mg film-coated tablets

Aluminium-aluminium blisters packed in cartons containing 14, 28, 84 and 98 film-coated tablets.

Aluminium-aluminium perforated unit-dose blisters packed in cartons containing 14x1, 28x1, 84x1and 98x1 film-coated tablets.

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Accord Healthcare S.L.U.

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7 mg film-coated tablets

EU/1/22/1693/005 14 tablets

EU/1/22/1693/006 14 x 1 tablets (unit dose)

EU/1/22/1693/007 28 tablets

EU/1/22/1693/008 28 x 1 tablets (unit dose)

EU/1/22/1693/009 84 tablets

EU/1/22/1693/010 84 x 1 tablets (unit dose)

EU/1/22/1693/011 98 tablets

EU/1/22/1693/012 98 x 1 tablets (unit dose)14 mg film-coated tablets

EU/1/22/1693/001 28 tablets

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EU/1/22/1693/003 84 tablets

EU/1/22/1693/004 84 x 1 tablets (unit dose)

Date of first authorisation: 09 November 2022.

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.