TERIFLUNOMIDA VIATRIS 14mg tablets medication leaflet

Teriflunomide Viatris 14 mg film-coated tablets

Each film-coated tablet contains 14 mg of teriflunomide.

Each tablet contains 85.4 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Pale blue to pastel blue coloured, round, biconvex, film-coated tablets debossed with ‘T’ on one side and‘1’ on the other side, approximately 7.6 mm in diameter.

Teriflunomide Viatris is indicated for the treatment of adult patients and paediatric patients aged 10 yearsand older with relapsing remitting multiple sclerosis (MS) (please refer to section 5.1 for importantinformation 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 body weight:

- 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 once daily.

Teriflunomide Viatris is only available as 14 mg film-coated tablets. Thus, it is not possible to administer

Teriflunomide Viatris to patients that require less than a full 14 mg dose. If an alternate dose is required,other teriflunomide products offering such an option should be used.

Teriflunomide should be used with caution in patients aged 65 years and over due to insufficient data onsafety 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 iscontraindicated 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.

No data are available.

The film-coated tablets are for oral use. The tablets should be swallowed whole with some water. Theycan 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 (see section4.6). 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, neutropeniaor 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 months oftreatment, and regularly thereafter.

o Consider additional monitoring when Teriflunomide Viatris is given in patients with pre-existing liver disorders, given with other potentially hepatotoxic drugs or as indicated byclinical signs and symptoms such as unexplained nausea, vomiting, abdominal pain, fatigue,anorexia, or jaundice and/or dark urine. Liver enzymes should be assessed every two weeksduring the first 6 months of treatment, and at least every 8 weeks thereafter for at least 2 yearsfrom initiation of treatment.

o For ALT (SGPT) elevations between 2- and 3-fold the upper limit of normal, monitoringmust 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, ittakes 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 elimination procedurecan be used at any time after discontinuation of teriflunomide (see sections 4.6 and 5.2 for proceduraldetails).

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 with pre-existing liver disorder, concomitant treatment with other hepatotoxic drugs, and/or consumption ofsubstantial quantities of alcohol. Patients should therefore be closely monitored for signs and symptoms ofliver injury.

Teriflunomide therapy should be discontinued and accelerated elimination procedure considered if liverinjury is suspected. If elevated liver enzymes (greater than 3-fold ULN) are confirmed, teriflunomidetherapy 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 infection untilresolution.

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 herpetic meningoencephalitisand 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, as tuberculosisscreening was not systematically performed in clinical studies. Patients who tested positive in tuberculosisscreening 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 post-marketing 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 and dyspnoea,may be a reason for discontinuation of the therapy and for further investigation, as appropriate. Ifdiscontinuation of the medicinal product is necessary, initiation of an accelerated elimination procedureshould 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 blood cellcount and platelets, should be available before the initiation of treatment and the complete blood cell countshould 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 of haematologicaldisorders is increased. If such effects occur, the accelerated elimination procedure (see above) to reduceplasma levels of teriflunomide should be considered.

In cases of severe haematological reactions, including pancytopenia, teriflunomide and any concomitantmyelosuppressive treatment must be discontinued and a teriflunomide accelerated elimination procedureshould be considered.

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

If skin and /or mucosal reactions (ulcerative stomatitis) are observed which raise the suspicion of severegeneralised major skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis-Lyell’ssyndrome or drug reaction with eosinophilia and systemic symptoms), teriflunomide and any otherpossibly associated treatment must be discontinued, and an accelerated procedure initiated immediately. Insuch cases patients should not be re-exposed to teriflunomide (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 (see section 4.8).

Most patients improved after discontinuation of teriflunomide. However, there was a wide variability infinal outcome, i.e. in some patients the neuropathy resolved and some patients had persistent symptoms. Ifa patient taking teriflunomide develops a confirmed peripheral neuropathy, discontinuing teriflunomidetherapy and performing the accelerated elimination procedure should be considered.

Two clinical studies have shown that vaccinations to inactivated neoantigen (first vaccination) or recallantigen (re-exposure) were safe and effective during teriflunomide treatment. The use of live attenuatedvaccines 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 therapiesused for treatment of MS has not been evaluated. Safety studies, in which teriflunomide wasconcomitantly administered with interferon beta or with glatiramer acetate for up to one year did notreveal any specific safety concerns, but a higher adverse reaction rate as compared to teriflunomidemonotherapy was observed. The long-term safety of these combinations in the treatment of multiplesclerosis has not been established.

Switching to or from teriflunomide

Based on the clinical data related to concomitant administration of teriflunomide with interferon beta orwith glatiramer acetate, no waiting period is required when initiating teriflunomide after interferon beta orglatiramer 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 from thecirculation and a 1 to 2-month period is needed for lymphocytes to return to normal range followingdiscontinuation of fingolimod. Starting teriflunomide during this interval will result in concomitantexposure to fingolimod. This may lead to an additive effect on the immune system and caution is,therefore, indicated.

In MS patients, the median t1/2z was approximately 19 days after repeated doses of 14 mg. If a decision ismade to stop treatment with teriflunomide, during the interval of 5 half-lives (approximately 3.5 monthsalthough may be longer in some patients), starting other therapies will result in concomitant exposure toteriflunomide. This may lead to an additive effect on the immune system and caution 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 of ionisedcalcium analyser used (e.g. blood gas analyser). Therefore, the plausibility of observed decreased ionisedcalcium levels needs to be questioned in patients under treatment with leflunomide or teriflunomide. Incase of doubtful measurements, it is recommended to determine the total albumin adjusted serum calciumconcentration.

In the paediatric clinical trial, cases of pancreatitis, some acute, have been observed in patients receivingteriflunomide (see section 4.8). Clinical symptoms included abdominal pain, nausea and/or vomiting.

Serum amylase and lipase were elevated in these patients. The time to onset ranged from a few months upto three years. Patients should be informed of the characteristic symptoms of pancreatitis. If pancreatitis issuspected, pancreatic enzymes and related laboratory parameters should be obtained. If pancreatitis isconfirmed, teriflunomide should be discontinued and an accelerated elimination procedure should beinitiated (see section 5.2).

Teriflunomide Viatris 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] and breast cancerresistant protein [BCRP] with teriflunomide (70 mg single dose) resulted in an approximately 40%decrease in teriflunomide exposure. Rifampicin and other known potent CYP and transporter inducerssuch as carbamazepine, phenobarbital, phenytoin and St John’s Wort should be used with caution duringthe treatment with teriflunomide.

It is recommended that patients receiving teriflunomide are not treated with cholestyramine or activatedcharcoal because this leads to a rapid and significant decrease in plasma concentration unless anaccelerated 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, pioglitazone orrosiglitazone, 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) andlevonorgestrel 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 efficacy oforal contraceptives, it should be considered when selecting or adjusting oral contraceptive treatment usedin combination with teriflunomide.

Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine (CYP1A2 substrate) by 18%and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2 in vivo.

Therefore, medicinal products metabolised by CYP1A2 (such as duloxetine, 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 peak internationalnormalised ratio (INR) was observed when teriflunomide was co-administered with warfarin as comparedwith warfarin alone. Therefore, when warfarin is co-administered with teriflunomide, close INR follow-upand 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 co-administered with substrates of OAT3, such as cefaclor, benzylpenicillin,ciprofloxacin, indometacin, ketoprofen, furosemide, cimetidine, methotrexate, zidovudine, caution isrecommended.

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), followingrepeated doses of teriflunomide. However, there was no apparent impact of this increase in plasmarosuvastatin exposure on the HMG-CoA reductase activity. For rosuvastatin, a dose reduction by 50% isrecommended for co-administration with teriflunomide. For other substrates of BCRP (e.g., methotrexate,topotecan, sulfasalazine, daunorubicin, doxorubicin) and the OATP family especially HMG-Co reductaseinhibitors (e.g., simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, repaglinide, rifampicin)concomitant administration of teriflunomide should also be undertaken with caution. Patients should beclosely monitored for signs and symptoms of excessive exposure to the medicinal products and reductionof the dose of these medicinal products should be considered.

The risk of male-mediated embryo-foetal toxicity through teriflunomide treatment is considered low (seesection 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 after treatmentas long as teriflunomide plasma concentration is above 0.02 mg/l. During this period women shoulddiscuss any plans to stop or change contraception with the treating physician. Female children and/orparents/caregivers of female children should be informed about the need to contact the treating physicianonce the female child under teriflunomide treatment experiences menses. Counselling should be providedto the new patients of child-bearing potential about contraception and the potential risk 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 possible thatrapidly lowering the blood level of teriflunomide, by instituting the accelerated elimination proceduredescribed 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 to reachplasma concentration below 0.02 mg/l. Therefore, teriflunomide plasma concentrations should bemeasured 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 g threetimes 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 separate testsat 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 during theaccelerated elimination procedure with cholestyramine or activated powdered charcoal. Use of alternativecontraceptive methods is recommended.

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

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

Teriflunomide 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, the parentcompound, the patient’s ability to concentrate and to react properly may be impaired. In such cases,patients should refrain from driving 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 mild tomoderate, 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 prescribing teriflunomidein MS patients.

Teriflunomide was evaluated in a total of 2,267 patients exposed to teriflunomide (1,155 on teriflunomide7 mg and 1,112 on teriflunomide 14 mg) once daily for a median duration of about 672 days in fourplacebo-controlled studies (1,045 and 1,002 patients for teriflunomide 7 mg and 14 mg, respectively) andone active comparator study (110 patients in each of the teriflunomide treatment groups) in adult patientswith relapsing forms of MS (Relapsing Multiple Sclerosis, RMS).

Listed below are the adverse reactions reported with teriflunomide in placebo-controlled studies, reportedfor teriflunomide 7 mg or 14 mg from clinical studies in adult patients. Frequencies were defined using thefollowing 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); not known (cannot be estimated from theavailable data). Within each frequency grouping, adverse reactions are ranked in order of decreasingseriousness.

System organ Very common Common Uncommon Rare Very Not knownclass rare

Infections and Influenza, Severe infectionsinfestations Upper respiratory including sepsisatract infection,

Urinary tractinfection,

Bronchitis,

Sinusitis,

Pharyngitis,

Cystitis,

System organ Very common Common Uncommon Rare Very Not knownclass rare

Gastroenteritisviral,

Herpes virusinfectionsb,

Tooth infection,

Laryngitis,

Tinea pedis

Blood and Neutropeniab, Mildlymphatic Anaemia thrombocytopeniasystem disorders (platelets< 100 G/l)

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

Metabolism and Dyslipidaemianutritiondisorders

Psychiatric Anxietydisorders

Nervous system Headache Paraesthesia, Hyperaesthesia,disorders Sciatica, Neuralgia,

Carpal tunnel Peripheralsyndrome neuropathy

Cardiac Palpitationsdisorders

Vascular Hypertensionbdisorders

Respiratory, Interstitial lung Pulmonarythoracic and disease hypertensionmediastinaldisorders

Gastrointestinal Diarrhoea, Pancreatitisb,c, Stomatitis,disorders Nausea Abdominal pain Colitisupper,

Vomiting,

Toothache

Hepatobiliary Alanine Gamma- Acute Drug-induceddisorders aminotransferase glutamyltransferase hepatitis liver injury(ALT) increaseb (GGT) increaseb, (DILI)

Aspartateaminotransferaseincreaseb

Skin and Alopecia Rash, Nail disorders,subcutaneous Acne Psoriasistissue disorders (includingpustular)a,b,

System organ Very common Common Uncommon Rare Very Not knownclass rare

Severe skinreactionsa

Musculoskeletal Musculoskeletaland connective pain,tissue disorders Myalgia,

Arthralgia

Renal and Pollakiuriaurinarydisorders

Reproductive Menorrhagiasystem andbreast disorders

General Pain, Astheniaadisorders andadministrationsite conditions

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 treated withplacebo. Most cases were described as diffuse or generalised over the scalp (no complete hair lossreported) and occurred most often during the first 6 months and with resolution in 121 of 139 (87.1%)patients treated with teriflunomide 14 mg. Discontinuation because of alopecia was 1.3% in theteriflunomide 14 mg 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 ULN andhigher was balanced across treatment groups. These elevations in transaminase occurred mostly within thefirst 6 months of treatment and were reversible after treatment cessation. The recovery time variedbetween 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/day teriflunomideas compared to 15.5% receiving placebo;

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

- diastolic blood pressure was > 90 mm Hg in 21.4% of patients receiving 14 mg/day teriflunomide ascompared 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 occurred in0.2% of each group. Severe infections including sepsis, sometimes fatal have been reported post-marketing.

A mean decrease affecting white blood cell (WBC) count (< 15% from baseline levels, mainly neutrophiland lymphocytes decrease) was observed in placebo-controlled trials with teriflunomide in adult patients,although a greater decrease was observed in some patients. The decrease in mean count from baselineoccurred during the first 6 weeks then stabilised over time while on-treatment but at decreased levels (lessthan 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 polyneuropathy andmononeuropathy (e.g., carpal tunnel syndrome), was reported more frequently in patients takingteriflunomide than in patients taking placebo. In the pivotal, placebo-controlled studies, the incidence ofperipheral neuropathy confirmed by nerve conduction studies was 1.9% (17 patients out of 898) on 14 mgof teriflunomide, compared with 0.4% (4 patients out of 898) on placebo. Treatment was discontinued in 5patients with peripheral neuropathy on teriflunomide 14 mg. Recovery following treatmentdiscontinuation 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% in theplacebo, 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 at anytime during treatment with teriflunomide, which may lead to hospitalisation and/or require correctivetreatment.

The observed safety profile in paediatric patients (from 10 to 17 years-old) receiving teriflunomide dailywas overall similar to that seen in adult patients. However, in the paediatric study (166 patients: 109 in theteriflunomide group and 57 in the placebo group), cases of pancreatitis were reported in 1.8% (2/109) ofthe teriflunomide-treated patients compared to none in the placebo group, in the double-blind phase. Oneof these events led to hospitalisation and required corrective treatment. In paediatric patients treated withteriflunomide in the open-label phase of the study, 2 additional cases of pancreatitis (one was reported as aserious 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 these 3 patients, pancreatitis led to hospitalisation.

Clinical symptoms included abdominal pain, nausea and/ or vomiting and serum amylase and lipase wereelevated in these patients. All patients recovered after treatment discontinuation and acceleratedelimination procedure (see section 4.4) and corrective treatment.

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

- 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% in patientstreated with placebo. Among them, nasopharyngitis and upper respiratory tract infections weremore 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 physical exercise.

- Paraesthesia was reported in 11.0% of patients treated with teriflunomide versus 1.8% in patientstreated 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. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

There is no experience regarding teriflunomide overdose or intoxication in humans. Teriflunomide 70 mgdaily was administered up to 14 days in healthy subjects. The adverse reactions were consistent with thesafety 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 a dayfor 11 days. If this is not well tolerated, cholestyramine 4 g three times a day for 11 days can be used.

Alternatively, when cholestyramine is not available, activated charcoal 50 g twice a day for 11 days mayalso be used. In addition, if required for tolerability reasons, administration of cholestyramine or activatedcharcoal 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 of pyrimidineto expand. The exact mechanism by which teriflunomide exerts its therapeutic effect in MS is not fullyunderstood, but this is mediated by a reduced number of lymphocytes.

Immune system

Effects on immune cell numbers in the blood: In the placebo-controlled studies, teriflunomide 14 mg oncea day led to a mild mean reduction in lymphocyte count, of less than 0.3 x 109/l, which occurred over thefirst 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 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 3.45 ms with the upperbound 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 serum phosphoruswas around 10% in the teriflunomide group compared to placebo. These effects are considered to berelated to increase in renal tubular excretion and not related to changes in glomerular functions.

The efficacy of teriflunomide was demonstrated in two placebo-controlled studies, the TEMSO and the

TOWER study, that evaluated once daily doses of teriflunomide 7 mg and 14 mg in adult patients with

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 definite diagnosisof MS (based on McDonald criteria (2001)), exhibited a relapsing clinical course, with or withoutprogression, and experienced at least 1 relapse over the year preceding the trial or at least 2 relapses overthe 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-remitting multiple sclerosis (91.5%), but a subgroup of patients had secondary progressive (4.7%) orprogressive relapsing 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 present anynew 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 weeks afterlast 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 least 1 relapse overthe year preceding the trial or at least 2 relapses over the 2 years preceding the trial. At entry, patients hadan 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 study inclusionwas 1.4. Gadolinium-enhancing lesions at baseline: no data. The median EDSS score at baseline was 2.50;298 patients (25.5%) had an EDSS score › 3.5 at baseline. The mean duration of disease, since firstsymptoms, was 8.0 years. A majority of patients (67.2%) had not received disease-modifying therapyduring 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)***95% -0.18 (-0.27, -0.09)****

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 Disability20.2% 27.3% 15.8% 19.7%

Progression week 108

Hazard ratio (CI95%) 0.70 (0.51, 0.97)* 0.68 (0.47, 1.00) *6-month Sustained Disability13.8% 18.7% 11.7% 11.9%

Progression 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

Change relative to placebo 67%***

Mean Number of Gd-enhancing0.38 1.18lesions at week 108

Change relative to placebo Not measured

- 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 of thestudy, 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 datawere 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 while ontherapy, 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 of 618 patientswere randomised to receive 7 mg (n=205) or 14 mg (n=216) of teriflunomide or placebo (n=197). The riskof a second clinical attack over 2 years was 35.9% in the placebo group and 24.0% in the teriflunomide14 mg treatment group (hazard ratio: 0.57, 95% confidence interval: 0.38 to 0.87, p=0.0087). The resultsfrom the TOPIC study confirmed the efficacy of teriflunomide in RRMS (including early RRMS with firstclinical demyelinating event and MRI lesions disseminated in time and 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) withminimum treatment duration of 48 weeks (maximum 114 weeks). The risk of failure (confirmed relapse orpermanent treatment discontinuation whichever came first) was the primary endpoint. The number ofpatients with permanent treatment discontinuation in the teriflunomide 14 mg group was 22 out of 111(19.8%), the reasons being adverse events (10.8%), lack of efficacy (3.6%), other reason (4.5%) and lostto follow-up (0.9%). The number of patients with permanent treatment discontinuation in thesubcutaneous interferon beta-1a group was 30 out of 104 (28 .8%), the reasons being adverse events(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: the estimatedpercentage 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).

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 of teriflunomide(adjusted to reach an exposure equivalent to the dose of 14 mg in adults) for up to 96 weeks followed byan open-label extension. All patients had experienced at least 1 relapse over 1 year or at least 2 relapsesover 2 years preceding the study. Neurological evaluations were performed at screening and every24 weeks until the completion, and at unscheduled visits for suspected relapse. Patients with a clinicalrelapse or high MRI activity of at least 5 new or enlarging T2 lesions on 2 consecutive scans wereswitched prior to 96 weeks to the open-label extension to ensure active treatment. The primary endpointwas time to first clinical relapse after randomisation. Time to first confirmed clinical relapse or high MRIactivity, whichever came first, was pre-defined as a sensitivity analysis because it includes both clinicaland MRI conditions qualifying for switching into the 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 mean weight was58.1 kg; the mean disease duration since diagnosis was 1.4 years; and the mean T1 Gd-enhancing lesionsper MRI scan was 3.9 lesions at baseline. All patients had relapsing remitting MS with the median EDSSscore of 1.5 at baseline. The mean treatment time was 362 days on placebo and 488 days on teriflunomide.

Switching from the double-blind period to open-label treatment due to high MRI activity was morefrequent than anticipated, and more frequent and earlier in the placebo group than in the teriflunomidegroup (26% on placebo, 13% on teriflunomide).

Teriflunomide reduced the risk of clinical relapse by 34% relative to placebo, without reaching statisticalsignificance (p = 0.29) (Table 2). In the pre-defined sensitivity analysis, teriflunomide achieved astatistically significant reduction in the combined risk of clinical relapse or high MRI activity 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 number of

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=57)(N=109)

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 activity 0.51 (0.41, 0.60) 0.72 (0.58, 0.82)at Week 96

Probability (95%CI) of confirmed relapse or high MRI activity 0.38 (0.29, 0.47) 0.56 (0.42, 0.68)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 baseline 3.57 (1.97, 6.46) 5.37 (2.84, 10.16)

T2 counts

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

Relative risk (95% CI), post-hoc analysis also adjusted for 0.67 (0.45, 0.99)*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-dose followingrepeated oral administration of teriflunomide, with high bioavailability (approximately 100%).

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 to steady-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 mainly distributedin plasma. The volume of distribution is 11 l after a single intravenous (IV) administration. However, thisis most likely an underestimation since extensive organ distribution was observed in rats.

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 is excreted viafaeces (37.5%) and urine (22.6%). After the rapid elimination procedure with cholestyramine, anadditional 23.1% was recovered (mostly in faeces). Based on individual prediction of pharmacokineticparameters using the PopPK model of teriflunomide in healthy volunteers and MS patients, median t1/2zwas approximately 19 days after repeated doses of 14 mg. After a single intravenous administration, thetotal 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 three timesa day or 50 g activated charcoal twice a day following cessation of teriflunomide treatment have shownthat these regimens were effective in accelerating teriflunomide elimination, leading to more than 98%decrease in teriflunomide plasma concentrations, with cholestyramine being faster than charcoal.

Following discontinuation of teriflunomide and the administration of cholestyramine 8 g three 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 choice between the 3 eliminationprocedures should depend on the patient’s tolerability. If cholestyramine 8 g three times a day is not well-tolerated, cholestyramine 4 g three times a day can be used. Alternatively, activated charcoal may also beused (the 11 days do not need to be consecutive unless there is a need to lower teriflunomide plasmaconcentration rapidly).

Systemic exposure increases in a dose proportional manner after oral administration teriflunomide from 7to 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, teriflunomideis 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 exposures werein 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 limited clinicaldata and simulations) led to steady state exposures in the range observed in adult patients treated with 14mg 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/ gastrointestinal tract, reproductive organs, and pancreas. Evidence of an oxidative effect on redblood cells was also observed. Anaemia, decreased platelet counts and effects on the immune system,including leucopenia, 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 the compound(inhibition of dividing cells). Animals are more sensitive to the pharmacology, and therefore toxicity, ofteriflunomide than humans. As a result, toxicity in animals was found at exposures equivalent or belowhuman 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 the pharmacologyof DHO-DH inhibition. The minor metabolite TFMA (4-trifluoromethylaniline) caused mutagenicity andclastogenicity 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-foetal toxicity through teriflunomide treatment is consideredlow. The estimated female plasma exposure via the semen of a treated patient is expected to be 100 timeslower 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 revealed noadverse 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 greatly decreased

IgM and IgG concentrations, which generally coincided with observations in repeat-dose toxicity studiesin adult rats. However, the increase in B cells observed in juvenile rats was not observed in adult rats. Thesignificance of this difference is unknown, but complete reversibility was demonstrated as for most of theother findings.

Due to the high sensitivity of animals to teriflunomide, juvenile rats were exposed to lower levels thanthose in children and adolescents at the maximum recommended human dose (MRHD).

Lactose monohydrate

Maize starch

Microcrystalline cellulose (E460i)

Sodium starch glycolate (Type A)

Hydroxypropylcellulose (E463)

Magnesium stearate (E470b)

Colloidal anhydrous silica

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol 6000 (E1521)

Talc (E553b)

Indigo carmine aluminium lake (E132)

Not applicable.

2 years

Store below 25°C.

OPA/Aluminium/PVC-Aluminium blister packs of 14, 28 or 84 tablets, perforated unit dose blisters of 14x 1, 28 x 1, 84 x 1 or 98 x 1 tablets or calendar packs of 14, 28, 84 or 98 tablets.

High Density Polyethylene (HDPE) bottles with polypropylene (PP) screw closure in packs of 84 or 98tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Mylan Pharmaceuticals Limited

Damastown Industrial Park

Mulhuddart

Dublin 15

Dublin

Ireland

EU/1/22/1698/001 Blister (alu/OPA/PVC/alu) 28 tablets

EU/1/22/1698/002 Blister (alu/OPA/PVC/alu) 84 tablets

EU/1/22/1698/003 Blister (alu/OPA/PVC/alu) 28 x 1 tablets (unit dose)

EU/1/22/1698/004 Blister (alu/OPA/PVC/alu) 84 x 1 tablets (unit dose)

EU/1/22/1698/005 Blister (alu/OPA/PVC/alu) 98 x 1 tablets (unit dose)

EU/1/22/1698/006 Bottle (HDPE) 84 tablets

EU/1/22/1698/007 Bottle (HDPE) 98 tablets

EU/1/22/1698/008 Blister (alu/OPA/PVC/alu) 14 tablets

EU/1/22/1698/009 Blister (alu/OPA/PVC/alu) 14 x 1 tablets (unit dose)

EU/1/22/1698/010 Blister Calendar (alu/OPA/PVC/alu) 14 tablets

EU/1/22/1698/011 Blister Calendar (alu/OPA/PVC/alu) 28 tablets

EU/1/22/1698/012 Blister Calendar (alu/OPA/PVC/alu) 84 tablets

EU/1/22/1698/013 Blister Calendar (alu/OPA/PVC/alu) 98 tablets

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.