Pharmacotherapeutic group: immunosuppressants, dihydroorotate dehydrogenase (DHODH) inhibitors, ATC code: L04AK02
Mechanism of action
Teriflunomide is an immunomodulatory agent with anti-inflammatory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), which is functionally linked to the respiratory chain. Through inhibition, teriflunomide generally reduces the proliferation of rapidly dividing cells that are dependent on de novo pyrimidine synthesis for growth. The precise mechanism by which teriflunomide exerts its therapeutic effect in MS is not fully understood, but is based on a reduction in lymphocyte count.
Pharmacodynamic effects
Immune system
Effects on immune cell counts in blood: In placebo-controlled studies, administration of teriflunomide 14 mg once daily led to a mild mean decrease in lymphocyte count of less than 0.3 × 10
9
/L, which occurred during the first 3 months of treatment and levels were maintained until the end of treatment.
Potential for QT interval prolongation
In a placebo-controlled thorough QT study in healthy subjects, teriflunomide at mean steady-state concentrations did not show any potential for QTcF interval prolongation compared to placebo: the largest mean time-matched difference between teriflunomide and placebo was 3.45 ms, with the upper bound of the 90% CI being 6.45 ms.
Effect on renal tubular function
In placebo-controlled studies, mean decreases in serum uric acid levels of 20 to 30% were observed in patients treated with teriflunomide compared to placebo. Mean decrease in serum phosphorus was approximately 10% in the teriflunomide group compared to placebo. These effects are considered to be due to increased renal tubular excretion and should not be associated with changes in glomerular filtration.
Clinical efficacy and safety
The efficacy of teriflunomide was demonstrated in two placebo-controlled studies, TEMSO and TOWER, which evaluated the effect of teriflunomide at doses of 7 mg and 14 mg administered once daily in adult patients with RMS.
In the TEMSO study, a total of 1088 patients with RMS were randomized to the following groups: 7 mg (n=366) or 14 mg (n=359) teriflunomide or placebo (n=363) for 108 weeks. All patients had a definitive diagnosis of MS (McDonald criteria (2001)), exhibited a relapsing clinical course with or without progression, and had experienced at least 1 relapse in the year preceding the study or at least 2 relapses in the 2 years preceding the study. At study entry, patients had an Expanded Disability Status Scale (EDSS) score ≤5.5.
The mean age of the study population was 37.9 years. The majority of patients had relapsing-remitting multiple sclerosis (91.5%), but a subgroup of patients had secondary progressive (4.7%) or progressive relapsing (3.9%) multiple sclerosis. The mean number of relapses in the year prior to study entry was 1.4, with 36.2% of patients having Gd-enhancing lesions on scans at baseline. The median EDSS score was 2.50 at baseline; 249 patients (22.9%) had a baseline EDSS score >3.5. The mean disease duration from first symptoms was 8.7 years. The majority of patients (73%) had not received any disease-modifying therapy during the 2 years prior to study entry. Study results are presented in Table 1.
Subsequent long-term results from the TEMSO long-term safety extension study (overall median treatment duration approximately 5 years, maximum treatment duration approximately 8.5 years) did not reveal any new or unexpected safety findings.
In the TOWER study, a total of 1169 patients with RMS were randomized to the following groups: 7 mg (n=408) or 14 mg (n=372) teriflunomide or placebo (n=389) for a variable treatment duration ending 48 weeks after randomization of the last patient. All patients had a definitive diagnosis of MS (McDonald criteria (2005)), exhibited a relapsing clinical course, with or without progression, and had experienced at least 1 relapse in the year preceding the study or at least 2 relapses in the 2 years preceding the study. At study entry, patients had an EDSS score ≤5.5.
The mean age of the study population was 37.9 years. The majority of patients had relapsing-remitting multiple sclerosis (97.5%), but a subgroup of patients had secondary progressive (0.8%) or progressive relapsing (1.7%) multiple sclerosis. The mean number of relapses in the year prior to study entry was 1.4. Data on Gd-enhancing lesions are not available. At baseline, the median EDSS score was 2.50; 298 patients (25.5%) had a baseline EDSS score >3.5. The mean disease duration from first symptoms was 8.0 years. The majority of patients (67.2%) had not received any disease-modifying therapy during the 2 years prior to study entry. Study results are presented in Table 1.
Table 1 – Main results (for the approved dose, ITT population)
TEMSO Study
TOWER Study
Teriflunomide 14 mg
Placebo
Teriflunomide 14 mg
Placebo
n
358
363
370
388
Clinical endpoints
Annualised relapse rate
0.37
0.54
0.32
0.50
Risk difference (95% CI)
-0.17 (-0.26; -0.08)***
-0.18 (-0.27; -0.09)****
Relapse-free at week 108
56.5%
45.6%
57.1%
46.8%
Hazard ratio (95% CI)
0.72, (0.58; 0.89)**
0.63, (0.50; 0.79)****
3-month confirmed
disability progression
week 108
20.2%
27.3%
15.8%
19.7%
Hazard ratio (95% CI)
0.70 (0.51; 0.97)*
0.68 (0.47; 1.00)*
6-month confirmed
disability progression
week 108
13.8%
18.7%
11.7%
11.9%
Hazard ratio (95% CI)
0.75 (0.50; 1.11)
0.84 (0.53; 1.33)
MRI endpoints
Not measured
Change in BOD at week 108
(1)
0.72
2.21
Change versus placebo
67%***
Mean number of Gd-enhancing lesions at week 108
0.38
1.18
Change versus placebo (95% CI)
-0.80 (-1.20; -0.39)****
Number of unique active lesions/scan
0.75
2.46
Change versus placebo (95% CI)
69%, (59%; 77%)****
****p<0.0001 *** p<0.001 ** p<0.01 * p<0.05 compared to placebo
(1) BOD: burden of disease: total lesion volume (T2 and T1 hypointense) in mL
Efficacy in patients with high disease activity:
In the TEMSO study, a consistent treatment effect on relapses and time to 3-month confirmed disability progression was observed in the subgroup of patients with high disease activity (n=127). Based on the study design, high disease activity was defined as 2 or more relapses during one year and one or more Gd-enhancing lesions on brain MRI. A similar subgroup analysis was not performed in the TOWER study, therefore MRI data are not available.
No data are available from patients who did not complete a full and adequate course of interferon beta treatment (usually at least one year of treatment), who had at least one relapse during the previous year while on treatment and at least 9 T2 hyperintense lesions on brain MRI or at least 1 Gd-enhancing lesion, or who had an unchanged or increased relapse rate in the previous year compared with the previous 2 years.
The TOPIC study is a double-blind, placebo-controlled study evaluating teriflunomide doses of 7 mg and 14 mg once daily for up to 108 weeks in patients with a first demyelinating event (mean age 32.1 years). The primary endpoint was time to a second clinical episode (to relapse). A total of 618 patients were randomized to the following groups: 7 mg (n=205) or 14 mg (n=216) teriflunomide or placebo (n=197). The risk of a second clinical episode after more than 2 years was 35.9% in the placebo group and 24.0% in the teriflunomide 14 mg group (hazard ratio: 0.57; 95% confidence interval: 0.38 to 0.87; p=0.0087). Results from the TOPIC study confirm the efficacy of teriflunomide in RRMS (including early RRMS with a first clinical demyelinating event and MRI lesions disseminated in time and space).
The efficacy of teriflunomide compared to subcutaneous interferon beta-1a (at the recommended dose of 44 µg three times weekly) was compared in a study (TENERE) involving 324 randomized patients, with a minimum treatment duration of 48 weeks (maximum 114 weeks). The primary endpoint was risk of treatment failure (confirmed relapse or permanent treatment discontinuation, whichever occurred first). In the teriflunomide 14 mg group, treatment was permanently discontinued in 22 of 111 patients (19.8%), due to adverse events (10.8%), lack of efficacy (3.6%), other reasons (4.5%), or incomplete post-treatment follow-up (0.9%). In the subcutaneous interferon beta-1a group, treatment was permanently discontinued in 30 of 104 patients (28.8%), due to adverse events (21.2%), lack of efficacy (1.9%), other reasons (4.8%), or non-compliance with the study protocol (1%). Teriflunomide 14 mg daily did not achieve statistically significantly higher results than interferon beta-1a for the primary endpoint: the estimated percentage of patients with treatment failure at week 96 using the Kaplan-Meier method was 41.1% compared to 44.4% (teriflunomide 14 mg group versus interferon beta-1a group, p=0.595).
Paediatric population
Children and adolescents (aged 10 to 17 years)
Study EFC11759/TERIKIDS was an international, double-blind, placebo-controlled study in paediatric patients aged 10 to 17 years with relapsing-remitting MS, evaluating teriflunomide doses administered once daily (adjusted to achieve exposure equivalent to the 14 mg dose in adults) for up to 96 weeks with a subsequent open-label extension. All patients had experienced at least 1 relapse within 1 year or at least 2 relapses within 2 years before study entry. Neurological assessments were performed at screening and every 24 weeks until termination and at unscheduled visits for suspected relapse. Patients with clinical relapse or high MRI activity with at least 5 new or enlarging T2 lesions on 2 consecutive scans were switched before week 96 to the subsequent open-label extension to ensure active treatment. The primary endpoint was time to first clinical relapse after randomization. Time to first confirmed clinical relapse or high MRI activity, whichever occurred first, was predefined as a sensitivity analysis because it includes both clinical and MRI conditions permitting switch to the open-label phase.
A total of 166 patients were randomized in a 2:1 ratio to receive teriflunomide (n=109) or placebo (n=57). At study entry, patients had an EDSS score ≤5.5; mean age was 14.6 years; mean body weight was 58.1 kg; mean disease duration since diagnosis was 1.4 years; and the mean number of T1 Gd-enhancing lesions on MRI was 3.9 lesions at treatment initiation. All patients had relapsing-remitting MS with a median EDSS score of 1.5 at treatment initiation. The mean treatment duration with placebo was 362 days and with teriflunomide was 488 days. Switch from the double-blind phase to the open-label treatment phase due to high MRI activity was more frequent than expected and even more frequent and earlier in the placebo group than in the teriflunomide group (26% for placebo, 13% for teriflunomide).
Teriflunomide reduced the risk of clinical relapse by 34% compared to placebo, without reaching statistical significance (p=0.29) (Table 2). In the predefined sensitivity analysis, teriflunomide achieved a statistically significant 43% reduction in the combined risk of clinical relapse or high MRI activity compared to placebo (p=0.04) (Table 2).
Teriflunomide significantly reduced the number of new and enlarging T2 lesions per scan by 55% (p=0.0006) (post-hoc analysis also adjusted for baseline T2 count: 34%, p=0.0446) and the number of T1 Gd-enhancing lesions per scan by 75% (p<0.0001) (Table 2).
Table 2 – Clinical and MRI results in EFC11759/TERIKIDS
EFC11759 ITT population
Teriflunomide (n=109)
Placebo (n=57)
Clinical endpoints
Time to first confirmed clinical relapse
Probability (95% CI) of confirmed relapse at week 96
0.39 (0.29; 0.48)
0.53 (0.36; 0.68)
Probability (95% CI) of confirmed relapse at week 48
0.30 (0.21; 0.39)
0.39 (0.30; 0.52)
Hazard ratio (95% CI)
0.66 (0.39; 1.11)^
Time to first confirmed clinical relapse or high MRI activity
Probability (95% CI) of confirmed relapse or high MRI activity at week 96
0.51 (0.41; 0.60)
0.72 (0.58; 0.82)
Probability (95% CI) of confirmed relapse or high MRI activity at week 48
0.38 (0.29; 0.47)
0.56 (0.42; 0.68)
Hazard ratio (95% CI)
0.57 (0.37;
0.87)*
Key MRI endpoints
Adjusted number of new or enlarged T2 lesions,
Estimate (95% CI)
4.74 (2.12; 10.57)
10.52 (4.71; 23.50)
Estimate (95% CI), post-hoc analysis also adjusted for baseline T2 count
3.57 (1.97;
6.46)
5.37 (2.84; 10.16)
Relative risk (95% CI)
0.45 (0.29; 0.71)**
Relative risk (95% CI), post-hoc analysis also adjusted for baseline T2 count
0.67 (0.45;
0.99)*
Adjusted number of T1 Gd-enhancing lesions, Estimate (95% CI)
1.90 (0.66; 5.49)
7.51 (2.48; 22.70)
Relative risk (95% CI)
0.25 (0.13; 0.51)***
^p≥0.05 compared to placebo, * p<0.05, ** p<0.001, *** p<0.0001 Probability is based on the Kaplan-Meier estimate and week 96 was the end of treatment (EOT).
The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicinal product containing teriflunomide in children from birth to 10 years in the treatment of multiple sclerosis (see section
4.2
for information on paediatric use).
⚠️ Warnings
Monitoring
Before treatment
Before initiating treatment with teriflunomide, the following should be assessed:
blood pressure
alanine aminotransferase/serum glutamate-pyruvate aminotransferase (ALT/SGPT)
complete blood count including differential white blood cell count and platelet count.
During treatment
During treatment with teriflunomide, the following should be monitored:
blood pressure
monitor regularly
alanine aminotransferase/serum glutamate-pyruvate transaminase (ALT/SGPT)
Hepatic enzyme levels should be checked at least every four weeks during the first 6 months of treatment and regularly thereafter.
Consider additional monitoring if teriflunomide is administered to patients with pre-existing hepatic impairment together with other potentially hepatotoxic medicinal products or if clinically indicated based on signs and symptoms such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia or jaundice and/or dark urine. Hepatic enzyme levels must be checked every two weeks during the first 6 months of treatment and at least every 8 weeks thereafter, for at least 2 years from the start of treatment.
If ALT (SGPT) elevation is between 2 and 3 times the upper limit of normal, monitoring must be performed weekly.
complete blood count based on clinical signs and symptoms (e.g. infections) occurring during treatment.
Accelerated elimination
Teriflunomide is slowly eliminated from plasma. Without an accelerated elimination procedure, it takes an average of 8 months to reach plasma concentrations lower than 0.02 mg/L. Due to individual variations in clearance, this process may take up to 2 years. An accelerated elimination procedure can be used at any time after discontinuation of teriflunomide treatment (the detailed procedure is described in sections 4.6 and 5.2).
Hepatic effects
Elevated liver enzymes have been observed in patients treated with teriflunomide (see section
4.8
). These elevations mostly occurred during the first 6 months from treatment initiation.
Cases of drug-induced liver injury (DILI), sometimes life-threatening, have been observed during treatment with teriflunomide. Most cases of DILI occurred within weeks or months after initiation of teriflunomide treatment; however, DILI may also occur after long-term use.
The risk of elevated liver enzymes and DILI with teriflunomide may be increased in patients with pre-existing hepatic impairment, those concomitantly treated with other hepatotoxic medicinal products and/or those consuming large amounts of alcohol. These patients should therefore be carefully monitored for signs and symptoms of liver injury.
If liver injury is suspected, teriflunomide treatment must be discontinued and accelerated elimination should be considered. If confirmed elevation of liver enzymes (more than 3 times ULN) occurs, teriflunomide treatment should be discontinued.
If teriflunomide is discontinued, liver function tests should be performed until aminotransferase levels have normalized.
Hypoproteinaemia
Since teriflunomide is highly protein bound and binding is dependent on albumin concentrations, higher concentrations of unbound plasma teriflunomide are expected in patients with hypoproteinaemia (e.g. nephrotic syndrome). Teriflunomide should not be used in patients with severe hypoproteinaemia.
Blood pressure
Blood pressure may increase during treatment with teriflunomide (see section
4.8
). Blood pressure must be checked before initiating teriflunomide treatment and regularly thereafter during treatment. Elevated blood pressure should be appropriately managed before and during teriflunomide treatment.
Infections
Initiation of teriflunomide treatment must be delayed in patients with severe active infection until resolution. No increase in the incidence of serious infections was observed in the teriflunomide group in placebo-controlled studies (see section
4.8
).
Cases of herpes virus infections have been reported with teriflunomide, including oral herpes and herpes zoster (see section
4.8
), some of which were serious, including herpes meningoencephalitis and disseminated herpes. These may occur at any time during treatment. If a patient develops any serious infection, suspension of teriflunomide treatment should be considered due to its immunomodulatory effect, and the benefit-risk balance for the individual patient should be reassessed before restarting treatment. Given the long elimination half-life, accelerated elimination with cholestyramine or activated charcoal may be considered.
Patients receiving teriflunomide must be instructed to report all symptoms of infection to their physician. Patients with active acute or chronic infections should not initiate teriflunomide treatment until the infection has resolved.
The safety of teriflunomide in individuals with latent tuberculosis infection is not known, as tuberculosis screening was not systematically performed in clinical studies. Patients testing positive for tuberculosis on screening should be treated according to standard practice before initiating teriflunomide treatment.
Respiratory reactions
Cases of interstitial lung disease (ILD) and pulmonary hypertension associated with teriflunomide have been reported in the post-marketing setting.
The risk of ILD may be increased in patients with a history of ILD.
ILD may occur acutely at any time during treatment with variable clinical presentation.
ILD may be fatal. New onset or worsening of pulmonary symptoms, such as persistent cough or dyspnoea, may be a reason for treatment discontinuation and further investigation depending on the specific situation. If discontinuation of the medicinal product is necessary, initiation of accelerated elimination should be considered.
Haematological effects
A mild decrease in white blood cell count of less than 15% from baseline values has been observed (see section
4.8
). As a precautionary measure, a recent complete blood count, including differential white blood cell count and platelet count, must be available before initiating treatment. The complete blood count should also be monitored during treatment based on clinical signs and symptoms (e.g. infections).
Patients with pre-existing anaemia, leucopenia and/or thrombocytopenia and patients with impaired bone marrow function or patients at risk of bone marrow suppression are at increased risk of developing haematological disorders. If such complications occur, the use of accelerated elimination (see above) should be considered to reduce plasma levels of teriflunomide.
In the case of serious haematological reactions including pancytopenia, teriflunomide treatment and all concomitant myelosuppressive therapy must be discontinued and accelerated elimination of teriflunomide should be considered.
Skin reactions
Cases of severe skin reactions, sometimes fatal, have been reported with teriflunomide, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS).
If skin and/or mucosal reactions (ulcerative stomatitis) occur that raise suspicion of severe generalized skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis – Lyell's syndrome or drug reaction with eosinophilia and systemic symptoms), teriflunomide and any other possibly related therapy must be discontinued and an accelerated elimination procedure must be initiated immediately. In such cases, patients must not be re-exposed to teriflunomide (see section
4.3
).
New onset of psoriasis (including pustular psoriasis) and worsening of pre-existing psoriasis have been reported during use of teriflunomide. Taking into account the patient's disease and medical history, discontinuation of treatment and initiation of accelerated elimination may be considered.
Peripheral neuropathy
Cases of peripheral neuropathy have been reported in patients treated with teriflunomide (see section
4.8
). The condition of most patients improved after discontinuation of teriflunomide treatment. However, the overall outcome was highly variable, i.e. in some patients the neuropathy resolved and in some, symptoms persisted. If a patient receiving teriflunomide develops confirmed peripheral neuropathy, discontinuation of teriflunomide treatment and accelerated elimination should be considered.
Vaccination
Two clinical studies showed that vaccination with an inactivated neoantigen (first vaccination) or a recall antigen (re-exposure) was safe and effective during teriflunomide treatment. The use of live attenuated vaccines is associated with a risk of infection and should therefore be avoided.
Immunosuppressive or immunomodulatory therapy
Since leflunomide is the parent compound of teriflunomide, concomitant use of teriflunomide with leflunomide is not recommended.
Combined use with antineoplastic or immunosuppressive therapy for the treatment of MS has not been evaluated. Safety studies in which teriflunomide was administered concomitantly with interferon beta or glatiramer acetate for up to one year did not reveal any specific safety concerns. However, the frequency of adverse events was higher compared to teriflunomide monotherapy. The long-term safety of these combinations in the treatment of multiple sclerosis has not been established.
Switching to teriflunomide or switching to another treatment
Based on clinical data associated with concomitant administration of teriflunomide with interferon beta or glatiramer acetate, no washout period is required when initiating teriflunomide treatment after switching from interferon beta or glatiramer acetate, or when initiating interferon beta or glatiramer acetate after switching from teriflunomide.
Due to the long half-life of natalizumab, concomitant exposure and therefore concomitant immune effects may occur if teriflunomide treatment is started immediately within 2–3 months of discontinuing natalizumab. Caution is therefore required when switching patients from natalizumab to teriflunomide.
Based on the half-life of fingolimod, a 6-week washout period is required to eliminate the product from the circulation. Lymphocytes return to the normal range 1 to 2 months after discontinuation of fingolimod. Initiating teriflunomide treatment during this period may result in concomitant exposure to fingolimod. This may have an additive effect on the immune system, and therefore caution is required.
In patients with MS, the median t1/2z was approximately 19 days after repeated dosing of 14 mg. If a decision is made to discontinue teriflunomide, initiation of another therapy within 5 half-lives (approximately 3.5 months, possibly longer in some patients) may result in concomitant exposure to teriflunomide. This may have an additive effect on the immune system, and therefore caution is required.
Interference with ionized calcium measurements
Measurement of ionized calcium levels during treatment with leflunomide and/or teriflunomide (the active metabolite of leflunomide) may yield falsely low values depending on the type of ionized calcium analyzer used (e.g. blood gas analyzer). Therefore, observed decreases in ionized calcium levels in patients undergoing treatment with leflunomide or teriflunomide should be interpreted with caution. In case of uncertainty regarding measured values, determination of total serum calcium concentration corrected for serum albumin is recommended.
Paediatric population
Pancreatitis
In the paediatric clinical study, cases of pancreatitis, some acute, were observed in patients receiving teriflunomide (see section
4.8
). Clinical symptoms included abdominal pain, nausea and/or vomiting. Elevated serum amylase and lipase levels were observed in these patients. Time to onset ranged from several months to three years. Patients must be informed about the characteristic symptoms of pancreatitis. If pancreatitis is suspected, pancreatic enzyme levels and related laboratory parameters must be determined. If pancreatitis is confirmed, teriflunomide treatment must be discontinued and accelerated elimination initiated (see section
5.2
).
Lactose
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Sodium
This medicinal product contains less than 1 mmol (23 mg) sodium per tablet, that is to say essentially 'sodium-free'.
