Aubagio

/ Sanofi

The recommended dose of this product is 14 mg once daily. 
Elderly population: This product should be used with caution in patients aged 65 years and over due to insufficient data on safety and efficacy.
Renal impairment: No dosage adjustment is necessary for patients with mild, moderate or severe renal impairment not undergoing dialysis. Patients with severe renal impairment undergoing dialysis were not evaluated. Teriflunomide is contraindicated in this population.
Hepatic impairment: No dosage adjustment is necessary for patients with mild and moderate hepatic impairment. Teriflunomide is contraindicated in patients with severe hepatic impairment.
Paediatric population: The safety and efficacy of this product in children aged from 10 to less than 18 years has not yet been established. There is no relevant use of teriflunomide in children aged from birth to less than 10 years for the treatment of multiple sclerosis. No data are available.
Method of administration: The film-coated tablets are for oral use. The tablets should be swallowed whole with some water. AUBAGIO can be taken with or without food.

Indicated for the treatment of adult patients with relapsing remitting forms of Multiple Sclerosis (MS) to reduce the frequency of clinical relapses and to delay the progression of physical disability.

Hypersensitivity to the active substance or to any of the excipients.
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. Pregnancy must be excluded before start of treatment.
Breast-feeding women.
Patients with severe immunodeficiency states, e.g. AIDS.
Patients with significantly impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia.
Patients with severe active infection until resolution.
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.

Monitoring:
Before treatment: Before starting treatment with teriflunomide the following should be assessed: Blood pressure, Alanine aminotransferase (ALT/SGPT), Complete blood cell count including differential white blood cell and platelet count.
Monitoring During treatment: During treatment with teriflunomide the following should be monitored: Blood pressure, Alanine aminotransferase (ALT/SGPT), Complete blood cell counts should be performed based on 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.
Hepatic effects: Elevations of liver enzymes have been observed in patients receiving teriflunomide. These elevations occurred mostly within the first 6 months of treatment. Liver enzymes should be assessed before initiation of teriflunomide therapy – every two weeks during the first 6 months of treatment, and every 8 weeks thereafter or as indicated by clinical signs and symptoms such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. For ALT (SGPT) elevations between 2- and 3-fold the upper limit of normal, monitoring must be performed weekly. Teriflunomide therapy should be discontinued if liver injury is suspected; consider discontinuing teriflunomide therapy if elevated liver enzymes (greater than 3-fold ULN) are confirmed. Patients with preexisting liver disease may be at increased risk of developing elevated liver enzymes when taking teriflunomide and should be closely monitored for signals of liver disease. The medicinal product should be used with caution in patients who consume substantial quantities of alcohol. Since teriflunomide is highly protein bound and as the binding is dependent upon the concentrations of albumin, unbound plasma teriflunomide concentrations are expected to be increased in patients with hypoproteinaemia, e.g. in nephrotic syndrome. Teriflunomide should not be used in patients with conditions of severe hypoproteinaemia.
Blood pressure: Elevation of blood presure may occur during treatment with teriflunomide. Blood pressure must be checked before the start of teriflunomide treatment and periodically thereafter. Blood pressure elevation should be appropriately managed before and during treatment with teriflunomide.
Infections: Initiation of treatment with teriflunomide should be delayed in patients with severe active infection until resolution. In placebo-controlled studies, no increase in serious infections was observed with teriflunomide. However, based on the immunomodulatory effect of this product, if a patient develops a serious infection, suspending treatment should be considered and the benefits and risks should be reassessed prior to re-initiation of therapy. Due to the prolonged half-life, accelerated elimination with cholestyramine or charcoal may be considered. Patients receiving this product should be instructed to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. The safety  in individuals with latent tuberculosis infection is unknown, as tuberculosis screening was not systematically performed in clinical studies. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with this product.
Respiratory reactions: No cases of interstitial lung diseases (ILD) have been reported with teriflunomide in the clinical trials. However, ILD, which is a potentially fatal disorder, has been reported during treatment with leflunomide, the parent compound. ILD may occur acutely during therapy; the risk is increased in patients who had a history of ILD when treated with leflunomide. Pulmonary symptoms, such as persistent cough and dyspnoea, may be a reason for discontinuation of the therapy and for further investigation, as appropriate.
Haematological effects: A mean decrease less than 15% from baseline affecting white blood cell count has been observed. As a precaution, a recent complete blood cell count, including differential white blood cell count and platelets, should be available before the initiation of treatment with this product and the complete blood cell 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 with impaired bone marrow function or those at risk of bone marrow suppression, the risk of haematological disorders is increased. If such effects occur, the accelerated elimination procedure to reduce plasma levels of teriflunomide should be considered. In cases of severe haematological reactions, including pancytopenia, this product and any concomitant myelosuppressive treatment must be discontinued and a teriflunomide accelerated elimination procedure should be considered.
Skin reactions: No cases of severe skins reactions have been reported with teriflunomide in the clinical trials. In patients treated with leflunomide, the parent compound, very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported. In case of ulcerative stomatitis, teriflunomide administration should be discontinued. If skin and /or mucosal reactions are observed which raise the suspicion of severe generalised major skin reactions (Stevens-Johnson syndrome, or toxic epidermal necrolysis-Lyell’s syndrome), teriflunomide and any other possibly associated treatment must be discontinued, and an accelerated procedure initiated immediately. In such cases patients should not be re-exposed to teriflunomide.
Peripheral neuropathy: Cases of peripheral neuropathy have been reported in patients receiving this product. Most patients improved after discontinuation of this product. However, there was a wide variability in final outcome, i.e. in some patients the neuropathy resolved and some patients had persistent symptoms. If a patient taking this product develops a confirmed peripheral neuropathy, consider discontinuing therapy and performing the accelerated elimination procedure.
Vaccination: In a clinical study, teriflunomide-treated patients mounted appropriate immune responses to a seasonal influenza vaccination, consistent with the preservation of a response to booster vaccine. Patients reached post-vaccination antibody titres, consistent with seroprotection. No clinical data are available on the efficacy and safety of vaccinations regarding primary immune response to neopathogens. The use of live attenuated vaccines may carry a risk of infections and should, therefore, be avoided.
Immunosuppressive or immunomodulating therapies: As leflunomide is the parent compound of teriflunomide, co-administration of teriflunomide with leflunomide is not recommended. Co-administration with antineoplastic or immunosuppressive therapies used for treatment of MS has not been evaluated. Safety studies, in which teriflunomide was concomitantly administered with interferon 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 long term safety of these combinations in the treatment of multiple sclerosis has not been established.
Switching to or from AUBAGIO: Based on the clinical data related to concomitant administration of teriflunomide with interferon beta or with glatiramer acetate, no waiting period is required when initiating teriflunomide after interferon beta or glatiramer acetate or when starting interferon beta or glatiramer acetate, after teriflunomide. Due to the long half-life of natalizumab, concomitant exposure, and thus concomitant immune effects, could occur for up to 2-3 months following discontinuation of natalizumab if this product was immediately started. Therefore, caution is required when switching patients from natalizumab to this product. Based on the half-life of fingolimod, a 6-week interval without therapy is needed for clearance from the circulation and a 1 to 2 month period is needed for lymphocytes to return to normal range following discontinuation of fingolimod. Starting this product during this interval will result in concomitant exposure to fingolimod. This may lead to an additive effect on the immune system and caution is, therefore, indicated. In MS patients, the median t1/2z was approximately 19 days after repeated doses of 14 mg. If a decision is made to stop treatment with this product, during the interval of 5 half-lives (approximately 3.5 months although may be longer in some patients), starting other therapies will result in concomitant exposure to this product. This may lead to an additive effect on the immune system and caution is, therefore, indicated.
Lactose: Since the tablets contain lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicinal product.
Interference with determination of ionised calcium levels: The measurement of ionised calcium levels might show falsely decreased values under treatment with leflunomide and/or teriflunomide (the active metabolite of leflunomide) depending on the type of ionised calcium analyser used (e.g. blood gas analyser). Therefore, the plausibility of observed decreased ionised calcium levels needs to be questioned in patients under treatment with leflunomide or teriflunomide. In case of doubtful measurements, it is recommended to determine the total albumin adjusted serum calcium concentration.
For full details see prescribing information.

The most commonly reported adverse reactions in the teriflunomide treated patients were: headache, diarrhoea, increased ALT, nausea, and alopecia.
In general, headache, diarrhoea, nausea and alopecia, were mild to moderate, transient and infrequently led to treatment discontinuation.
For full details see prescribing information.

Pharmacokinetic interactions of other substances on teriflunomide: 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 C_max and AUC (1.7- and 2.4-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. Therefore, 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 contraceptive: 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel: There was an increase in mean ethinylestradiol C_max and AUC_0-24 (1.58- and 1.54-fold, respectively) and levonorgestrel C_max and AUC_0-24 (1.33- and 1.41-fold, respectively) following repeated doses of teriflunomide. While this interaction of teriflunomide is not expected to adversely impact the efficacy of oral contraceptives, consideration should be given to the type or dose of oral contraceptives used in combination with teriflunomide.
Effect of teriflunomide on CYP1A2 substrate: caffeine: Repeated doses of teriflunomide decreased mean C_max 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 duloxetin, alosetron, theophylline and tizanidine) should be used with caution during treatment with teriflunomide, as it could lead to the reduction of the efficacy of these products.
Effect of teriflunomide on warfarin: Repeated doses of teriflunomide had no effect on the pharmacokinetics of S-warfarin, indicating that teriflunomide is not an inhibitor or an inducer of CYP2C9. However, a 25% decrease in peak international normalised ratio (INR) was observed when teriflunomide was coadministered with warfarin as compared with warfarin alone. Therefore, when warfarin is co-administered with teriflunomide, close INR follow-up and monitoring is recommended.
Effect of teriflunomide on organic anion transporter 3 (OAT3) substrates: There was an increase in mean cefaclor C_max and AUC (1.43- and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of OAT3 in vivo. Therefore, when teriflunomide is coadministered with substrates of OAT3, such as cefaclor, 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 C_max and AUC (2.65- and 2.51-fold, respectively), following repeated doses of teriflunomide. However, there was no apparent impact of this increase in plasma rosuvastatin exposure on the HMG-CoA reductase activity. For rosuvastatin, a dose reduction by 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 with caution. Patients should be closely monitored for signs and symptoms of excessive exposure to the medicinal products and reduction of the dose of these medicinal products should be considered.
For full details see prescribing information.

Pregnancy: There are limited amount of data from the use of teriflunomide in pregnant women. Studies in animals have shown reproductive toxicity. Teriflunomide may cause serious birth defects when administered during pregnancy. Teriflunomide is contraindicated in pregnancy. 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. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing, and if positive, the physician and patient must discuss the risk to the pregnancy.
Breast-feeding: Animal studies have shown excretion of teriflunomide in breast milk. Breast-feeding women must, therefore, not receive teriflunomide.
See prescribing information for full details.

Symptoms: There is no experience regarding teriflunomide overdose or intoxication in humans. Teriflunomide 70 mg daily was administered up to 14 days in healthy subjects. The adverse reactions were consistent with the safety profile for teriflunomide in MS patients.
Management: In the event of relevant overdose or toxicity, cholestyramine or activated charcoal is recommended to accelerate elimination. The recommended elimination procedure is cholestyramine 8 g three times a day for 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 may also be used. In addition, if required for tolerability reasons, administration of cholestyramine or activated charcoal does not need to occur on consecutive days.