Section 4.4

update with a warning concerning alcohol use with clarification of "with caution" term

a: please refer to the detailed description section

b: see section 4.4

Severe skin reactions

Cases of severe skin reactions have been reported with teriflunomide post-marketing (see section 4.4).

Asthenia

In placebo-controlled studies, frequencies for asthenia were 2.0%, 1.6% and 2.2% in the placebo, teriflunomide 7 mg and teriflunomide 14 mg group, respectively.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9     Overdose

Long term follow-up results from TEMSO long term extension safety study (overall median treatment duration approximately 5 years, maximum treatment duration approximately 8.5 years) did not present any new or unexpected safety findings.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

• Removal of black triangle

Section 4.3 Contraindications

AIDs removed and replaced with acquired immunodeficiency syndrome (AIDS).

Section 4.4 Special warnings and precautions for use

Wording added into section:-

• serum glutamic pyruvic transaminase
• Check periodically
• serum glutamic pyruvic transaminase
• Liver enzymes should be assessed 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.

Hepatic effects:-

Wording removed from section:-

• 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.

Subtitle added:-

• Hypoproteinaemia

Respiratory reactions  

Amendments to paragraph

• Drug removed and replaced with medicinal product.
• Consider removed and replaced with should be considered.

Lactose

Minor wording amendments to paragraph

Section 4.5 Interaction with other medicinal products and other forms of interaction

Grammatical errors amended and medicinal added into paragraph

Section 4.6 Fertility, pregnancy and lactation

Medicine replaced by medicinal product

Breast-feeding

Added

• Teriflunomide is contraindicated during breast-feeding
• (see section 4.3).

Removed

• women must, therefore, not receive teriflunomide
• Breast

Section 4.7          Effects on ability to drive and use machines

• The word cars removed

Section 4.8          Undesirable effects

• Minor amendments to tabulated list of adverse reactions

Section 5.1          Pharmacodynamic properties

Added:

• Immunosuppressants,
• Minor spelling amendments updated

Section 5.2          Pharmacokinetic properties

• IV replaced with intravenous

Section 6.5          Nature and contents of container

• Aluminium replaced with Polyamide/aluminium/poly(vinyl chloride)

Section 9

• Renewal date added 28May2018

Section 4.4: Under Skin reactions the following update has been made;

Cases of severe skins reactions have been reported with teriflunomide postmarketing (including Stevens-Johnson syndrome, and toxic epidermal necrolysis).

 In patients treated with leflunomide, the parent compound, very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported as well. 

Section 4.8: The following additions to the Adverse Reactions table have been made; Headache, palpitations, arthralgia, blood creatine phosphokinase increased.

Addition of terms from post marketing safety reports for teriflunomide also included; Severe infections including sepsis, Hyper-sensitivity reactions (immediate or delayed)  including anaphylaxis and angioedema, Pancreatitis,  Stomatitis, Severe skin reactions. These terms have all been placed in the new column for frequency ‘Not known’. Consequentially, the following sentence has been added below the ADR table, under the heading for infections: “Severe infections including sepsis, sometimes fatal have been reported post marketing.”

Section 4.4: Under Skin reactions the following update has been made;

Cases of severe skins reactions have been reported with teriflunomide postmarketing (including Stevens-Johnson syndrome, and toxic epidermal necrolysis).

 In patients treated with leflunomide, the parent compound, very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported as well. 

Section 4.8: The following additions to the Adverse Reactions table have been made; Headache, palpitations, arthralgia, blood creatine phosphokinase increased.

Addition of terms from post marketing safety reports for teriflunomide also included; Severe infections including sepsis, Hyper-sensitivity reactions (immediate or delayed)  including anaphylaxis and angioedema, Pancreatitis,  Stomatitis, Severe skin reactions. These terms have all been placed in the new column for frequency ‘Not known’. Consequentially, the following sentence has been added below the ADR table, under the heading for infections: “Severe infections including sepsis, sometimes fatal have been reported post marketing.”

4.4         Special warnings and precautions for use

Skin reactions

No cCases of severe skins reactions have been reported with teriflunomide postmarketing in the clinical trials. In patients treated with leflunomide, the parent compound, very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported as well.

4.8         Undesirable effects

Severe skin reactions

Cases of severe skins reactions have been reported with teriflunomide post-marketing (see section 4.4).

4.4         Special warnings and precautions for use

Skin reactions

No cCases of severe skins reactions have been reported with teriflunomide postmarketing in the clinical trials. In patients treated with leflunomide, the parent compound, very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported as well.

4.8         Undesirable effects

Severe skin reactions

Cases of severe skins reactions have been reported with teriflunomide post-marketing (see section 4.4).

Section 4.4: Inclusion of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) under the skin reactions section in patients treated with the parent compound leflunomide.

Section 4.4: Inclusion of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) under the skin reactions section in patients treated with the parent compound leflunomide.

Section 4.5: improvement of the oral contraceptive PK interaction wording.

Section 4.8 update of AEs vs placebo (i.e. data pool of all placebo-controlled phase2/3 clinical trials).

Section 5.1: addition of TOPIC efficacy study results.

Section 4.5: improvement of the oral contraceptive PK interaction wording.

Section 4.8 update of AEs vs placebo (i.e. data pool of all placebo-controlled phase2/3 clinical trials).

Section 5.1: addition of TOPIC efficacy study results.

In section 4.4: Addition of two clinical study results in the vaccination paragraph as below;

From:

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.

To:

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.

In section 4.4: Addition of two clinical study results in the vaccination paragraph as below;

From:

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.

To:

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.