Aubagio film-coated tablets 14 mg blister No. 28

Instructions for use Aubagio film-coated tablets 14 mg blister No. 28

Composition

active ingredient: teriflunomide;

1 film-coated tablet contains teriflunomide 14 mg;

Excipients: tablet core: lactose monohydrate, corn starch, hydroxypropylcellulose, microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate; tablet shell: hypromellose, titanium dioxide (E 171), talc, macrogol, indigo carmine (E 132).

Dosage form

Film-coated tablets.

Main physicochemical properties: pale blue pentagonal tablets, film-coated, with an imprint of the active substance content in the form of the number "14" on one side and an engraved corporate logo on the other.

Pharmacotherapeutic group

Selective immunosuppressants. Teriflunomide.

ATX code L04A A31.

Pharmacological properties

Pharmacodynamics.

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 required for de novo pyrimidine synthesis. As a result, teriflunomide reduces the proliferation of dividing cells that require de novo pyrimidine synthesis for their development. The precise mechanism by which teriflunomide exerts its therapeutic effect in multiple sclerosis (MS) is not fully understood, but it is mediated by a reduction in the number of lymphocytes.

Pharmacodynamic effects.

Immune system: Effects on blood immunocompetent cell counts: In placebo-controlled studies, teriflunomide 14 mg once daily caused a mild decrease in lymphocyte counts—on average less than 0.3 × 109/L—during the first 3 months of treatment, after which this level was maintained until the end of treatment.

Potential for QT prolongation: In a placebo-controlled comprehensive QT study in healthy volunteers, teriflunomide at steady-state had no potential to prolong the QTcF interval compared to placebo: the largest difference between the mean teriflunomide and placebo mean at the respective time points was 3.45 ms with an upper 90% CI of 6.45 ms.

Effects on renal tubular function. In placebo-controlled studies, patients treated with teriflunomide had a mean reduction in serum uric acid of 20% to 30% compared with those treated with placebo. The mean reduction in serum phosphorus was approximately 10% in the teriflunomide group compared with placebo. These effects are considered to be related to increased renal tubular excretion and not to changes in glomerular function.

Clinical efficacy and safety.

The efficacy of Aubagio® was demonstrated in two placebo-controlled studies, TEMSO and TOWER, which evaluated teriflunomide at doses of 7 mg and 14 mg once daily in patients with relapsing multiple sclerosis (RMS).

In the TEMSO study, a total of 1088 patients with MS were randomized to receive either teriflunomide 7 mg (n = 366) or 14 mg (n = 359) or placebo (n = 363) for 108 weeks. All patients had a confirmed diagnosis of MS (based on the McDonald criteria, 2001) with a relapsing clinical course, with or without progression, and had at least 1 relapse in the year preceding the study or at least 2 relapses in the 2 years preceding the study. At the time of study entry, patients had an Expanded Disability Status Scale (EDSS) score ≤ 5.5. The mean age of the study participants was 37.9 years. The majority of patients had relapsing-remitting multiple sclerosis (91.5%), but a small subset of patients had secondary-progressive (4.7%) or progressive relapsing multiple sclerosis (3.9%). The median number of relapses during the year prior to study entry was 1.4, with 36.2% of patients having gadolinium-enhancing lesions at baseline. The median EDSS score at baseline was 2.50, with 249 patients (22.9%) having an EDSS score >3.5 at baseline. The median duration of disease from the time of first symptoms was 8.7 years. The majority of patients (73%) had not received disease-modifying drugs for multiple sclerosis for 2 years prior to study entry. The results of the study are shown in Table 1.

The mean age of the study participants was 37.9 years. The majority of patients had relapsing-remitting multiple sclerosis (97.5%), but a small subset of patients had secondary-progressive (0.8%) or progressive relapsing multiple sclerosis (1.7%). The mean number of relapses during the year prior to study entry was 1.4. No data were available on the presence of gadolinium-enhancing lesions at baseline. The median EDSS score at baseline was 2.50, with 298 patients (25.5%) having an EDSS score of >3.5 at baseline. The mean duration of disease from the time of onset of symptoms was 8 years. The majority of patients (67.2%) had not received a disease-modifying drug for multiple sclerosis in the 2 years prior to study entry. The results of the study are shown in Table 1.

Table 1

Key results for the approved dose (data for the population of patients who were randomized and received at least one dose of the drug [ITT])

**** p < 0.0001 *** p < 0.001 ** p < 0.01 * p < 0.05 compared to placebo

1TS — disease severity: total volume of lesions (T2 and T1, hypointense) in milliliters.

Effectiveness of therapy in patients with high disease activity

In the TEMSO study, a consistent treatment effect was observed on relapse rate and sustained disability progression at 3 months in the subgroup of patients with high disease activity (n = 127). According to the study design, high disease activity was defined as 2 or more relapses within 1 year with 1 or more gadolinium-enhancing lesions on brain MRI. Similar subgroup analyses were not performed in the TOWER study because MRI data were not available in this study. There are no data on the number of patients who did not respond to a full and adequate course of beta interferon therapy (usually at least 1 year of treatment), who had at least 1 relapse during the previous year on treatment, and who had at least 9 T2-hypointense lesions or at least 1 gadolinium-enhancing lesion on brain MRI, or on the number of patients whose relapse rate during the year preceding the study was unchanged or increased compared to the previous 2 years.

The efficacy of teriflunomide was compared with that of subcutaneous interferon beta-1a (at the recommended dose of 44 mcg three times a week) in 324 randomised patients in the TENERE study with a minimum treatment duration of 48 weeks (maximum 114 weeks). The primary endpoint was the risk of treatment failure (confirmed relapse or permanent discontinuation of study drug, whichever occurred first). The number of patients who permanently discontinued study drug in the teriflunomide 14 mg group was 22 of 111 patients (19.8%), and the reasons for this were adverse reactions (10.8%), lack of efficacy (3.6%), other reasons (4.5%), and inability to follow up (0.9%). The number of patients who permanently discontinued study drug in the subcutaneous interferon beta-1a group was 30 of 104 patients (28.8%), and the reasons for this were adverse reactions (21.2%), lack of efficacy (1.9%), other reasons (4.8%), and poor compliance with the study protocol (1%). Teriflunomide 14 mg/day was not superior to interferon beta-1a for the primary endpoint: the percentage of patients with treatment failure at 96 weeks, calculated by the Kaplan-Meier method, was 41.1% versus 44.4% (teriflunomide 14 mg versus interferon beta-1a, p = 0.5953).

Pediatric population.

The European Medicines Agency has waived the obligation to submit the results of studies with Aubagio® in children aged from birth to less than 10 years for the treatment of multiple sclerosis (for information on the use of the drug in children, see section 4.2). The European Medicines Agency has deferred the obligation to submit the results of studies with Aubagio® in one or more subsets of the paediatric population for the treatment of multiple sclerosis (for information on the use of the drug in children, see section 4.2).

Pharmacokinetics.

Absorption.

The median time to peak plasma concentrations after multiple oral doses of teriflunomide is 1 to 4 hours post-dose; bioavailability is high (approximately 100%).

Food has no clinically significant effect on the pharmacokinetics of teriflunomide.

Based on the mean predicted pharmacokinetic parameters calculated from the results of a population pharmacokinetic analysis (PKPA) using data from healthy volunteers and MS patients, steady-state drug concentrations are achieved slowly (approximately 100 days, 3.5 months, to reach 95% of steady-state concentrations), and the calculated AUC accumulation ratio is approximately 34.

Distribution.

Teriflunomide is highly bound to plasma proteins (>99%), presumably albumin, and is distributed primarily in plasma. The volume of distribution after a single intravenous dose is 11 L. However, this level is likely an underestimate, as extensive organ distribution was observed in rats.

Biotransformation

Teriflunomide is moderately metabolized and is the only compound detected in plasma. The major biotransformation pathway of teriflunomide is hydrolysis; oxidation is a minor pathway. Minor metabolic pathways include oxidation, N-acetylation, and sulfate conjugation.

Elimination.

Teriflunomide is excreted in the gastrointestinal tract primarily in the bile as unchanged drug, most likely by direct secretion. Teriflunomide is a substrate for the efflux transporter BCRP, which may participate in direct secretion. Over the 21st day, 60.1% of the administered dose is excreted in the feces (37.5%) and urine (22.6%). After a rapid elimination procedure using cholestyramine, another 23.1% is excreted (mainly in the feces). Based on the results of individual pharmacokinetic prediction using the Teriflunomide PopPK model, the median terminal elimination half-life (t1/2z) was approximately 19 days after multiple doses of 14 mg in healthy volunteers and MS patients. After a single intravenous dose, the total clearance of teriflunomide is 30.5 ml/h.

Teriflunomide elimination from the circulation can be accelerated by the administration of cholestyramine or activated charcoal, which are thought to block intestinal reabsorption. Teriflunomide concentrations determined during an 11-day teriflunomide elimination regimen with 8 g cholestyramine three times daily, 4 g cholestyramine three times daily, or 50 g activated charcoal twice daily after teriflunomide treatment was discontinued demonstrated the efficacy of these regimens in accelerating teriflunomide elimination, resulting in a greater than 98% reduction in teriflunomide plasma concentrations, with cholestyramine acting more rapidly than activated charcoal. After teriflunomide was discontinued and cholestyramine 8 g three times daily was administered, teriflunomide plasma concentrations decreased by 52% at the end of day 1, 91% at the end of day 3, 99.2% at the end of day 7, and 99.9% at the end of day 11. The choice of one of these three procedures for accelerating drug elimination is determined by the patient's tolerability. If cholestyramine 8 g three times daily is poorly tolerated, cholestyramine 4 g three times daily may be administered. Activated charcoal may also be used as an alternative (these 11 days do not have to be consecutive unless a rapid decrease in teriflunomide plasma concentrations is required).

Linearity/nonlinearity.

Systemic exposure after oral administration of teriflunomide at doses from 7 to 14 mg increases proportionally to the dose.

Characteristics in individual patient groups.

Male/Female, Elderly, Pediatric. Several individual factors contributing to the pharmacokinetic variability of the drug were identified in the PopPK analysis in healthy volunteers and MS patients: age, body weight, gender, race, and albumin and bilirubin levels. However, the impact of these factors on the pharmacokinetics of the drug remains limited (≤ 31%).

Hepatic impairment. Mild to moderate hepatic impairment does not affect the pharmacokinetics of teriflunomide. Therefore, no dose adjustment is recommended for patients with mild to moderate hepatic impairment. However, teriflunomide is contraindicated in patients with severe hepatic dysfunction (see sections 4.2 and 4.3).

Renal impairment: Severe renal impairment does not affect the pharmacokinetics of teriflunomide. Therefore, no dose adjustment is recommended for patients with mild, moderate, or severe renal impairment.

Preclinical safety data. Following repeated oral administration of teriflunomide to mice, rats and dogs for up to 3, 6 and 12 months, respectively, the main target organs of toxicity were the red bone marrow, lymphoid organs, oral cavity/gastrointestinal tract, reproductive organs and pancreas. Signs of oxidative effects on erythrocytes were also observed. Anaemia, decreased platelet count and immune system effects including leukopenia, lymphopenia and secondary infections were associated with effects on the red bone marrow and/or lymphoid organs. Most of the effects reflect the primary mechanism of action of the compound (inhibition of cell division). Animals are more sensitive to the pharmacological and, consequently, toxic effects of teriflunomide than humans. As a result, toxic effects of the drug in animals were observed at exposure levels equivalent to or lower than those in humans at therapeutic doses.

Teriflunomide was not mutagenic in vitro or clastogenic in vivo. The clastogenicity observed in vitro was considered to be an indirect effect related to the imbalance of the nucleotide pool due to the pharmacological effects of DHO-DH inhibition. The minor metabolite TFMA (4-trifluoromethylaniline) was mutagenic and clastogenic in vitro but not in vivo.

No signs of carcinogenicity of the drug were detected in rats and mice.

Fertility in rats was not affected, despite adverse effects of teriflunomide on male reproductive organs, including decreased sperm count. No external malformations were observed in the offspring of male rats administered teriflunomide prior to mating with intact females. Teriflunomide was embryotoxic in rats and rabbits at doses within the human therapeutic range. Teriflunomide was also embryotoxic in rats and rabbits when administered to pregnant rats during gestation and lactation. The risk of embryofetal toxicity resulting from paternal exposure to teriflunomide is considered low. The estimated plasma exposure in females from transmission through the family of a patient receiving teriflunomide is expected to be 100-fold lower than the plasma exposure following oral administration of 14 mg teriflunomide.

Indication

Aubagio® is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis (MS) (see Pharmacodynamics for important information on the patient population for which efficacy has been established).

Contraindication

Hypersensitivity to the active substance or to any of the excipients listed in the "Composition" section.

Pregnancy: Women of childbearing potential should use reliable methods of contraception during and after teriflunomide treatment as long as plasma levels remain above 0.02 mg/L (see section 4.6). Pregnancy should be excluded before initiating treatment (see section 4.6).

Breastfeeding (see section "Use during pregnancy or breastfeeding").

Severe immunodeficiency conditions, such as acquired immunodeficiency syndrome (AIDS).

Significant red bone marrow dysfunction or significant anemia, leukopenia, neutropenia, or thrombocytopenia.

Severe active infection, until recovery (see section "Special instructions").

Severe renal impairment requiring dialysis, as clinical experience with the drug in such circumstances is currently insufficient.

Severe hypoproteinemia, for example, in nephrotic syndrome.

Interaction with other medicinal products and other types of interactions

Pharmacokinetic interaction effects of other substances on teriflunomide.

The main biotransformation pathway of teriflunomide is hydrolysis, with oxidation being a less significant pathway.

Potent inducers of cytochrome P450 (CYP) and transporters. Co-administration of multiple doses (600 mg once daily for 22 days) of rifampicin (an inducer of CYP2B6, 2C8, 2C9, 2C19, 3A), which is also an inducer of the efflux transporters P-glycoprotein [P-gp] and breast cancer resistant protein [BCRP], with teriflunomide (single dose of 70 mg) resulted in an approximately 40% decrease in teriflunomide exposure. Rifampicin and other known potent inducers of CYP and transporters, such as carbamazepine, phenobarbital, phenytoin, and St. John's wort, should be used with caution during treatment with teriflunomide.

Cholestyramine or activated charcoal: It is recommended that patients receiving teriflunomide not be given cholestyramine or activated charcoal as this results in a rapid and substantial decrease in plasma concentrations of teriflunomide, unless accelerated elimination is desired. The mechanism of this effect is thought to be due to inhibition of enterohepatic recirculation of teriflunomide and/or gastrointestinal dialysis of teriflunomide.

Pharmacokinetic interaction-induced effects of teriflunomide on other substances.

Effect of teriflunomide on CYP2C8 substrates: repaglinide. After multiple doses of teriflunomide, an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively) was observed, indicating an inhibitory effect of teriflunomide on CYP2C8 in vivo. Therefore, medicinal products metabolised by CYP2C8, such as repaglinide, paclitaxel, pioglitazone or rosiglitazone, should be used with caution during treatment with teriflunomide.

Effect of teriflunomide on oral contraceptives: 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel. After multiple doses of teriflunomide, mean Cmax and AUC0-24 of ethinyl estradiol were increased (1.58- and 1.54-fold, respectively) and Cmax and AUC0-24 of levonorgestrel (1.33- and 1.41-fold, respectively). Although this interaction with teriflunomide is not expected to have an adverse effect on the efficacy of oral contraceptives, it should be considered when choosing an oral contraceptive or adjusting its dose when used in combination with teriflunomide.

Effect of teriflunomide on CYP1A2 substrate: caffeine. After multiple doses of teriflunomide, mean Cmax and AUC of caffeine (a CYP1A2 substrate) were decreased by 18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2 in vivo. Therefore, medicinal products metabolised by CYP1A2 (such as duloxetine, alosetron, theophylline and tizanidine) should be used with caution during treatment with teriflunomide as teriflunomide may reduce the efficacy of these medicinal products.

Effect of teriflunomide on warfarin. There was no effect on the pharmacokinetics of S-warfarin after multiple doses of teriflunomide, indicating that teriflunomide is neither an inhibitor nor an inducer of CYP2C9. However, when teriflunomide and warfarin were co-administered, a 25% decrease in maximum international normalized ratio (INR) was observed compared to warfarin alone. Therefore, careful monitoring of INR is recommended when warfarin is co-administered with teriflunomide.

Effects of teriflunomide on substrates of BCRP and/or organic anion transporter polypeptides B1 and B3 (OATP1B1/B3). After multiple doses of teriflunomide, an increase in mean rosuvastatin Cmax and AUC was observed (2.65-fold and 2.51-fold, respectively). However, no significant effect of this increase in rosuvastatin plasma exposure on HMG-CoA (hydroxymethylglutaryl-coenzyme A) reductase activity was observed. A 50% reduction in the dose of rosuvastatin is recommended when co-administered with teriflunomide. Concomitant use of other BCRP substrates (e.g. methotrexate, topotecan, sulfasalazine, daunorubicin, doxorubicin) and OATP transporters, especially HMG-CoA reductase inhibitors (e.g. simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, repaglinide, rifampicin) with teriflunomide requires caution. Patients should be closely monitored for symptoms of excessive blood concentrations of these drugs and dose reductions should be considered.

Application features

This medicinal product contains sodium starch glycolate (type A). Caution should be exercised when administered to patients on a controlled sodium diet.

Monitoring

Before treatment.

The following parameters should be assessed before initiating treatment with teriflunomide:

blood pressure;

alanine aminotransferase/serum glutamate-pyruvate transaminase (ALT/SGPT) level;

a comprehensive blood test, including a complete blood count and platelet count.

During treatment. During treatment with teriflunomide, the following parameters should be monitored:

blood pressure (check periodically);

Alanine aminotransferase/serum glutamic-pyruvate transaminase (ALT/SGPT) levels. Liver enzymes should be assessed every two weeks for the first 6 months of treatment, then every 8 weeks or if clinical symptoms such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine occur. If ALT (SGPT) levels are elevated 2-3 times the upper limit of normal, monitoring should be performed weekly;

During treatment, a complete blood count should be performed to monitor the development of symptoms (e.g., infections).

Accelerated withdrawal procedure.

Teriflunomide is slowly eliminated from plasma. Without the use of an accelerated elimination procedure, it takes an average of 8 months to achieve plasma concentrations below 0.02 mg/l, although due to individual variability in active substance clearance, this process may take up to 2 years. The accelerated elimination procedure can be used at any time after teriflunomide discontinuation (see detailed description of the procedure in the sections “Pharmacokinetics” and “Use during pregnancy or lactation”).

Hepatic effects: Elevations in liver enzymes have been observed in patients taking teriflunomide (see section 4.8). These elevations occur predominantly within the first 6 months of treatment.

If liver injury is suspected, teriflunomide should be discontinued; teriflunomide discontinuation should be considered if liver enzyme elevations greater than 3 times the upper limit of normal are confirmed. Patients with pre-existing liver disease may be at increased risk of liver enzyme elevations while taking teriflunomide and should be closely monitored for signs of liver disease.

This medicine should be used with caution in patients who abuse alcohol.

Hypoproteinemia

Since teriflunomide is highly protein bound and since binding is dependent on albumin concentration, unbound teriflunomide plasma concentrations are expected to be increased in patients with hypoproteinemia, such as nephrotic syndrome. Teriflunomide should not be used in patients with severe hypoproteinemia.

Effects on blood pressure: An increase in blood pressure may occur during treatment with teriflunomide (see section 4.8). Blood pressure should be monitored before initiating therapy with teriflunomide and periodically thereafter. Elevated blood pressure requires appropriate treatment before and during therapy with teriflunomide.

Infections: In patients with severe active infections, initiation of teriflunomide therapy should be delayed until recovery.

In placebo-controlled studies, no increase in the incidence of serious infections was observed with teriflunomide (see section 4.8). However, given the immunomodulatory effects of teriflunomide, if a patient develops a serious infection, consideration should be given to interrupting treatment with Aubagio® and re-evaluating the benefits and risks before resuming therapy. Given the long half-life of the drug, accelerated elimination with cholestyramine or activated charcoal may be considered.

The safety of teriflunomide in patients with latent tuberculosis is currently unknown, as systematic screening for tuberculosis was not performed in clinical trials. Patients with positive tuberculosis screening results should be treated according to standard medical practice before starting therapy with Aubagio®.

Respiratory reactions.

In the post-marketing period, cases of interstitial lung disease (ILD) have been reported with teriflunomide.

Cases of ILD and worsening of pre-existing ILD have been observed during treatment with leflunomide, the prodrug of teriflunomide. This risk is increased in patients with a history of ILD while receiving leflunomide.

ILD can develop acutely at any time during therapy and have various clinical manifestations.

ILD can be fatal. The appearance or worsening of existing pulmonary symptoms, such as persistent cough and dyspnea, may be a reason for discontinuation of therapy and for further investigation, if indicated. If discontinuation of treatment is necessary, consideration should be given to the feasibility of conducting an accelerated withdrawal procedure.

Effects on hematopoiesis: A mean decrease in white blood cell count of less than 15% from baseline has been observed (see Adverse Reactions). As a precautionary measure, a complete blood count, including differential and platelet count, should be obtained shortly before initiating treatment with Aubagio® and a complete blood count should be performed during Aubagio® therapy in response to clinical signs and symptoms (e.g., if an infection develops).

Patients with pre-existing anaemia, leukopenia and/or thrombocytopenia, or patients with or at risk of red bone marrow depression are at increased risk of developing haematopoietic disorders. If such effects occur, the use of an accelerated elimination procedure (see ‘Accelerated Elimination Procedure’ below) to reduce teriflunomide plasma levels should be considered.

In the event of severe hematological reactions, including pancytopenia, Aubagio® and all concomitant myelosuppressive agents should be discontinued and an accelerated teriflunomide washout procedure should be considered.

Skin reactions: Cases of severe skin reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in the post-marketing setting.

Very rare cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have also been observed in patients receiving leflunomide (the precursor compound of teriflunomide).

If ulcerative stomatitis develops, teriflunomide should be discontinued. If a patient develops skin and/or mucous membrane reactions that are suspicious for a severe generalized skin reaction (Stevens-Johnson syndrome or toxic epidermal necrolysis - Lyell's syndrome), teriflunomide and all other agents with which such a reaction may be associated should be discontinued and an accelerated withdrawal procedure should be initiated immediately. In such cases, patients should not be re-administered teriflunomide (see section 4.3).

Peripheral neuropathy: Peripheral neuropathy has been reported in patients receiving Aubagio® (see Adverse Reactions). Most patients improved after discontinuation of Aubagio®. However, there was considerable variability in the outcome of this adverse reaction, with some patients experiencing complete resolution of neuropathy and others experiencing persistent symptoms. If a patient develops confirmed peripheral neuropathy while receiving Aubagio®, discontinuation of Aubagio® and an accelerated withdrawal procedure should be considered.

Vaccination: Two clinical studies have shown that vaccination with inactivated neoantigen (primary vaccination) or sensitizing antigen (revaccination) was safe and effective during treatment with Aubagio®. The use of live attenuated vaccines may carry a risk of infections and should therefore be avoided.

Immunosuppressive or immunomodulatory therapy: Since leflunomide is a prodrug of teriflunomide, concomitant use of teriflunomide and leflunomide is not recommended.

Concomitant use with antineoplastic or immunosuppressive drugs used in the treatment of MS has not been studied. Safety studies in which teriflunomide was administered