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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: Check periodically.
Alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT): Liver enzymes should be assessed at least every four weeks during the first 6 months of treatment and regularly thereafter.
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.
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 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 Use in Pregnancy & Lactation and Pharmacology: Pharmacokinetics for procedural details under Actions).
Hypoproteinaemia: 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 pressure may occur during treatment with teriflunomide (see Adverse Reactions). 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 (see Adverse Reactions). However, based on the immunomodulatory effect of AUBAGIO, if a patient develops a serious infection, suspending treatment with AUBAGIO 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 AUBAGIO should be instructed to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment with AUBAGIO until the infection(s) is resolved.
The safety of AUBAGIO 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 AUBAGIO.
Respiratory reactions: Interstitial lung disease (ILD) as well as cases of pulmonary hypertension have been reported with teriflunomide 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 and dyspnoea, may be a reason for discontinuation of the therapy and for further investigation, as appropriate. If discontinuation of the drug is necessary, consider initiation of an accelerated elimination procedure.
Haematological effects: A mean decrease less than 15% from baseline affecting white blood cell count has been observed (see Adverse Reactions). 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 AUBAGIO and the complete blood cell count should be assessed during AUBAGIO 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 (see previously mentioned) to reduce plasma levels of teriflunomide should be considered.
In cases of severe haematological reactions, including pancytopenia, AUBAGIO and any concomitant myelosuppressive treatment must be discontinued and a teriflunomide accelerated elimination procedure should be considered.
Skin reactions: Cases of serious skin reactions, sometimes fatal including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with AUBAGIO.
If skin and/or mucosal reactions (ulcerative stomatitis) are observed which raise the suspicion of severe generalised major skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis-Lyell's syndrome, or drug reaction with eosinophilia and systemic symptoms), 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 (see Contraindications).
New onset of psoriasis (including pustular psoriasis) and worsening of pre-existing psoriasis have been reported during the use of teriflunomide. Treatment withdrawal and initiation of an accelerated elimination procedure may be considered taking into account patient's disease and medical history.
Peripheral neuropathy: Cases of peripheral neuropathy have been reported in patients receiving AUBAGIO (see Adverse Reactions). Most patients improved after discontinuation of AUBAGIO. 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 AUBAGIO develops a confirmed peripheral neuropathy, consider discontinuing AUBAGIO therapy and performing the accelerated elimination procedure.
Vaccination: Two clinical studies have shown that vaccinations to inactivated neoantigen (first vaccination), or recall antigen (reexposure) were safe and effective during AUBAGIO treatment. 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.
Lactose: Since AUBAGIO 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.
Sodium: This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially "sodium free".
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 ionized calcium analyser used (e.g. blood gas analyser). Therefore, the plausibility of observed decreased ionized 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.
Effects on ability to drive and use machines: AUBAGIO 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 parent compound, the patient's ability to concentrate and to react properly may be impaired. In such cases, patients should refrain from driving cars and using machines.
Hepatic effects: Elevations of liver enzymes have been observed in patients receiving teriflunomide (see Adverse Reactions). 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 with teriflunomide might be higher in patients with pre-existing liver disorder, concomitant treatment with other hepatotoxic drugs, and/or consumption of substantial quantities of alcohol. Patients should therefore be closely monitored for signs and symptoms of liver injury.
Teriflunomide therapy should be discontinued and accelerated elimination procedure considered if liver injury is suspected. Consider to discontinue teriflunomide therapy if elevated liver enzymes (greater than 3-fold ULN) are confirmed.
In case of treatment discontinuation, liver tests should be pursued until normalisation of transaminase levels.
