Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
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 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. If elevated liver enzymes (greater than3-fold ULN) are confirmed, teriflunomide therapy should be discontinued.

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

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 section 4.8). 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 section 4.8).
Cases of herpes virus infections, including oral herpes and herpes zoster, have been reported with teriflunomide (see section 4.8), with some of them being serious, including herpetic meningoencephalitis and herpes dissemination. They may occur at any time during treatment.
Based on the immunomodulatory effect of teriflunomide, if a patient develops any serious infection, suspending treatment with 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 teriflunomide in individuals with latent tuberculosis infection is unknown, as tuberculosis screening was not systematically performed in clinical studies. Patients tested positive in tuberculosis screening, should be treated by standard medical practice prior to therapy.

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 medicinal product is necessary, initiation of an accelerated elimination procedure should be considered.

Haematological effects

A mean decrease less than 15% from baseline affecting white blood cell count has been observed (see section 4.8). 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 and the completeblood 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 (see above) 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 section 4.3).

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 section 4.8). 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, discontinuing AUBAGIOtherapy and performing the accelerated elimination procedure should be considered.

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.

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 AUBAGIO was immediately started.
Therefore, caution is required when switching patients from natalizumab to AUBAGIO.
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 AUBAGIO 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 AUBAGIO, 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 AUBAGIO. This may lead to an additive effect on the immune system and caution is, therefore, indicated.

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.

Lactose

Since AUBAGIO tablets contain lactose, patients with rare hereditary problems of galactose intolerance, total 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”.

Effects on Driving

4.7 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 and using machines.