Teriflunomide

Registered South African indications:

• Multiple sclerosis

Warning: Hepatotoxicity and risk of teratogenicity Hepatotoxicity Severe liver injury, including fatal liver failure, has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Obtain transaminase and bilirubin levels within six months before initiation of teriflunomide and monitor alanine aminotransferase (ALT) levels at least monthly for six months. If drug-induced liver injury is suspected, discontinue teriflunomide and start an accelerated elimination procedure. Concomitant use of teriflunomide with other potentially hepatotoxic medicines may increase the risk of severe liver injury. Risk of teratogenicity Based on animal data, teriflunomide may cause major birth defects if used during pregnancy. Teriflunomide is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during teriflunomide treatment.

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Women of childbearing potential who are not using reliable contraception during treatment and thereafter (with plasma levels >0.02 mg/l)
• Breastfeeding women
• Severe renal impairment and undergoing dialysis
• Severe hepatic impairment (Child-Pugh Class C)
• Severe immunodeficiency states, such as acquired immunodeficiency syndrome (AIDS)
• Significantly impaired bone marrow function
• Significant anaemia, leucopenia, neutropenia or thrombocytopenia
• Severe active infection (until resolution)
• Severe hypoproteinaemia, such as in nephrotic syndrome

Cautions

• Elderly
• Pre-existing liver disease and/or substantial alcohol consumption
• Hypoproteinaemia
• Latent tuberculosis
• Pre-existing interstitial lung disease (ILD) or history thereof when treated with leflunomide
• Pre-existing anaemia, leucopenia and/or thrombocytopenia
• Impaired bone marrow function
• Risk of bone marrow suppression
• Risk of haematological disorders
• Psoriasis
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption

Forms avail. in SA and covered in this monograph: tab

Relapsing remitting multiple sclerosis (MS)

•  Oral (tab): 14mg, dly

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The treatment should be initiated and supervised by a physician experienced in the management of multiple sclerosis

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Tablets should be swallowed whole

Not established for use in children below 18 years

Pregnancy

• Contraindicated
• 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. Thus, 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. It is possible that rapidly lowering the blood level of teriflunomide, by instituting the accelerated elimination procedure described below, at the first delay of menses, may decrease the risk to the foetus. For women receiving teriflunomide treatment, who wish to become pregnant, the medicinal product should be stopped and an accelerated elimination procedure is recommended in order to more rapidly achieve concentration below 0.02 mg/l
• If an accelerated elimination procedure is not used, teriflunomide plasma levels can be expected to be above 0.02 mg/l for an average of 8 months, however, in some patients it may take up to 2 years to reach plasma concentration below 0.02 mg/l. Therefore, teriflunomide plasma concentrations should be measured before a woman begins to attempt to become pregnant. Once the teriflunomide plasma concentration is determined to be below 0.02 mg/l, the plasma concentration must be determined again after an interval of at least 14 days. If both plasma concentrations are below 0.02 mg/l, no risk to the foetus is to be expected
• Accelerated elimination procedure: After stopping treatment with teriflunomide:
  - Cholestyramine 8g is administered 3 times daily for a period of 11 days, or cholestyramine 4g three times a day can be
  used, if cholestyramine 8g three times a day is not well tolerated
  - Alternatively, 50 g of activated powdered charcoal is administered every 12 hours for a period of 11 days
  - However, also following either of the accelerated elimination procedures, verification by 2 separate tests at an interval of at least 14 days and a waiting period of one-and-a-half months between the first occurrence of a plasma concentration below 0.02 mg/l and fertilisation is required
  - Both cholestyramine and activated powdered charcoal may influence the absorption of oestrogens and progestogens such that reliable contraception with oral contraceptives may not be guaranteed during the accelerated elimination procedure with cholestyramine or activated powdered charcoal. Use of alternative contraceptive methods is recommended

Breastfeeding

• Contraindicated
• Animal studies have shown excretion of teriflunomide in milk. Therefore, teriflunomide is contraindicated during breastfeeding

Fertility

• Results of studies in animals have not shown an effect on fertility. Although human data are lacking, no effect on male and female fertility is anticipated

Renal impairment

• No dose adjustment recommended
• Haemodialysis: Contraindicated
  Patients with severe renal impairment undergoing dialysis have not been evaluated

Hepatic impairment

• Mild to moderate (Child-Pugh Classes A & B): No dose adjustment recommended
• Severe (Child-Pugh Class C): Contraindicated

Elderly

• Caution; no dose adjustment recommended 

Porphyria

• Probably not porphyrinogenic (PNP)
  Immunosuppressive therapy increases infection risk and may trigger acute cases of porphyria
  Nausea and vomiting are reported as side effects of teriflunomide that may potentially be porphyrinogenic if leading to a decrease in carbohydrate intake

Drugs in sport

• Permitted - No warnings

Central Nervous System Disorders

• Anxiety
• Headache
• Paraesthesia
• Sciatica
• Carpal tunnel syndrome
• Hyperaesthesia
• Neuralgia
• Peripheral neuropathy
• Asthenia

Cardiovascular Disorders

• Palpitations
• Hypertension

Respiratory Disorders

• Upper respiratory tract infection
• Influenza
• Bronchitis
• Sinusitis
• Pharyngitis
• Laryngitis
• Interstitial lung disease

Gastrointestinal Disorders

• Viral gastroenteritis
• Diarrhoea
• Nausea and vomiting
• Upper abdominal pain
• Vomiting
• Pancreatitis
• Stomatitis
• Tooth infection
• Toothache
• Oral herpes

Hepatobiliary Disorders

• Increased alanine aminotransferase (ALT)
• Increased gamma-glutamyltransferase (GGT)
• Increased aspartate aminotransferase
• Acute hepatitis

Genitourinary Disorders

• Cystitis
• Urinary tract infection
• Pollakiuria
• Menorrhagia

Endocrine and Metabolic Disorders

• Dyslipidaemia
• Decreased weight

Musculoskeletal Disorders

• Musculoskeletal pain
• Myalgia
• Arthralgia
• Increased blood creatine phosphokinase

Skin and Subcutaneous Tissue Disorders

• Tinea pedis
• Alopecia
• Rash
• Acne
• Nail disorders
• Severe skin reactions
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
• Psoriasis (including pustular)

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Mild thrombocytopenia (platelets <100G/l)
• Neutropenia
• Severe infections including sepsis
• Mild allergic reactions
• Hypersensitivity reactions (immediate or delayed), including anaphylaxis and angioedema
• Decreased neutrophil count
• Decreased white blood cell count

Others

• Pain
• Post-traumatic pain

• Potent CYP450 inducers
• Rifampicin
• P-glycoprotein transporter inducers
• Carbamazepine
• Phenobarbital
• Phenytoin
• Breast cancer resistant protein (BCRP) inducers
• Cholestyramine
• Activated charcoal
• CYP2C8 substrates
• Repaglinide
• Paclitaxel
• Pioglitazone
• Rosiglitazone
• Oral contraceptives
• Ethinylestradiol  
• Levonorgestrel
• CYP1A2 substrates
• Caffeine
• Duloxetine
• Alosetron
• Theophylline
• Tizanidine
• Warfarin
• Organic anion transporter 3 (OAT3) substrates
• Cefaclor
• Benzylpenicillin
• Ciprofloxacin
• Indomethacin
• Ketoprofen
• Furosemide
• Cimetidine
• Methotrexate
• Zidovudine
• Organic anion transporting polypeptide B1 and B3 (OATP1B1/B3) substrates
• HMG-Co reductase inhibitors
• Rosuvastatin
• Simvastatin
• Atorvastatin
• Pravastatin
• Nateglinide
• Repaglinide
• Breast cancer resistant protein (BCRP) substrates
• Topotecan
• Sulfasalazine
• Daunorubicin
• Doxorubicin
• Leflunomide
• Live vaccines

Other interactions

• St John's Wort 

• Blood pressure
• Hepatic function
• Full blood count, including differential white blood cell and platelet count

None routine. Some cases may require

• Renal function
• Phosphate level
• Tuberculosis screening
• Pregnancytest

Additional observations

• Signs and symptoms of
  - Infection
  - Hepatotoxicity
  - Hypophosphataemia

Switching to and from teriflunomide

• 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 teriflunomide was immediately started. Therefore, caution is required when switching patients from natalizumab to teriflunomide
• 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 teriflunomide 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 t was approximately 19 days after repeated doses of 14mg. If a decision is made to stop 1/2z treatment with teriflunomide, 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 teriflunomide. This may lead to an additive effect on the immune system and caution is, therefore, indicated

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

Coadministration with vaccines

• Two clinical studies have shown that vaccinations to inactivated neoantigen (first vaccination), or recall antigen (re-exposure) were safe and effective during treatment
• The use of live attenuated vaccines may carry a risk of infections and should therefore be avoided

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

Teriflunomide is an immunomodulatory agent with anti-inflammatory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), required for the de novo pyrimidine synthesis. As a consequence teriflunomide reduces the proliferation of dividing cells that need de novo synthesis of pyrimidine to expand. The exact mechanism by which teriflunomide exerts its therapeutic effect in multiple sclerosis is not fully understood, but this is mediated by a reduced number of lymphocytes.

Tablet 14mg

• Aubagio (Sanofi Aventis) originator
• Teriflunomide 14 Teva (Teva Pharmaceuticals)