Generic name: Teriflunomide
Brand name: Tebazio
Pharmacologic Category: Pyrimidine Synthesis Inhibitor
1. Indication: Tebazio (Teriflunomide) is indicated as monotherapy for the treatment of patients with relapsing multiple sclerosis (RMS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.
Dosage Form: Film-coated tablet/14 mg
The safety and efficacy of TEBAZIO in pediatric and Geriatrics patients with MS below the age of 18 years have not been evaluated. TEBAZIO is not indicated in patients below 18 years and over 65 years of age
TEBAZIO (Teriflunomide) is contraindicated in patients:
with known hypersensitivity to Teriflunomide, Leflunomide or to any of the non-medicinal ingredients in the formulation
who are currently treated with leflunomide
Co-administration of Teriflunomide with leflunomide is contraindicated.
with severe hepatic impairment
who are pregnant or women of childbearing potential not using reliable contraception TEBAZIO may cause fetal harm when administered to a pregnant woman. Pregnancy must be excluded before start of treatment.
with immunodeficiency states (e.g. AIDS)
with impaired bone marrow function or significant anemia, leucopenia, neutropenia or thrombocytopenia
with serious active infections
STORAGE AND STABILITY
Store at 20°C to 25°C
TEBAZIO must be kept out of the reach and sight of children.
May be taken without regard to meals.
2. Action and clinical pharmacology
Mechanism of Action
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 blocks the proliferation of stimulated lymphocytes, which need de novo synthesis of pyrimidine to expand, may diminish the numbers of activated lymphocytes in peripheral blood. The exact mechanism by which Teriflunomide exerts its therapeutic effect in MS is not known, but may involve reduced numbers of activated lymphocytes available for migration into the central nervous system (CNS).
Teriflunomide is the main active metabolite of leflunomide.
Pharmacokinetic analysis of Teriflunomide using data from healthy subjects and MS patients, median t1/2z was approximately 19 days after repeated doses of 14 mg. It takes approximately 3 months to reach steady-state concentrations.
Absorption: Median time to reach maximum plasma concentrations occurs between 1 to 4 hours post-dose following oral administration of Teriflunomide.
Food does not have a clinically relevant effect on Teriflunomide pharmacokinetics.
Distribution: Teriflunomide is extensively bound to plasma protein (>99%), and is mainly distributed in plasma.
Metabolism: Teriflunomide is moderately metabolized and is the major circulating moiety detected in plasma. The primary biotransformation pathway to minor metabolites of Teriflunomide is hydrolysis, with oxidation being a minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation.
Excretion: Teriflunomide was excreted in the gastrointestinal tract mainly through the bile as unchanged drug and possibly by direct secretion. The metabolites of Teriflunomide are mainly excreted by the kidneys. Over 21 days, 60.1% of the administered dose was excreted via feces (37.5%) and urine (22.6%). After the accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces).
3. Efficacy: Clinical Trials
Data from4placebo- controlled, randomized trials support Teriflunomide use in adults with RMS.The14- mg dose had a significant impact on 3 key measures of MS disease activity: risk of sustained disability progression, ARR, and various MRI measures. The trial findings are summarized in Table1.
Table1: Overview of placebo-controlled trials of Teriflunomide
4. Adverse Reactions Significant
Central nervous system: Headache (19% to 22%)
Dermatologic: Alopecia (10% to 13%)
Endocrine & metabolic: Hypophosphatemia (5% to 18%)
Gastrointestinal: Diarrhea (15% to 18%), nausea (9% to 14%)
Hematologic: Neutropenia (2% to 15%)
Hepatic: ALT increased (12% to 14%)
Miscellaneous: Influenza (12%)
1% to 10%:
Cardiovascular: Hypertension (4%), palpitation (2% to 3%)
Central nervous system: Anxiety (3% to 4%)
Acne (3%), burning sensation (2% to 3%)
Endocrine & metabolic: Hyperkalemia (1%)
Gastrointestinal: Abdominal pain (5% to 6%), toothache (4%), viral gastroenteritis (2% to 4%), weight loss (2% to 3%), abdominal distension (1% to 2%)
Genitourinary: Cystitis (2% to 4%)
Hematologic: Thrombocytopenia (10%), lymphocytopenia (7% to 10%), leukopenia (1% to 2%)
Hepatic: GGT increased (3% to 5%), AST increased (2% to 3%)
Neuromuscular & skeletal: Paresthesia (9% to 10%), musculoskeletal pain (4% to 5%), myalgia (3% to 4%), sciatica (3%), carpal tunnel syndrome (1% to 3%), peripheral neuropathy (1% to 2%)
Ocular: Blurred vision (3%), conjunctivitis (3%)
Renal: Renal failure (transient, 1%)
Respiratory: Upper respiratory tract infection (9%), bronchitis (8%), sinusitis (6%)
Miscellaneous: Herpes simplex (4%), seasonal allergy (2% to 3%)
<1% (Limited to important or life-threatening): Cytomegalovirus hepatitis reactivation, jaundice, infection, MI
Accelerated Elimination Procedure
Teriflunomide is eliminated slowly from the plasma.
Without an accelerated elimination procedure, it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L, however, due to individual variations in drug clearance it may take as long as 2 years.
Elimination can be accelerated by either of the following procedures:
• Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g three times a day is not well tolerated, cholestyramine 4 g three times a day can be used.
• Administration of 50 g oral activated charcoal powder every 12 hours for 11 days.
If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower Teriflunomide plasma concentration in an accelerated manner.
At the end of 11 days, both regimens successfully accelerated Teriflunomide elimination, leading to more than 98% decrease in Teriflunomide plasma concentrations.
Use of the accelerated elimination procedure may potentially result in a gradual return of disease activity if the patient had been responding to TEBAZIO treatment.
Both cholestyramine and activated powdered charcoal may interact with the absorption of some concomitant medications. In particular, it can influence the absorption of estrogens and progesterone such that reliable contraception with oral contraceptives may not be guaranteed during the accelerated elimination procedure with cholestyramine or activated charcoal. Use of alternative contraceptive method is recommended.
5. Warnings and precautions
The safety profile of leflunomide in patients suffering from rheumatoid arthritis may be pertinent when prescribing Teriflunomide in MS patients.
Concerns related to adverse effects:
Rare cases of dermatologic reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with leflunomide, therefore patients taking teriflunomide may also be at risk; discontinue if evidence of severe dermatologic reaction occurs, and begin drug elimination procedures (eg, cholestyramine, activated charcoal).
Use of leflunomide has been associated with rare reports of hepatotoxicity, hepatic failure, and death, therefore, a similar risk is expected with Teriflunomide. Treatment should not be initiated in patients with pre-existing acute or chronic liver disease or ALT >2 x ULN; use is contraindicated in patients with severe impairment. Use caution in patients with concurrent exposure to potentially hepatotoxic drugs. Monitor ALT levels at least monthly for first 6 months during therapy; discontinue if ALT >3 x ULN occurs and, if hepatotoxicity is likely Teriflunomide-induced, start drug elimination procedures (e.g., cholestyramine, activated charcoal) and monitor liver function tests weekly until normalized. Due to a potential for additive hepatotoxic effects, alcohol consumption should be avoided during treatment with TEBAZIO.
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 hypoproteinemia, e.g. in nephrotic syndrome. Teriflunomide is not recommended in patients with conditions of severe hypoproteinemia.
Hyperkalemia: Severe hyperkalemia (>7.0 mmol/L) has been reported. Monitor levels in patients with symptoms or acute renal failure.
Infections: May increase susceptibility to infection, including opportunistic pathogens. Severe infections, sepsis, and fatalities have been reported with leflunomide. Not recommended in patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. Patients who develop a new infection while undergoing treatment should be monitored closely; consider discontinuation of therapy and drug elimination procedures (eg, cholestyramine, activated charcoal) if infection is serious.
• Interstitial lung disease: Use of leflunomide has been associated (rarely) with interstitial lung disease, therefore patients taking Teriflunomide may also be at risk; discontinue in patients who develop new onset or worsening of pulmonary symptoms. Drug elimination procedures (e.g., cholestyramine, activated charcoal) should be considered if evidence of interstitial lung disease; fatal outcomes have been reported.
• Peripheral neuropathy: Cases of peripheral neuropathy have been reported; use with caution in patients >60 years of age, receiving concomitant neurotoxic medications or patients with diabetes; discontinue if evidence of peripheral neuropathy occurs and begin drug elimination procedures (e.g., cholestyramine, activated charcoal).
• Renal effects: several transient acute renal failure, has been reported. Increased serum creatinine typically occurred 12 weeks to 2 years after the first dose; serum creatinine usually normalized with continued use.
Concomitant use of Immunosuppressive or Immunomodulating Therapies
As leflunomide is the parent compound of Teriflunomide, co-administration of TEBAZIO with leflunomide is contraindicated.
Co-administration with antineoplastic or immunosuppressive therapies has not been evaluated and is not recommended due to the potential risk of additive immune system effects.
No clinical data are available on the efficacy and safety of live vaccinations in patients taking TEBAZIO Vaccination with live vaccines, however, not recommended. The long half-life of TEBAZIO should be considered when contemplating administration of a live vaccine after stopping TEBAZIO
• Hematologic disorders: Use with caution in patients with a prior history of significant hematologic abnormalities; avoid use with bone marrow dysplasia. Neutropenia, leukopenia, and thrombocytopenia have been reported in clinical trials. Use of leflunomide has been associated with agranulocytosis, and thrombocytopenia, therefore, a similar risk may be expected with Teriflunomide. Monitoring of hematologic function is required; discontinue if evidence of bone marrow suppression and begin drug elimination procedures (e.g., cholestyramine, activated charcoal).
• Tuberculosis: Safety has not been established in patients with latent tuberculosis infection. Patients should be screened for tuberculosis and if necessary, treated prior to initiating therapy.
6. Special populations:
Pregnancy/women of childbearing potential:
Based on animal data, Teriflunomide may cause major birth defects if used in pregnant women. Teriflunomide is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during therapy or prior to completing the accelerated elimination treatment protocol.
Use in Women of Childbearing Potential
TEBAZIO is contraindicated in women who are pregnant or women of child bearing potential not using reliable contraception. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, the drug should be immediately discontinued and an accelerated elimination procedure should be initiated (see WARNINGS AND PRECAUTIONS, General, and Accelerated Elimination Procedure). Under these conditions, the patient should be referred to an obstetrician/gynecologist, preferably experienced in reproductive toxicity, for further evaluation and counseling.
There are no adequate and well-controlled studies of TEBAZIO in pregnant women.
Before starting treatment with TEBAZIO, patients must be fully counseled on the potential for serious risk to the fetus. 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 fetus.
Upon discontinuation TEBAZIO, it is recommended that all women of childbearing potential not using reliable contraception undergo an accelerated elimination procedure. Women receiving TEBAZIO treatment who wish to become pregnant must discontinue TEBAZIO and undergo an accelerated elimination procedure, which includes verification that Teriflunomide plasma concentrations decreases to at least 0.02 mg/L. Human plasma concentrations of Teriflunomide less than 0.02 mg/L are expected to have minimal risk.
TEBAZIO can increase the plasma concentration of oral contraceptives 1.54-fold, therefore consideration should be given to the type or dose of oral contraceptives used (see DRUG INTERACTIONS).
Use in males
Teriflunomide is detected in human semen. Based on preclinical safety data, there were no external malformations in the offspring of male rats administered Teriflunomide prior to mating with untreated female rats. In addition, the estimated female plasma exposure via the semen of a treated patient is expected to be 100 times lower than the plasma exposure after 14 mg of oral Teriflunomide. However, to minimize any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of TEBAZIO and undergo an accelerated elimination procedure to decrease the plasma concentration of Teriflunomide to less than 0.02 mg/L.
It is not known whether Teriflunomide is secreted in human milk. Because the potential for serious adverse reactions exists in the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
7. Drug Interactions
BCG: immunosuppressant may diminish the therapeutic effect of BCG. Risk X: Avoid combination
Bile Acid Sequestrates: May decrease the serum concentration of Teriflunomide. Management: Unless using this combination to intentionally enhance Teriflunomide elimination, consider an alternative to the bile acid sequestrates when possible. Separating drug administration is unlikely to be effective at avoiding the interaction. Risk D: Consider therapy modification
Caffeine: Teriflunomide may decrease the serum concentration of Caffeine. Risk C: Monitor therapy
Charcoal, Activated: May decrease the serum concentration of Teriflunomide. Management: Unless using this combination to intentionally enhance Teriflunomide elimination, consider an alternative to charcoal when possible. Separating drug administration is not likely to be effective at avoiding this interaction. Risk D: Consider therapy modification
Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: Monitor therapy
CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of immunosuppressant. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Leflunomide: May enhance the adverse/toxic effect of Teriflunomide. Leflunomide may increase the serum concentration of Teriflunomide. Risk X: Avoid combination
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Repaglinide: Teriflunomide may increase the serum concentration of Repaglinide. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Warfarin: Teriflunomide may decrease the serum concentration of Warfarin. Risk C: Monitor therapy
Pregnancy Risk Factor: X
8. Safety monitoring guidelines for Teriflunomide.
Prior to initiation
CBC (within 6 months prior to initiation)
CBC should be assessed
if signs/symptoms of hematologic toxicity periodically
LFTs (within 6
months prior to initiation)
Monthly LFTs for the first 6 months, then every 6 months thereafter
Measure blood pressure
Monitor blood pressure periodically
Counsel patients to continue use of reliable contraception during therapy
Screen for latent tuberculosis