Teriflunomide (Tablets) Instructions for Use

ATC Code

L04AA31 (Teriflunomide)

Active Substance

Teriflunomide (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Immunosuppressive drug used in multiple sclerosis

Pharmacotherapeutic Group

Selective immunosuppressant

Pharmacological Action

Mechanism of action

Teriflunomide is an immunomodulatory drug with anti-inflammatory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which is necessary for de novo pyrimidine synthesis. Thus, Teriflunomide blocks the proliferation of stimulated lymphocytes, which require de novo pyrimidine synthesis. The exact mechanism by which Teriflunomide exerts its therapeutic effect in multiple sclerosis is not fully understood, but it may involve a reduction in the number of activated lymphocytes in the CNS. It is possible that Teriflunomide reduces the number of peripheral activated lymphocytes that can migrate into the CNS.

Pharmacodynamic effects

Immune system (effect on the number of immune cells in the blood)

Effect on the number of immune cells in the blood: In placebo-controlled studies, administration of teriflunomide at a dose of 14 mg once daily led to a slight decrease in the mean lymphocyte count in peripheral blood (less than 0.3×10⁹/L), which was observed during the first 3 months of treatment, after which the lymphocyte count in peripheral blood stabilized at the achieved level and remained at this level until the end of treatment.

In a clinical study, patients treated with teriflunomide maintained adequate immune responses to seasonal influenza vaccination, which corresponded to the maintenance of an active immunization response. Patients in both teriflunomide groups (7 mg/day and 14 mg/day) achieved seroprotective antibody titers after vaccination: after vaccination, more than 90% of patients achieved an antibody titer of ≥40 against H1N1 and B strains. For the H3N2 strain, antibody titers of ≥40 were achieved in >90% of patients in the 7 mg/day teriflunomide group and in 77% of patients in the 14 mg/day teriflunomide group.

In another randomized, double-blind, placebo-controlled pharmacodynamic study conducted in healthy volunteers, the immune response to the administration of an inactivated rabies vaccine (a neoantigen) was studied. At the end of the vaccination schedule, the geometric mean titers of antibodies to the rabies vaccine in the teriflunomide group were lower than in the placebo group, reaching a post-vaccination therapeutic ratio of antibody titer values in the teriflunomide group versus the placebo group [90% CI] of 0.53 [0.35, 0.81]. However, all volunteers had post-vaccination anti-rabies antibody titers above 0.5 IU/mL (the threshold titer for seroprotection). In the same study, the ability of volunteers receiving Teriflunomide to exhibit delayed-type hypersensitivity skin reactions to repeated administration of antigens such as Candida albicans, Trichophyton antigens, or purified protein derivative of tuberculin did not differ from that of volunteers in the placebo group.

Effect on the QT interval

In a placebo-controlled study involving healthy volunteers, Teriflunomide at steady-state average concentrations did not show any potential for QT_cF interval prolongation compared to placebo: the largest mean difference between teriflunomide and placebo was 3.45 ms with an upper bound of the 90% confidence interval of 6.45 ms. At the same time, no QT_cF value was ≥480 ms, and no change in the duration of this interval was >60 ms compared to the baseline value.

Effect on renal tubular function

In placebo-controlled studies, a 20-30% decrease in serum uric acid concentration was observed in patients taking Teriflunomide compared to the placebo group. The mean decrease in serum phosphorus was about 10-15% in the teriflunomide group compared to the placebo group. Such effects are considered to be associated with increased renal tubular excretion and are not associated with changes in glomerular renal function.

Clinical efficacy and safety

The efficacy of teriflunomide was demonstrated in the EFC6049/TEMSO and TOWER studies, which evaluated the daily administration of teriflunomide at doses of 7 mg and 14 mg in patients with relapsing-remitting multiple sclerosis (RRMS).

Overall, 1088 patients with RRMS were randomized in the TEMSO study to receive teriflunomide 7 mg (n=366) or 14 mg (n=359), or placebo (n=363) for 108 weeks. All patients had a confirmed diagnosis of multiple sclerosis (MS) (based on McDonald’s criteria (2001)), relapsing course with or without progression; patients had experienced at least 1 relapse in the year prior to the study or at least 2 relapses in the 2 years prior to the study. At study entry, patients had a mean Expanded Disability Status Scale (EDSS) score of ≤5.5. The mean age of the study patient group was 37.9 years. The majority of patients had relapsing-remitting multiple sclerosis (91.5%), with subgroups of patients also represented with secondary progressive (4.7%) or progressive-relapsing multiple sclerosis (3.9%). The mean number of exacerbations in the year prior to study entry was 1.4, with 36.2% of patients having gadolinium-enhancing lesions at baseline. The median EDSS score of patients at study entry was 2.50: 249 patients (22.9%) had a baseline EDSS score greater than 3.5. The mean disease duration from the onset of first symptoms was 8.7 years. The majority of patients (73%) had not taken disease-modifying therapies (DMTs) within 2 years prior to study entry. The study results are presented in Table 1.

Overall, 1169 patients with RRMS were included in the TOWER study to receive teriflunomide 7 mg (n=408) or 14 mg (n=372), or placebo (n=389). The treatment duration was 48 weeks after the inclusion of the last patient. All patients had a confirmed diagnosis of multiple sclerosis (based on McDonald’s criteria (2001)), a relapsing course with or without progression, and had experienced at least one relapse in the year prior to the study, or at least 2 relapses in the two years prior to the study. At study entry, patients had an Expanded EDSS score of ≤5.5.

The mean age of the study patient group was 37.9 years. The majority of patients had relapsing-remitting multiple sclerosis (97.5%), but there were subgroups of patients with secondary progressive (0.8%) or progressive-relapsing multiple sclerosis (1.7%). The mean number of relapses in the year prior to study entry was 1.4. The median EDSS score of patients at study entry was 2.50. The mean disease duration from the onset of first symptoms was 8 years. The majority of patients (67.2%) had not taken disease-modifying drugs within 2 years prior to study entry. The study results are presented in Table 1.

Table 1. Main results (for the approved dose, ITT population, patients who started treatment)

**** p<0.0001;
*** p<0.001;
** p<0.01;
* p<0.05 compared to placebo.
¹TLV: total lesion volume in mL (T2 and hypointense T1).

Efficacy in patients with high disease activity

In the TEMSO study, in a subgroup of patients with high disease activity (n=127), a sustained effect of teriflunomide therapy on MS relapses and confirmed (over 12 weeks) disability progression was observed. According to the study design, high disease activity was defined as the presence of 2 or more relapses in the year with imaging of one or more gadolinium-enhancing lesions on brain MRI. A similar subgroup analysis was not performed in the TOWER study because MRI data were not obtained. There are no data on patients who did not respond to a full and adequate course of treatment (on average 1 year of therapy) with beta-interferon and had at least 1 relapse during the previous year while on therapy, and at least 9 T2-hyperintense lesions on brain MRI or at least 1 gadolinium-enhancing lesion, or on patients whose relapse rate did not change or decreased during the previous year compared to the previous 2 years.

The TOPIC clinical trial was a double-blind, placebo-controlled study that evaluated once-daily doses of teriflunomide 7 mg and 14 mg over 108 weeks in patients with a first clinical demyelinating episode (mean age 32.1 years). The primary endpoint was time to the second clinical episode (relapse). A total of 618 patients were randomized to receive 7 mg (n=205) or 14 mg (n=216) teriflunomide, or placebo (n=197). The risk of a second clinical exacerbation over 2 years was 35.9% in the placebo group and 24.0% in the teriflunomide 14 mg treatment group (hazard ratio: 0.57, 95% confidence interval: 0.38-0.87, p=0.0087). The results obtained in the TOPIC clinical trial confirmed the efficacy of teriflunomide in relapsing-remitting multiple sclerosis (RRMS) (including early RRMS with a first clinical demyelinating episode and MRI lesions of varying age and location).

The efficacy of teriflunomide was compared with the efficacy of subcutaneous interferon beta-1a (at the recommended dose of 44 mcg, three times a week) in a study involving 324 patients (TENERE). The minimum duration of treatment was 48 weeks; the maximum was 114 weeks. Time to treatment failure (confirmed relapse or permanent treatment discontinuation, whichever occurred first) was the primary endpoint. The number of patients who permanently discontinued treatment in the teriflunomide 14 mg group was 22 out of 111 (19.8%). The reasons were adverse events (10.8%), lack of efficacy (3.6%), other reasons (4.5%), and loss to follow-up (0.9%). The number of patients who permanently discontinued treatment in the interferon beta-1a group was 30 out of 104 (28.8%). The reasons were adverse events (21.2%), lack of efficacy (1.9%), other reasons (4.8%), and protocol non-compliance (1%).

No statistically significant differences in the effect on the primary endpoint between teriflunomide 14 mg/day and subcutaneous interferon beta-1a 44 mcg were found. The percentage of patients with confirmed treatment failure at week 96 by the Kaplan-Meier method was 41.1% on teriflunomide 14 mg compared to 44.4% on interferon beta-1a (p=0.5953).

There are no clinical data on the efficacy and safety of teriflunomide in children and adolescents under 18 years of age.

Pharmacokinetics

Absorption

The bioavailability of the drug is approximately 100%. During repeated oral administration of teriflunomide, the mean T_max ranges from 1 to 4 hours. Food does not have a clinically significant effect on the pharmacokinetics of teriflunomide.

After oral administration of 7 mg and 14 mg of teriflunomide, its systemic exposure increases proportionally to the dose.

Based on mean predicted pharmacokinetic parameters calculated from a population pharmacokinetic (PopPK) analysis using data from healthy volunteers and patients with multiple sclerosis, slow attainment of C_ss was observed with teriflunomide administration (approximately 95% of C_ss is reached after 100 days (3.5 months)), and the estimated accumulation factor of teriflunomide at C_ss is 34 (when assessed by AUC).

Distribution

Teriflunomide is highly bound (>99%) to plasma proteins, likely albumin, and is predominantly distributed in plasma. The V_d after a single intravenous administration of teriflunomide is 11 L.

Metabolism

Teriflunomide is moderately metabolized and is the only substance detected in plasma. The main pathway of biotransformation for a small amount of teriflunomide metabolites is hydrolysis, with oxidation as a secondary metabolic pathway. Secondary metabolic pathways include oxidation, N-acetylation, and sulfate conjugation.

Excretion

Teriflunomide is excreted through the gastrointestinal tract, mainly in the bile unchanged and possibly by direct secretion. Within 21 days, 60.1% of the administered dose of the drug is excreted, with 37.5% through the gastrointestinal tract (in feces) and 22.6% through the kidneys (in urine). When using an accelerated elimination procedure for teriflunomide using cholestyramine, an additional 23.1% is excreted (mainly in feces). After a single intravenous administration, the total clearance of teriflunomide from the body is 30.5 mL/h.

Teriflunomide is slowly eliminated from plasma. Without an accelerated elimination procedure, it takes an average of 6 months to achieve a teriflunomide plasma concentration of less than 0.25 mg/L, and due to individual differences in teriflunomide clearance, it can take up to 2 years. The accelerated elimination procedure for teriflunomide can be applied at any time after discontinuation of Teriflunomide.

Elimination can be accelerated using one of the following procedures

• Oral administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g three times a day is poorly tolerated, a regimen of cholestyramine 4 g every 8 hours may be used;
• Oral administration of 50 g of activated charcoal powder every 12 hours for 11 days.

If any accelerated teriflunomide elimination procedure is poorly tolerated, and if there is no need for rapid reduction of teriflunomide plasma concentration, then cholestyramine and activated charcoal do not necessarily have to be taken daily.

By the end of 11 days, both treatment regimens successfully accelerated the elimination of teriflunomide, leading to a reduction in teriflunomide plasma concentration of more than 98%.

If the patient responded to treatment with Teriflunomide, the use of an accelerated elimination procedure may lead to a return of disease activity.

Pharmacokinetics in special patient groups

Based on the results of a population pharmacokinetic analysis in healthy volunteers and patients with multiple sclerosis, several causes of intrinsic variability in pharmacokinetic parameters were identified: age, body weight, sex, race, and blood concentrations of albumin and bilirubin. However, their impact remains limited (change in pharmacokinetic parameters ≤31%).

Mild and moderate hepatic impairment does not affect the pharmacokinetics of teriflunomide. Therefore, no dose adjustment is anticipated in patients with mild and moderate hepatic impairment. The pharmacokinetics of teriflunomide in patients with severe hepatic impairment has not been studied (see section “Contraindications”).

Severe renal impairment does not affect the pharmacokinetics of teriflunomide. Therefore, no dose adjustment is required in patients with severe renal impairment.

Indications

• Treatment of adult patients with relapsing-remitting multiple sclerosis.

ICD codes

Dosage Regimen

Take the tablet orally once daily.

Swallow the tablet whole with water.

Administer the tablet regardless of meals.

The recommended dose for adult patients is 14 mg daily.

Do not initiate therapy without first excluding pregnancy.

Ensure women of childbearing potential use effective contraception during treatment and until plasma concentrations fall below 0.02 µg/mL.

Perform baseline assessments including blood pressure, ALT, and a complete blood count before starting treatment.

Monitor blood pressure and ALT levels regularly during therapy.

Consider an accelerated elimination procedure with cholestyramine or activated charcoal if rapid drug clearance is required.

Discontinue treatment and initiate accelerated elimination if severe hepatic impairment, severe infection, or significant hematological toxicity occurs.

Use with caution in patients aged 65 years and older due to limited data.

The safety and efficacy in patients under 18 years of age have not been established.

Adverse Reactions

Summary of the safety profile (based on clinical trials)

A total of 2267 patients received teriflunomide in clinical trials (1155 patients received a daily dose of 7 mg, and 1112 patients received a dose of 14 mg). In four placebo-controlled trials (1045 and 1002 patients in the 7 mg and 14 mg teriflunomide groups, respectively) and one active comparator trial (110 patients in each teriflunomide treatment group), the mean duration of teriflunomide use in patients with relapsing-remitting multiple sclerosis (RRMS) was approximately 672 days.

Teriflunomide is the primary metabolite of leflunomide. Information on the safety profile of leflunomide in patients with rheumatoid or psoriatic arthritis may be applicable to teriflunomide taken by patients with multiple sclerosis.

The analysis of pooled data from placebo-controlled trials was based on the experience of once-daily teriflunomide use in 2047 patients with relapsing forms of multiple sclerosis. The following adverse reactions were most frequently reported in patients receiving teriflunomide therapy: headache, diarrhea, increased ALT activity, nausea, and alopecia. Typically, headache, diarrhea, nausea, and alopecia were mild or moderate in severity, transient, and rarely led to treatment discontinuation.

The following are adverse reactions that occurred with teriflunomide at doses of 7 mg and 14 mg with a frequency of ≥1% and at least ≥1% more frequently than with placebo during placebo-controlled trials. Frequency was defined as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency not known (cannot be estimated from the available data).

Infections and infestations common – influenza, upper respiratory tract infections, urinary tract infections, bronchitis, sinusitis, pharyngitis, cystitis, viral gastroenteritis, oral herpes, dental infections, laryngitis, tinea pedis; frequency not known – severe infections, including sepsis (post-marketing experience).

Blood and lymphatic system disorders common – neutropenia, anemia; uncommon – mild thrombocytopenia (platelets <100×10⁹/L).

Immune system disorders common – mild allergic reactions; frequency not known – hypersensitivity reactions (immediate and delayed type), including anaphylaxis and angioedema (post-marketing experience).

Psychiatric disorders common – anxiety.

Nervous system disorders very common – headache; common – paresthesia, lumbosacral radiculopathy, carpal tunnel syndrome; uncommon – hyperesthesia, neuralgia, peripheral neuropathy.

Cardiac disorders common – palpitations, hypertension (see section “Special Precautions”).

Respiratory, thoracic and mediastinal disorders: frequency not known – interstitial lung disease (post-marketing experience).

Gastrointestinal disorders very common – diarrhea, nausea; common – epigastric pain, vomiting, toothache; frequency not known – pancreatitis, stomatitis (aphthous or ulcerative) (post-marketing experience).

Skin and subcutaneous tissue disorders very common – alopecia; common – rash, acne; frequency not known – severe skin reactions, including epidermal necrolysis or Stevens-Johnson syndrome (post-marketing experience).

Musculoskeletal and connective tissue disorders common – musculoskeletal pain, myalgia, arthralgia.

Renal and urinary disorders common – pollakiuria (frequent urination).

Reproductive system and breast disorders common – menorrhagia (heavy menstrual bleeding).

General disorders and administration site conditions common – pain.

Investigations very common – increased ALT (see section “Special Precautions”); common – increased GGT, AST (see section “Special Precautions”), weight decrease, decreased neutrophil count in peripheral blood, decreased white blood cell count in peripheral blood, increased blood CPK activity.

Injury, poisoning and procedural complications uncommon – post-traumatic pain.

Description of selected adverse reactions

Alopecia

Alopecia was described as hair thinning, decreased hair density, hair loss, with or without changes in hair texture in 13.9% of patients taking Teriflunomide 14 mg compared to 5.1% of patients taking placebo. Most cases were described as diffuse or generalized involvement of the entire scalp (without complete hair loss). In most cases, this adverse reaction occurred within the first 6 months, with spontaneous resolution in 121 out of 139 (87.1%) patients. In the teriflunomide group, 1.3% of patients discontinued treatment due to alopecia compared to 0.1% in the placebo group.

Hepatic adverse reactions (data from placebo-controlled trials)

In patient groups receiving Teriflunomide compared to placebo, an increase in ALT activity less than or equal to 3 ULN was observed more frequently. The percentage of patients with ALT elevations above 3 ULN was comparable in both groups. Such increases in ALT activity occurred mainly during the first 6 months of treatment. After discontinuation of treatment, ALT enzyme activity returned to normal. The time to normalization of ALT enzyme activity varied from several months to several years.

Effect on blood pressure (data from placebo-controlled trials)

• Increase in systolic BP above 140 mmHg in 19.9% of patients taking Teriflunomide 14 mg daily, compared to 15.5% with placebo.
• Increase in systolic BP above 160 mmHg in 3.8% of patients taking Teriflunomide 14 mg daily compared to 2.0% with placebo.
• Increase in diastolic BP above 90 mmHg in 21.4% of patients taking Teriflunomide 14 mg daily, compared to 13.6% with placebo.

Infections

In placebo-controlled trials, no increase in the number of severe infections was observed in the teriflunomide 14 mg group (2.7% vs. 2% in the placebo group). Severe opportunistic infections (infections caused by opportunistic pathogens) occurred in 0.2% of cases in each group.

During post-marketing use, severe infections, including sepsis, sometimes fatal, have been observed.

Hematological effects

In placebo-controlled trials, a moderate decrease in peripheral white blood cell count (<15% from baseline, mainly a decrease in neutrophils and lymphocytes) was observed during teriflunomide use. However, some patients experienced a more pronounced decrease in white blood cell count. This adverse reaction occurred within the first 6 weeks. Then, with continued treatment, the peripheral white blood cell count stabilized at a reduced level (<15% decrease from baseline). The effect on the decrease in peripheral red blood cell count (<2%) and peripheral platelet count (<10%) was less pronounced.

Peripheral neuropathy

Peripheral neuropathy (polyneuropathies and mononeuropathies (carpal tunnel syndrome)) developed more frequently in the group of patients taking Teriflunomide 14 mg compared to the group of patients taking placebo in placebo-controlled trials. In the main placebo-controlled trials, peripheral polyneuropathy confirmed by nerve conduction studies was noted in 1.9% of patients (17 out of 898 patients) in the teriflunomide 14 mg group compared to 0.4% of patients (4 out of 898 patients) in the placebo group. Treatment was discontinued in 5 patients with peripheral neuropathy taking Teriflunomide 14 mg; recovery after discontinuation of treatment was reported in 4 of them.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Clinical trials did not record an increased risk of malignant tumors with teriflunomide use. The risk of malignant tumors, namely lymphoproliferative disorders, increases with the use of some other drugs affecting the immune system (class effect).

Contraindications

• Hypersensitivity to the active substance or any of the excipients of the drug;
• Severe hepatic impairment (Child-Pugh class C);
• Pregnancy (pregnancy must be excluded before starting teriflunomide therapy);
• Women of childbearing potential not using reliable methods of contraception during teriflunomide treatment (after completion of teriflunomide treatment, women should not become pregnant until the plasma concentration of teriflunomide remains above 0.02 µg/ml;
• Breastfeeding period;
• Severe immunodeficiency, e.g., AIDS;
• Severe bone marrow hematopoiesis impairment or clinically significant anemia, leukopenia, neutropenia, or thrombocytopenia;
• Severe renal failure requiring hemodialysis (insufficient clinical experience);
• Severe active infections until recovery from them;
• Severe hypoproteinemia (e.g., in nephrotic syndrome);
• Lactase deficiency, galactose intolerance, glucose-galactose malabsorption;
• Age under 18 years.

Use in Pregnancy and Lactation

Pregnancy

Adequate and well-controlled studies on the use of teriflunomide in pregnant women have not been conducted. However, based on studies conducted in animals, Teriflunomide may increase the risk of fetal death and have teratogenic effects when used in pregnant women. Therefore, the use of teriflunomide during pregnancy is contraindicated (see section “Contraindications”).

Based on animal data, minimal risk is expected when the plasma concentration of teriflunomide in humans is less than 0.02 µg/ml. If teriflunomide use must be discontinued, an accelerated elimination procedure for teriflunomide is recommended (see section “Pharmacokinetics”, subsection “Elimination” and section “Special Precautions”).

Women of childbearing age must assess the potential serious risk to the fetus before starting treatment and use effective methods of contraception during teriflunomide treatment and after discontinuation of therapy until the drug concentration in plasma is no more than 0.02 µg/ml (this period is usually 8 months). If menstruation is delayed while taking Teriflunomide, the doctor must be informed immediately and a pregnancy test performed. If the result is positive, the doctor should discuss all risks associated with the use of the drug during pregnancy with the patient and check the residual concentration of teriflunomide. If the concentration exceeds 0.02 mg/L, an accelerated elimination procedure for teriflunomide is recommended.

Women taking Teriflunomide and planning pregnancy should be advised to undergo an accelerated elimination procedure for teriflunomide to rapidly reduce the plasma concentration of teriflunomide. Due to individual variations in the elimination process of teriflunomide, monitoring of teriflunomide plasma concentrations may be required for up to 2 years after discontinuation of therapy. The accelerated elimination procedure for teriflunomide can also be used at any time after discontinuation of Teriflunomide therapy.

Breastfeeding period

Animal studies have demonstrated that Teriflunomide passes into breast milk. It is not known whether Teriflunomide passes into human breast milk.

Since many drugs pass into breast milk, and due to the likelihood of serious adverse reactions in breastfed infants associated with the action of Teriflunomide, a decision should be made either to discontinue breastfeeding or to discontinue the drug, taking into account the mother’s need for the drug.

Fertility

Results from animal studies have not demonstrated any effect of teriflunomide on fertility. Although relevant human data are lacking, an effect on male and female fertility is considered unlikely.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment (Child-Pugh class C).

No dose adjustment is required in patients with mild or moderate hepatic impairment.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal failure requiring hemodialysis.

No dose adjustment is required in patients with mild, moderate, or severe renal impairment not on hemodialysis.

Pediatric Use

The use of the drug is contraindicated under the age of 18 years.

Geriatric Use

The drug should be used with caution in patients aged 65 years and older.

Special Precautions

Treatment should be conducted under the supervision of a physician experienced in the treatment of patients with multiple sclerosis.

Monitoring

The following tests should be performed before starting treatment

• Blood pressure measurement;
• Determination of ALT activity;
• Complete blood count with differential and platelet count in peripheral blood.

During teriflunomide treatment, the following parameters should be regularly monitored

• Blood pressure;
• ALT activity;
• In case of new symptoms and signs (e.g., infections) during treatment, a complete blood count with differential and platelet count in peripheral blood should be performed.

Accelerated elimination procedure for teriflunomide

Teriflunomide is slowly eliminated from plasma: plasma concentrations reach values below 0.02 mg/L on average in 8 months, although due to individual variations in the drug elimination process, elimination may last up to 2 years.

The elimination of teriflunomide can be accelerated using the accelerated elimination procedure for teriflunomide, described in the section “Pharmacokinetics”, subsection “Elimination”, leading to a reduction of more than 98% in the plasma concentration of teriflunomide.

Elderly patients

Teriflunomide should be prescribed with caution to patients aged 65 years and older due to insufficient data on the efficacy and safety of teriflunomide in this age group.

Renal impairment

No dose adjustment is required in patients with mild, moderate, or severe renal impairment not on hemodialysis.

Patients with severe renal impairment on hemodialysis did not participate in clinical trials. This group of patients is contraindicated to take teriflunomide.

Pediatric patients

The safety and efficacy of Teriflunomide in children and adolescents under 18 years of age have not been established.

Hepatic impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment.

Teriflunomide is contraindicated in patients with severe hepatic impairment.

Increased liver enzyme activity was observed in patients taking Teriflunomide. Increases in ALT were mainly noted during the first 6 months of treatment. In half of the cases, the values returned to normal without drug discontinuation. In clinical trials, teriflunomide was discontinued if the increase in ALT activity exceeded 3 times the ULN on two occasions. Serum transaminase activity returned to normal within approximately 2 months after discontinuation of teriflunomide.

Serum transaminase activity and bilirubin concentration should be monitored for 6 months before starting treatment with Teriflunomide. ALT activity should be determined every 2 weeks for 6 months after starting Teriflunomide. The issue of monitoring liver function parameters should also be considered when Teriflunomide is used concomitantly with other potentially hepatotoxic drugs. Discontinuation of Teriflunomide should be considered if confirmed elevation of serum transaminases more than 3 times the ULN occurs. Serum transaminase activity and bilirubin concentration should be monitored during therapy with Teriflunomide, especially in patients who develop symptoms indicative of liver dysfunction such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice and/or dark urine. If liver damage caused by Teriflunomide is suspected, its administration should be discontinued and an accelerated elimination procedure for teriflunomide initiated (see section “Pharmacokinetics”, subsection “Elimination”) with weekly monitoring of liver function parameters until they normalize. If teriflunomide-induced liver damage is unlikely due to the identification of another probable cause, resumption of teriflunomide treatment may be considered.

Teriflunomide should be prescribed with caution to patients who abuse alcohol.

Since Teriflunomide is highly bound to blood proteins, mainly albumin, the concentration of unbound teriflunomide in plasma may increase in patients with hypoproteinemia, e.g., in nephrotic syndrome. Teriflunomide should not be prescribed to patients with severe hypoproteinemia.

Blood pressure

An increase in BP may be noted during teriflunomide use. BP should be checked before starting teriflunomide treatment and periodically thereafter. If BP increases, appropriate antihypertensive therapy should be administered before and during teriflunomide treatment.

Infections

In patients with severe active infections, initiation of teriflunomide treatment should be postponed until complete recovery.

In placebo-controlled trials, no increase in the frequency of severe infections was observed with teriflunomide use. However, given the immunomodulatory effect of Teriflunomide, if a patient develops a severe infection, the necessity of discontinuing treatment with the drug should be considered, and the potential benefits and risks should be assessed before resuming therapy. Due to the long T_1/2 of the drug, the necessity of performing an accelerated elimination procedure for teriflunomide using cholestyramine or activated charcoal should be considered.

Patients taking Teriflunomide should immediately report symptoms of infection to their doctor. Patients with active acute and chronic infections should not start treatment with Teriflunomide until they are completely cured. The use of Teriflunomide is not recommended in cases of severe immunodeficiency, bone marrow disorders, or severe uncontrolled infections.

The safety of Teriflunomide in patients with latent tuberculosis is unknown. Screening for tuberculosis was not systematically performed in clinical studies. Patients with a positive tuberculosis test during screening require appropriate treatment before starting Teriflunomide.

Effect on the Respiratory System

No cases of interstitial lung disorders were observed in clinical studies of teriflunomide. During post-marketing use of teriflunomide, interstitial lung diseases, including acute interstitial pneumonitis, have been observed.

During treatment with leflunomide, whose active metabolite is Teriflunomide, the development of interstitial lung diseases and the exacerbation of pre-existing interstitial lung diseases have been reported. Interstitial lung diseases can develop acutely at any time during treatment and have various clinical manifestations.

Interstitial lung diseases can be fatal.

The development of new or worsening of existing pulmonary symptoms, such as cough and shortness of breath, with or without fever, may be a reason to discontinue therapy and to conduct further appropriate patient examination. If drug discontinuation is necessary, the initiation of an accelerated elimination procedure for teriflunomide should be considered (see the “Pharmacokinetics” section, subsection “Elimination”).

Hematological Effects

In placebo-controlled studies, a decrease in the mean white blood cell count of approximately 15% from baseline (primarily neutrophils and lymphocytes) and a decrease in platelet count of approximately 10% were observed. A complete blood count with differential white blood cell count and platelet count should be performed before starting Teriflunomide therapy and during treatment. Additional monitoring is necessary during Teriflunomide therapy if clinical symptoms and signs indicating an infection appear.

Patients with existing anemia, leukopenia, and/or thrombocytopenia, as well as patients with bone marrow hematopoiesis disorders or those at high risk of bone marrow suppression, have an increased risk of developing hematological disorders when using Teriflunomide. If these adverse reactions occur, the use of an accelerated elimination procedure for teriflunomide should be considered to reduce the plasma concentration of teriflunomide.

In cases of severe hematological reactions, including pancytopenia, the use of Teriflunomide and any other bone marrow-suppressing drug should be discontinued, and an accelerated elimination procedure for teriflunomide should be considered.

Skin Reactions

No cases of severe skin reactions were identified during clinical studies of teriflunomide. Such cases, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been rarely observed during the post-marketing use of the drug.

In patients treated with leflunomide, the parent compound whose main metabolite is Teriflunomide, very rare cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported.

If ulcerative stomatitis occurs, teriflunomide should be discontinued. If skin and/or mucous membrane reactions are suspected to be severe generalized skin reactions (Stevens-Johnson syndrome or toxic epidermal necrolysis/Lyell’s syndrome), teriflunomide and any other drugs potentially causing such reactions should be discontinued, and an accelerated elimination procedure for teriflunomide should be initiated immediately. In such cases, patients should not resume treatment with teriflunomide (see the “Contraindications” section).

Peripheral Neuropathy

Cases of peripheral neuropathy have been observed in patients taking Teriflunomide. After discontinuation of the drug, the condition of most patients improved. However, there was significant variability in the outcome of peripheral neuropathy, i.e., neuropathy resolved in some patients, while the intensity of symptoms remained unchanged in others. If peripheral neuropathy is diagnosed in a patient taking Teriflunomide, discontinuation of Teriflunomide and performance of an accelerated elimination procedure for teriflunomide should be considered.

Vaccination

Two clinical studies showed that vaccination with an inactivated neo-antigen (primary vaccination) or a recall antigen (booster) or a sensitizing antigen (challenge) was safe and effective during treatment with teriflunomide. The use of live attenuated vaccines may be associated with a risk of infection and should therefore be avoided.

Immunosuppressive and Immunomodulatory Therapy

Since leflunomide is the parent compound of teriflunomide, concurrent administration of teriflunomide with leflunomide is not recommended.

Concomitant use of teriflunomide with antineoplastic or immunosuppressive drugs used to treat multiple sclerosis has not been studied. Safety studies in which Teriflunomide was taken concomitantly with interferon beta or glatiramer acetate for up to one year did not reveal any safety concerns. The safety of this combination for long-term use in treating multiple sclerosis has not been studied.

Use in Women of Childbearing Potential/Pregnant Women

Data from animal studies indicate a risk to the fetus. Women of childbearing potential should use effective contraception to prevent pregnancy while taking Teriflunomide. If Teriflunomide therapy is discontinued, women should continue contraception until a confirmed decrease in the plasma concentration of teriflunomide to 0.02 µg/ml or lower is achieved. Women who are planning a pregnancy or are pregnant should be advised to undergo an accelerated elimination procedure for teriflunomide to rapidly reduce the plasma concentration of teriflunomide. Without the accelerated elimination procedure, the time to reach a plasma drug concentration less than or equal to 0.02 µg/ml averages 8 months; however, due to individual differences in the elimination process of teriflunomide, this period can last up to 2 years. The accelerated elimination procedure for teriflunomide can be used at any time after discontinuation of Teriflunomide therapy (see the “Pharmacokinetics” section, subsection “Elimination”).

Use in Men

The risk of embryofetal toxicity associated with teriflunomide treatment in men is considered low.

Switching To or From Teriflunomide

Based on clinical data related to the concomitant use of teriflunomide with interferon beta or glatiramer acetate, there is no need for a waiting period when starting teriflunomide therapy after interferon beta or glatiramer acetate, or when starting interferon beta or glatiramer acetate therapy after teriflunomide therapy.

Due to the long half-life of natalizumab, simultaneous systemic exposure, and therefore simultaneous impact on the immune system, may occur if Teriflunomide therapy is started within 2-3 months after discontinuation of natalizumab. Therefore, precautions should be taken when switching from natalizumab therapy to Teriflunomide.

Considering the half-life of fingolimod, a 6-week therapy-free interval is required for the elimination of circulating substances from the body. It takes 1 to 2 months for lymphocyte counts to return to normal after discontinuation of fingolimod. Starting Teriflunomide treatment within this time interval may lead to simultaneous systemic exposure to fingolimod and teriflunomide. This may result in an additive effect on the immune system. Therefore, precautions should be taken when switching from fingolimod therapy to Teriflunomide therapy.

In patients with multiple sclerosis, the median elimination half-life (T_1/2z) from the body was approximately 19 days during repeated dosing of teriflunomide 14 mg. If a decision is made to discontinue Teriflunomide treatment, starting another therapy within 5 half-lives (approximately 3.5 months, although it may be longer in some patients) will lead to simultaneous systemic exposure with Teriflunomide. This may lead to an additive effect on the immune system, which requires mandatory precautions.

Lactose

Since Teriflunomide tablets contain lactose, patients with galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Effect on Ability to Drive and Use Machines

Teriflunomide has no or negligible influence on the ability to drive and use machines. However, if adverse reactions from the nervous system occur, such as dizziness, driving vehicles and engaging in other potentially hazardous activities should be refrained from.

Overdose

Symptoms

There is no information on overdose or poisoning with teriflunomide in humans. Healthy volunteers took Teriflunomide at a dose of 70 mg daily for 14 days. The observed adverse reactions were consistent with the safety profile of teriflunomide in patients with multiple sclerosis.

Treatment

In case of a significant overdose or poisoning, administration of cholestyramine or activated charcoal is recommended for the accelerated elimination of teriflunomide. The recommended procedure is to take cholestyramine at a dose of 8 g three times a day for 11 days; if this dose is poorly tolerated, the dose of cholestyramine can be reduced to 4 g three times a day. As an alternative, 50 g of activated charcoal can be taken every 12 hours for 11 days.

Drug Interactions

Interactions Related to the Effect of Other Drugs on the Pharmacokinetics of Teriflunomide

The main pathway of teriflunomide biotransformation is hydrolysis; a minor pathway is oxidation, with minimal involvement of cytochrome P450 (CYP) system isoenzymes and flavin-containing monoamine oxidase isoenzymes.

Potent Inducers of Cytochrome P450 (CYP) Isoenzymes

Concomitant daily administration of rifampicin (an inducer of CYP2B6, 2C8, 2C9, 2C19, 3A isoenzymes) at a dose of 600 mg once daily for 22 days, as well as an inducer of efflux transporters P-glycoprotein [P-gp] and Breast Cancer Resistance Protein [BCRP], and teriflunomide (a single dose of 70 mg) led to an approximately 40% reduction in the systemic exposure of teriflunomide. During treatment with teriflunomide, rifampicin and other known inducers of CYP and transporter proteins, such as carbamazepine, phenobarbital, phenytoin, and St. John’s wort, should be prescribed with caution.

Cholestyramine or Activated Charcoal

Concomitant administration of teriflunomide and cholestyramine or activated charcoal is not recommended, as it leads to a rapid and significant decrease in the plasma concentration of teriflunomide, except when accelerated elimination of teriflunomide is necessary. The mechanism of accelerated elimination is believed to be due to the interruption of the enterohepatic recirculation of teriflunomide and/or gastrointestinal dialysis of teriflunomide.

Interactions Related to the Effect of Teriflunomide on the Pharmacokinetics of Other Drugs

Effect of Teriflunomide on CYP2C8 Substrate (Repaglinide)

An increase in the mean C_max and AUC for repaglinide (1.7- and 2.4-fold, respectively) was noted after repeated doses of teriflunomide, suggesting that Teriflunomide is an inhibitor of the CYP2C8 isoenzyme in vivo. Therefore, drugs metabolized by the CYP2C8 isoenzyme, such as repaglinide, paclitaxel, pioglitazone, or rosiglitazone, should be used with caution during teriflunomide treatment.

Effect of Teriflunomide on Oral Contraceptives (0.03 mg Ethinyl Estradiol and 0.15 mg Levonorgestrel)

During repeated dosing of teriflunomide, an increase in the mean C_max and AUC_0-24 for ethinyl estradiol (1.58- and 1.54-fold, respectively) and C_max and AUC_0-24 for levonorgestrel (1.33- and 1.41-fold, respectively) was noted. Although an interaction with teriflunomide is not expected to adversely affect the efficacy of oral contraceptives, it should be taken into account when selecting and adjusting doses of oral contraceptives in combination with teriflunomide.

Effect of Teriflunomide on CYP1A2 Substrate (Caffeine)

Repeated doses of teriflunomide reduced the mean C_max and AUC_0-24 of caffeine (a CYP1A2 substrate) by 18% and 55%, respectively, suggesting that Teriflunomide is a weak inducer of the CYP1A2 isoenzyme in vivo. Therefore, drugs metabolized by the CYP1A2 isoenzyme (such as duloxetine, alosetron, theophylline, and tizanidine) should be used with caution during teriflunomide treatment, as this may lead to reduced efficacy of these drugs.

Effect of Teriflunomide on Warfarin

Repeated doses of teriflunomide did not affect the pharmacokinetics of S-warfarin, indicating that Teriflunomide is not an inhibitor or inducer of the CYP2C9 isoenzyme. However, a 25% decrease in peak INR was noted with the concomitant use of teriflunomide and warfarin compared to warfarin monotherapy. Therefore, careful patient observation and INR monitoring are recommended when warfarin and teriflunomide are used concomitantly.

Effect of Teriflunomide on Organic Anion Transporter 3 (OAT3) Substrates

During course administration of teriflunomide, an increase in C_max and AUC_0-24 (1.43 and 1.54-fold, respectively) of cefaclor was observed, indicating that Teriflunomide is an inhibitor of OAT3 in vivo. Therefore, caution should be exercised when teriflunomide and OAT3 substrates such as cefaclor, benzylpenicillin, ciprofloxacin, indomethacin, ketoprofen, furosemide, cimetidine, methotrexate, and zidovudine are used concomitantly.

Effect of Teriflunomide on BCRP and/or Organic Anion Transporting Polypeptides B1 and B3 (OATP1B1/B3) Substrates

During repeated dosing of teriflunomide, an increase in the mean C_max and AUC_0-24 (2.64- and 2.51-fold, respectively) of rosuvastatin was observed. However, no noticeable effect of this increase in systemic exposure of rosuvastatin in plasma on HMG-CoA reductase activity was observed. A 50% reduction in the dose of rosuvastatin is recommended when taken concomitantly with teriflunomide. Other BCRP substrates (such as methotrexate, topotecan, sulfasalazine, daunorubicin, doxorubicin) and OATP family substrates, especially HMG-CoA reductase inhibitors (such as simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, repaglinide, rifampicin), should be used with caution concomitantly with teriflunomide. Patients should be closely monitored for signs and symptoms of increased systemic exposure to these drugs, and, if necessary, a dose reduction should be considered.

Storage Conditions

The drug should be stored in the original packaging, out of the reach of children, at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.