Teriflunomide Adco 14 mg Tablet

TERIFLUNOMIDE ADCO is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of relapses and to delay the accumulation of physical disability.

Posology
The treatment should be initiated and supervised by a medical practitioner experienced in multiple sclerosis.
The recommended dose of TERIFLUNOMIDE ADCO is 14 mg orally once daily.
Special populations
Elderly population
TERIFLUNOMIDE ADCO has not been specifically studied in the elderly.
Renal impairment
No dosage adjustment is necessary for patients with mild, moderate or severe renal impairment.
Hepatic impairment
No dosage adjustment is necessary for patients with mild and moderate hepatic impairment. TERIFLUNOMIDE ADCO is contraindicated in patients with severe hepatic impairment (see section 4.3).
Paediatric population:
The safety and efficacy of TERIFLUNOMIDE ADCO in children aged 0 to 18 years has not yet been established. Use in this age group is not recommended.
Method of administration
The film-coated tablets are for oral use. The film-coated tablet should be swallowed whole with some water. TERIFLUNOMIDE ADCO can be taken with or without food.

• Hypersensitivity to teriflunomide or to any of the excipients of TERIFLUNOMIDE ADCO listed in section 6.1.
• Patients with severe hepatic impairment (Child-Pugh class C).
• As leflunomide is the parent compound of teriflunomide, co-administration of TERIFLUNOMIDE ADCO with leflunomide is not recommended (see section 4.4).
• TERIFLUNOMIDE ADCO is contraindicated for women during pregnancy or women of childbearing potential who are not on reliable contraception (see section 4.6).
• Breastfeeding 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.
• 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.

Monitoring
Before treatment
Before starting treatment with TERIFLUNOMIDE ADCO the following should be assessed:
u2022 Blood pressure
u2022 Alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT)
u2022 Complete blood cell count including differential white blood cell and platelet count.
During treatment
During treatment with TERIFLUNOMIDE ADCO the following should be monitored:
u2022 Blood pressure
o Check periodically
u2022 Alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT)
o 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.
u2022 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 ADCO (see sections 4.6 and 5.2).

Pharmacokinetic interactions of other medicines on TERIFLUNOMIDE ADCO
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 (phenobarbitone), phenytoin and St John's Wort should be used with caution during the treatment with TERIFLUNOMIDE ADCO.
Cholestyramine or activated charcoal
It is recommended that patients receiving TERIFLUNOMIDE ADCO 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.

Women of childbearing potential / Contraception in males and females
Use in males
The risk of male-mediated embryo-foetal toxicity through TERIFLUNOMIDE ADCO treatment is considered low; however, patients should be advised to use barrier contraception (see section 5.3).
Use in females
TERIFLUNOMIDE ADCO is contraindicated in women of childbearing potential not using reliable contraceptives (see section 4.3). Women of childbearing potential must use effective contraception during treatment and after treatment as long as TERIFLUNOMIDE ADCO plasma concentration is above 0,02 mg/l. During this period women should discuss any plans to stop or change contraception with the treating medical practitioner.
Pregnancy
TERIFLUNOMIDE ADCO is contraindicated during pregnancy (see section 4.3). There are no adequate and well-controlled studies of TERIFLUNOMIDE ADCO in pregnant women. However, based on animal studies, teriflunomide may increase the risk of fetal death or teratogenic effects when administered to pregnant women.
Human teriflunomide plasma concentration less than 0,02 u03bcg/mL is expected to have minimal risk based on available animal data. If TERIFLUNOMIDE ADCO is to be discontinued, an accelerated elimination procedure is recommended (see sections 4.4 and 5.2). Without the accelerated elimination procedure, on average it takes 6 months to reach plasma concentrations less than 0,02 u03bcg/mL. Due to individual variation in medicines clearance, teriflunomide plasma concentrations may need to be checked for up to 2 years after discontinuation. The accelerated elimination could be used at any time after discontinuation of TERIFLUNOMIDE ADCO.
Breastfeeding
Animal studies have shown excretion of teriflunomide in milk. TERIFLUNOMIDE ADCO is contraindicated during breastfeeding (see section 4.3).
Fertility
Results of studies in animals have not shown an effect on fertility (see section 5.3). Although human data are lacking, no effect on male and female fertility is anticipated.

TERIFLUNOMIDE ADCO 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.

a. Summary of the safety profile
The most frequent reported adverse reactions in treated patients were influenza, upper respiratory tract infection, urinary tract infection, paraesthesia, headache, diarrhoea, increased ALT, nausea, and alopecia. These side effects are usually mild to moderate, transient and infrequently leads to treatment discontinuation.
b. Tabulated list of adverse reactions
Infections and infestations
Frequent: Influenza, upper respiratory tract infection, urinary tract infection, bronchitis, sinusitis, pharyngitis, cystitis, viral gastroenteritis, oral herpes, tooth infection, laryngitis, tinea pedis
Frequency not known: Severe infections including sepsis
Blood and lymphatic system disorders
Frequent: Neutropenia, anaemia
Less frequent: Mild thrombocytopenia (platelets < 100 G/l)
Immune system disorders
Frequent: Mild allergic reactions, seasonal allergy
Frequency not known: Hypersensitivity reactions (immediate or delayed) including anaphylaxis and angioedema
Metabolism and nutrition disorders
Frequency not known: Dyslipidaemia
Psychiatric disorders
Frequent: Anxiety
Nervous system disorders
Frequent: Headache, paraesthesia, sciatica, carpal tunnel syndrome, hyperaesthesia, neuralgia
Less frequent: Peripheral neuropathy
Cardiac disorders
Frequent: Palpitations
Vascular disorders
Frequent: Hypertension
Respiratory, thoracic and mediastinal disorders
Frequency not known: Interstitial lung disease
Gastrointestinal disorders
Frequent: Diarrhoea, nausea, upper abdominal pain, vomiting, toothache
Frequency not known: Pancreatitis, stomatitis
Hepato-biliary disorders
Frequent: Alanine aminotransferase (ALT) increase, gamma glutamyl transferase (GGT) increase, aspartate aminotransferase increase
Frequency not known: Acute hepatitis
Skin and subcutaneous tissue disorders
Frequent: Alopecia, rash, acne
Less frequent: Nail disorders
Frequency not known: Severe skin reactions, psoriasis (including pustular)
Musculoskeletal and connective tissue disorders
Frequent: Musculoskeletal pain, myalgia, arthralgia
Renal and urinary disorders
Frequent: Pollakiuria
Reproductive system and breast disorders
Frequent: Menorrhagia
General disorders and administration site conditions
Frequent: Pain, asthenia
Investigations
Frequent: Weight decrease, neutrophil count decrease, white blood cell count decrease, blood creatine phosphokinase increased
Injury, poisoning and procedural complications
Less frequent: Post-traumatic pain

Symptoms
There is no experience regarding TERIFLUNOMIDE ADCO overdose or intoxication in humans.
Management:
In the event of relevant overdose or toxicity, cholestyramine or activated charcoal is recommended to accelerate elimination. Teriflunomide concentrations measured during an 11-day procedure to accelerate teriflunomide elimination with either 4 g cholestyramine three times a day, 8 g cholestyramine three times a day or 50 g activated charcoal twice a day following cessation of teriflunomide treatment have shown that these regimens were effective in accelerating teriflunomide elimination, leading to more than 98 % decrease in teriflunomide plasma concentrations, with cholestyramine being faster than charcoal. The choice between the 3 elimination procedures should depend on the patientu2019s tolerability. If cholestyramine 8 g three times a day is not well-tolerated, cholestyramine 4 g three times a day can be used. Alternatively, activated charcoal may also be used (the 11 days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly).