Aubagio · 4.1 Therapeutic indications · 1

HOS-096308 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The most frequently reported adverse reactions in the teriflunomide treated (7 mg and 14 mg) patients were: 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 to moderate, transient and infrequently led to treatment discontinuation. Teriflunomide is the main metabolite of leflunomide. The safety profile of leflunomide in patients suffering from rheumatoid arthritis or psoriatic arthritis may be pertinent when prescribing teriflunomide in MS patients. Tabulated list of adverse reactions Teriflunomide was evaluated in a total of 2,267 patients exposed to teriflunomide (1,155 on teriflunomide 7 mg and 1,112 on teriflunomide 14 mg) once daily for a median duration of about 672 days in four placebo-controlled studies (1,045 and 1,002 patients for teriflunomide 7 mg and 14 mg, respectively) and one active comparator study (110 patients in each of the teriflunomide treatment groups) in adult patients with relapsing forms of MS (Relapsing Multiple Sclerosis, RMS). Listed below are the adverse reactions reported with AUBAGIO in placebo-controlled studies in adult 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); 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 the available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness. System organ Very Common Uncommon Rare Very Not known class common rare Infections and Influenza, Upper Severe infections infestations respiratory tract including sepsisa infection, Urinary tract infection, Bronchitis, Sinusitis, Pharyngitis, Cystitis, Gastroenteritis viral,

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HOS-096304 · has-contraindication-information · PDF-Seite 3

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 during treatment with teriflunomide and thereafter as long as its plasma levels are above 0.02 mg/l (see section 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, leukopenia, neutropenia or thrombocytopenia. 3 Patients with severe active infection until resolution (see section 4.4). Patients with severe renal impairment undergoing dialysis, because insufficient clinical experience is available in this patient group. Patients with severe hypoproteinaemia, e.g. in nephrotic syndrome.

HOS-096303 · has-indication-information · PDF-Seite 2

AUBAGIO is indicated for the treatment of adult patients and paediatric patients aged 10 years and older with relapsing remitting multiple sclerosis (MS) (please refer to section 5.1 for important information on the population for which efficacy has been established).

HOS-096306 · has-interaction-information · PDF-Seite 7

Pharmacokinetic interactions of other substances on teriflunomide 7 The primary biotransformation pathway for teriflunomide is hydrolysis, with oxidation being a minor pathway. 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 cancer resistant 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 inducers such as carbamazepine, phenobarbital, phenytoin and St John’s Wort should be used with caution during the treatment with teriflunomide. Cholestyramine or activated charcoal It is recommended that patients receiving teriflunomide are not treated with cholestyramine or activated charcoal because this leads to a rapid and significant decrease in plasma concentration unless an accelerated elimination is desired. The mechanism is thought to be by interruption of enterohepatic recycling and/or gastrointestinal dialysis of teriflunomide. Pharmacokinetic interactions of teriflunomide on other substances Effect of teriflunomide on CYP2C8 substrate: repaglinide There was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. Therefore, medicinal products metabolised by CYP2C8, such as repaglinide, paclitaxel, pioglitazone or 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 of teriflunomide. While this interaction of teriflunomide is not expected to adversely impact the efficacy of oral contraceptives, it should be considered when selecting or adjusting oral contraceptive treatment used in combination with teriflunomide. Effect of teriflunomide on CYP1A2 substrate: caffeine Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine (CYP1A2 substrate) by 18% and 55%, respectively, suggesting that teriflunomide may be a

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HOS-096307 · has-pregnancy-information · PDF-Seite 9

Use in males The risk of male-mediated embryo-foetal toxicity through teriflunomide treatment is considered low (see section 5.3). Pregnancy There are limited amount of data from the use of teriflunomide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Teriflunomide may cause serious birth defects when administered during pregnancy. Teriflunomide is contraindicated in pregnancy (see section 4.3). Women of childbearing potential have to use effective contraception during treatment and after treatment as long as teriflunomide plasma concentration is above 0.02 mg/l. During this period women should discuss any plans to stop or change contraception with the treating physician. Female children and/or parents/caregivers of female children should be informed about the need to contact the treating physician once the female child under AUBAGIO treatment experiences menses. Counselling should be provided to 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 suspect pregnancy, they must discontinue AUBAGIO and notify the physician immediately for pregnancy testing, and if positive, the physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the blood level of teriflunomide, by instituting the accelerated elimination procedure 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 product should be stopped and an accelerated elimination procedure is recommended in order to more rapidly achieve concentration below 0.02 mg/l (see below). If an accelerated elimination procedure is not used, teriflunomide plasma levels can be expected to be above 0.02 mg/l for an average of 8 months, however, in some patients it may take up to 2 years to reach plasma concentration below 0.02 mg/l. Therefore, teriflunomide plasma concentrations should be measured before a woman begins to attempt to become pregnant. Once the teriflunomide plasma concentration is determined to be below 0.02 mg/l, the plasma concentration must be determined again after an interval of at least 14 days. If both plasma concentrations are below 0.02 mg/l, no risk to the foetus is to be expected. For further informat

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HOS-096305 · has-warning-information · PDF-Seite 4

Monitoring Before treatment 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 During treatment with teriflunomide the following should be monitored: • Blood pressure o 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 of treatment and regularly thereafter. o Consider additional monitoring when AUBAGIO is given in patients with pre-existing liver disorders, given with other potentially hepatotoxic drugs or as indicated by clinical 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 weeks during the first 6 months of treatment, and at least every 8 weeks thereafter for at least 2 years from initiation of treatment. o 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. Accelerated elimination procedure 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 to individual variation in substance clearance it may take up to 2 years. An accelerated elimination procedure can be used at any time after discontinuation of teriflunomide (see sections 4.6 and 5.2 for procedural details). Hepatic effects 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 several months after treatment initiation of teriflunomide, but DILI can also occur with prolonged use. The risk for liver enzyme increases and DILI

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