Included in the formulation
Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):VED
АТХ:L.04.A.A Selective immunosuppressants
L.04.A.A.31 Teriflunomide
Pharmacodynamics:Teriflunomide - an immunomodulatory agent with anti-inflammatory properties. The exact mechanism of its action in multiple sclerosis (MS) is not fully understood, but it can be caused by a decrease in the number of circulating lymphocytes. Teriflunomide, selectively and reversibly suppressing the activity of dihydroorotate dihydrogenase (DHODG), the key mitochondrial enzyme necessary for the synthesis of pyrimidine de novo, thereby blocking the proliferation of activated T and B lymphocytes involved in pathological processes in MS. Its cytotoxic effects extend only to cells using DGODG for the synthesis of pyrimidine, i.e. on activated, proliferating cells, and do not apply to slowly dividing cells of the hematopoietic system, which use the "spare" pathway for the formation of pyrimidine without the participation of DHODG. In this case, the pool of such cells does not decrease, so that protective immunity is preserved. Therefore, the action of teriflunomide is more often defined not as an immunosuppressive, although formally it refers to this group, but as an immunomodulatory,selectively suppressing the clonal expansion of autosensitized cells.
Teriflunomide changes the course of MS. In patients with relapsing-remitting MS, it reduces the frequency of relapse, reduces the risk of increasing disability (if used in a high dosage), as well as the disease activity (total lesions) at the level of the brain.
Pharmacokinetics:The average time to achieve Cmax in plasma is 1 to 4 hours after repeated oral administration. Pharmacokinetics is linear, bioavailability is high (approximately 100%). Food does not have a clinically significant effect on the pharmacokinetics of teriflunomide.
According to the average predicted pharmacokinetic parameters calculated from the analysis of population pharmacokinetics using the data on healthy volunteers and patients with MS, the equilibrium concentration is reached slowly (approximately 100 days before reaching 95% of the equilibrium concentration), and the calculated AUC cumulation ratio is approximately 34.
Teriflunomide almost completely binds to plasma proteins (> 99%), probably with albumin, and is predominantly distributed in plasma.The volume of distribution after a single IV injection is low (11 L).
Moderately metabolized and is the only component determined in the plasma. It is excreted unchanged through the gastrointestinal tract, mainly with bile. Within 21 days, 60.1% of the administered dose is excreted with feces (37.5%) and urine (22.6%). The half-life after repeated intake is 19 days. After a single intravenous injection, the total clearance of teriflunomide from the body was 30.5 ml / h.
The removal of teriflunomide from the bloodstream, if necessary, can be accelerated by the administration of orally cholestyramine (4 or 8 g 3 times / day) or activated charcoal (50 g 2 times / day). At the same time, the plasma concentration decreases by more than 98% within 11 days after the start of the elimination procedure. The effect of colestyramine is more rapid than activated charcoal.
Indications:Treatment of adult patients with relapsing-remitting MS.
VI.G35-G37.G35 Multiple sclerosis
Contraindications:- Hypersensitivity;
- Severe form of hepatic insufficiency (class C on the Child-Pugh scale);
- Pregnancy (pregnancy should be excluded before beginning therapy with teriflunomide), breast-feeding;
- Women with preserved reproductive potential, not using reliable methods of contraception, and with a plasma concentration of teriflunomide above 0.02 mg / l;
- Severe immunodeficiency (eg, AIDS);
- Severe disturbance of bone marrow hematopoiesis, including clinically significant anemia, leukopenia, neutropenia, or thrombocytopenia;
- Severe renal failure requiring hemodialysis;
- Severe active infections;
- Severe hypoproteinemia;
- Age to 18 years.
Carefully:Teriflunomide should be administered with caution to patients 65 years of age and older due to the lack of data on efficacy and safety in this age group, as well as patients who abuse alcohol.
Pregnancy and lactation:Pregnancy. Data on the use of teriflunomide by pregnant women are limited. Studies in animals have demonstrated its reproductive toxicity. Therefore, it is not recommended for pregnant women. Pregnant women should resort to an accelerated clearance procedure to rapidly reduce the concentration of teriflunomide in plasma.
Women of childbearing age before starting treatment, it is necessary to assess the possible serious potential risk to the fetus and to use effective contraception during the treatment with teriflunomide, and after discontinuation of therapy to achieve its plasma concentration no more than 0.02 mg / l (usually a period of 8 months). In case of delay in menstruation with the reception of teriflunomide, it is necessary to perform a pregnancy test, with a positive result - to discuss with the doctor all the risks associated with pregnancy, to check the residual concentration of teriflunomide. If it exceeds 0.02 mg / l, it is recommended to repeat the procedure of accelerated elimination.
Women seeking pregnancy, it is necessary to use an accelerated elimination procedure to rapidly reduce the concentration of teriflunomide in plasma.
Use in men. The risk of embryo-fetal toxicity as a result of taking teriflunomide by the father of a child is considered low.
Fertility. The results of animal studies did not reveal any effect of teriflunomide on fertility. Despite the lack of data for people, the impact on male and female fertility is unlikely.
Breast-feeding. Studies in animals have demonstrated the isolation of teriflunomide in breast milk. It is not known whether this drug enters the breast milk of women. Given that many drugs penetrate into breast milk, as well as the likelihood of developing serious adverse reactions associated with the action of teriflunomide, a decision should be made whether to stop breastfeeding or stop taking teriflunomide given the degree of its need for the mother.
Action category for the fetus by FDA - FROM
Dosing and Administration:Orally 14 mg 1 time / day, regardless of food intake.
Side effects:Teriflunomide is the main leflunomide metabolite. Information on the safety profile of leflunomide in patients with rheumatoid or psoriatic arthritis can be used in the administration of teriflunomide to patients with MS.
Against the background of therapy with teriflunomide, non-severe undesirable phenomena from the gastrointestinal tract, thinning of the hair cover, increase in the level of hepatic transaminases were noted. In general, diarrhea, nausea and alopecia were mild or moderate, passed quickly and occasionally led to discontinuation of therapy.The incidence of malignant neoplasms and serious infections was comparable in the groups of teriflunomide and placebo.
Undesirable reactions noted with the administration of teriflunomide at a dose of 14 mg / day during placebo-controlled studies
Infectious complications: very often - influenza, upper respiratory tract infections, urinary tract infections, laryngitis, foot mycosis; often - bronchitis, sinusitis, pharyngitis, cystitis, viral gastroenteritis, oral cavity herpes, periodontal infections.
From the hemopoietic system and lymphatic system: often - neutropenia (less than 15% of the baseline level), infrequently - anemia, thrombocytopenia of mild degree.
From the immune system: often - mild allergic reaction.
Mental disorders: often - anxiety.
From the nervous system: very often paresthesia; often - lumbosacral radiculitis, carpal tunnel disease, hyperesthesia, neuralgia, peripheral neuropathy.
From the cardiovascular system: often - hypertension.
From the respiratory system: very rarely - interstitial lung diseases (only based on information on the safety profile of leflunomide).
From the digestive system: very often - diarrhea, nausea; often - vomiting, toothache; very rarely - pancreatitis (only on the basis of information on the safety profile of leflunomide).
From the skin and subcutaneous tissues: very often - alopecia, often - a rash, acne.
From the side of the musculoskeletal system and connective tissue: often - musculo-skeletal pain, myalgia.
From the side of the kidneys and urinary tract: often - pollakiuria.
On the part of the reproductive system: often - menorahia.
Laboratory indicators: very often - an increase in the level of ALT; often - an increase in the level of gamma glutamyltransferase, AST, a decrease in body weight, a decrease in the number of neutrophils, a decrease in the number of leukocytes.
Overdose:There is no information on overdose or intoxication of teriflunomide in humans. Teriflunomide in a dose of 70 mg / day for 14 days was well tolerated by healthy people. The observed adverse reactions corresponded to the safety profile of teriflunomide when administered to patients with MS.
In case of a significant overdose or toxicity for accelerated elimination, it is recommended colestramine or Activated carbon (see "Pharmacokinetics").
Interaction:Pharmacokinetic interactions of other drugs with teriflunomide
The main way of biotransformation of teriflunomide is hydrolysis, less significant - oxidation. Simultaneous long-term use (600 mg 1 time / day for 22 days) of rifampicin (isoenzyme inducer CYP2B6, 2C8, 2C9, 2C19, 3A), as well as inducer of carrier proteins, P-glycoprotein and breast cancer resistance protein (BCRP ) and teriflunomide (single dose of 70 mg) led to a decrease in the effects of teriflunomide by approximately 40%. Rifampicin and other known inducers of CYP and carrier proteins (such as carbamazepine, phenobarbital, phenytoin and St. John's wort) should be administered with caution in the presence of teriflunomide therapy.
Colestyramine or Activated carbon. Simultaneous reception is not recommended, since it leads to a rapid and significant reduction in the concentration of teriflunomide in plasma, except when accelerated excretion is necessary.
Pharmacokinetic interactions of teriflunomide with other drugs
Substrates CYP2C8. Teriflunomide acts as an inhibitor of the isoenzyme CYP2C8 in vivo. Therefore, drugs metabolized by the isoenzyme CYP2C8 (repaglinide, paclitaxel, pioglitazone or rosiglitazone), against the background of teriflunomide should be used with caution because of an increase in the mean values of Cmax and AUC0-24 of these drugs.
Substrates of the isoenzyme CYP1A2. After repeated administration of teriflunomide, the average values of Cmax and AUC of caffeine (the substrate of the isoenzyme CYP1A2) decreased, which suggests that teriflunomide can be a weak inducer of CYP1A2 in vivo. Therefore, drugs whose metabolism is mediated by CYP1A2 (duloxetine, alosetron, theophylline and tizanidine) should be used with caution in the face of treatment with teriflunomide because of the possible reduction in their effectiveness.
Warfarin. Repeated doses of teriflunomide did not affect the pharmacokinetics of S-warfarin. This shows that teriflunomide is neither an inhibitor nor an inducer of the isoenzyme CYP2C9. However, with the simultaneous use of teriflunomide and warfarin, there was a 25% decrease in the maximal INR compared with that with warfarin alone. Therefore, with the simultaneous administration of warfarin and teriflunomide, a thorough current and subsequent monitoring of MHO is recommended.
Oral contraceptives. After repeated administration of teriflunomide, an increase in the average value of Cmax and AUC0-24 for ethinylestradiol and levonostrel was noted.Although this interaction of teriflunomide should not adversely affect the efficacy of oral contraceptives, their type or dose should be considered when concomitant with teriflunomide.
Substrates of carriers of organic anions 3 (PAAS). Repeated doses of teriflunomide increased C max and AUC of cefaclor. This shows that teriflunomide is a PAASE inhibitor in vivo. Therefore, caution should be exercised when assigning teriflunomide together with PAAS substrates (such as cefaclor, benzylpenicillin, ciprofloxacin, indomethacin, ketoprofen, furosemide, cimetidine, methotrexate and zidovudine).
Substrates BCRP and / or transporting organic anions of polypeptides B1 and B3 (OATP1B1 / B3). The introduction of repeated doses of teriflunomide increased the Cmax and AUC values of rosuvastatin (substrate OATP1B1 and BCRP), which did not affect the activity of HMG-CoA reductase. When taking a joint with teriflunomide, a dose of rosuvastatin should be reduced by 50%. Other BCRP substrates (eg, methotrexate, topotecan, sulfasalin, daunorubicin, doxorubicin) and the families of the OATP, especially HMG-CoA reductase inhibitors (eg, simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, repaglinide, rifampicin), concomitantly with teriflunomide should be administered with caution. Patients should be carefully monitored for signs and symptoms of excessive exposure to drugs and, if necessary, to reduce their dose.
Special instructions:Treatment should be conducted under the supervision of a physician with experience in the treatment of patients with MS. Before starting treatment, the patient should evaluate blood pressure and ALT activity, make a general blood test, including the definition of the leukocyte formula and the number of platelets. During treatment with teriflunomide, blood pressure and AJIT activity should be monitored regularly. In case of appearance during treatment of new symptoms and signs (for example, infection) it is necessary to perform a general blood test, including the definition of the leukocyte formula and the number of platelets.
Teriflunomide is slowly excreted from the plasma: its concentration in plasma reaches values below 0.02 mg / l on average for 8 months, although due to individual abnormalities in the excretion of drugs this process can last up to 2 years. Excretion can be accelerated by means of the above procedures with the use of colestyramine or activated charcoal: for 11 days the concentration of teriflunomide in the plasma decreases by more than 98%.The accelerated elimination procedure can be used at any time after the discontinuation of teriflunomide administration.
Patients of the older age group
Patients at the age of 65 and older should be administered with caution because of insufficient data on the efficacy and safety of teriflunomide in this age group.
Children's population
The safety and efficacy of teriflunomide in children aged 10 to 18 years is not established. Children under 10 years of age teriflunomide for treatment of MS is not assigned.
Renal insufficiency
Patients with mild, moderate or severe renal failure who are not on hemodialysis do not need dose adjustment. Patients with severe renal failure who are on hemodialysis did not participate in clinical studies. Teriflunomide this group of patients is contraindicated.
Effects on the liver
Patients with mild to moderate hepatic insufficiency are not required to adjust the dose. Patients with severe hepatic insufficiency teriflunomide is contraindicated.
In patients who took teriflunomide, an increase in the activity of liver enzymes was observed. These adverse reactions occurred mainly in the first 6 months of treatment. It is necessary to monitor the activity of liver enzymes before starting therapy with teriflunomide, then every 2 weeks for the first 6 months of treatment and every 8 weeks thereafter or when there are clinical signs and symptoms indicating a violation of liver function (such as nausea, vomiting, abdominal pain, fatigue, loss of appetite, jaundice and / or darkening of urine). For ALT it is permissible to increase the level, a multiple of 2-3 VGN, while monitoring should be carried out weekly. Therapy with teriflunomide should be discontinued if there is a suspicion of liver damage. The need for cessation of therapy is considered with a confirmed increase in the activity of hepatic enzymes more than 3 times that of VGN. Patients with a history of liver disease are at risk, in which the symptoms of liver damage should be carefully monitored.
Teriflunomide with caution prescribed to patients who abuse alcohol.
Hypoproteinemia
Triflunomide binds to a high degree with proteins, mainly with albumin.In patients with hypoproteinemia, the concentration of unbound tetrylunomide in the blood plasma may increase (for example, with nephrotic syndrome), so it should not be prescribed to such patients.
Arterial pressure
Against the background of the use of teriflunomide, there may be an increase in blood pressure, its level should be measured before treatment and periodically monitored thereafter. In the case of increased blood pressure, appropriate antihypertensive therapy should be performed before and during the treatment with teriflunomide.
Infections
Patients with active or chronic infections should not begin treatment with teriflunomide until complete recovery. In placebo-controlled studies, there was no increase in the incidence of serious infections when taking teriflunomide. However, given its immunomodulatory effect, when a patient develops a serious infection, the need to suspend therapy should be considered, and before its renewal, it should evaluate possible benefits and risks. In connection with a long half-life, if necessary, it is possible to accelerate the elimination of teriflunomide with the help of colestyramine or activated charcoal.
The safety of teriflunomide in persons with latent tuberculosis infection is unknown. Screening for tuberculosis in clinical studies has not been systematically performed. Patients who have a positive tuberculosis screening test should receive appropriate treatment before taking teriflunomide.
Respiratory reactions
In clinical studies, teriflunomide cases of interstitial lung diseases have not been documented. However, similar potentially fatal diseases have been reported in the study of the safety profile of leflunomide, the active metabolite of which is teriflunomide. Therefore, in the treatment with teriflunomide, interstitial lung diseases can develop, their risk is increased in patients who developed such diseases with leflunomide treatment. Pulmonary symptoms, such as persistent cough and shortness of breath, can lead to discontinuation of therapy and further examination.
Hematological effects
There is a decrease in the number of white blood cells less than 15% of the baseline level. As a precautionary measure, it is necessary to make a general clinical blood test withthe definition of the leukocyte formula and the number of platelets before the start of therapy and against treatment when certain symptoms and signs appear (for example, in infections). In patients with existing anemia, leukopenia and / or thrombocytopenia, as well as in patients with impaired bone marrow function or who have the risk of suppression of bone marrow hematopoiesis, the risk of hematological diseases with teriflunomide therapy is increased. In case of development of these undesirable reactions, it is necessary to consider the possibility of using the accelerated elimination procedure of teriflunomide to reduce its concentration in the plasma.
In cases of severe hematologic reactions, including pancytopenia, the taking of teriflunomide and any other myelosuppressive therapy should be discontinued and the expediency of the accelerated elimination procedure should be considered.
Skin Reactions
In clinical trials of teriflunomide, no cases of severe skin reactions have been reported, but patients who underwent leflunomide treatment had rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis.
When ulcerative stomatitis occurs against the background of teriflunomide, its administration should be discontinued. If cutaneous and / or mucous disorders cause suspicion of a serious generalized skin reaction (Stevens-Johnson syndrome or toxic epidermal necrolysis - Lyell's syndrome), the use of teriflunomide (and any other possibly related drugs) should be discontinued and immediately begin the procedure for its accelerated elimination. In such cases, patients should not be reassigned teriflunomide.
Peripheral Neuropathy
In patients who took teriflunomide, cases of peripheral neuropathy were documented. After discontinuation of the drug, the severity of the unwanted reaction in most patients decreased. However, in some patients the symptoms of peripheral neuropathy disappeared completely, while others remained. If the patient who took teriflunomide, has a confirmed peripheral neuropathy, consideration should be given to stopping therapy and carrying out an accelerated elimination procedure.
Vaccination
In clinical trials, patients who took teriflunomide, had a normal immune response to seasonal influenza vaccines corresponding to a normal response to booster vaccination. An antibody titer was achieved, sufficient for seroprotection. There are no data on the efficacy and safety of primary vaccination against neo-pathogens. The use of live attenuated vaccines may be associated with a risk of infection, so it should be avoided.
Immunosuppressive and immunomodulatory therapy
Because the teriflunomide is an active metabolite of leflunomide, their joint administration is not recommended. Joint administration with antineoplastic or immunosuppressive drugs used to treat MS has not been studied. Safety Studies in which teriflunomide was simultaneously administered with interferon beta or with glatiramer acetate for one year, did not reveal any safety problems, but a higher incidence of adverse reactions compared with teriflunomide monotherapy was observed. The safety of this combination with long-term admission for the treatment of MS has not been investigated.
Transition to or from teriflunomide
On the basis of clinical data on the simultaneous administration of teriflunomide with interferon beta or with glatiramer acetate,that there is no need for a waiting period for the initiation of therapy with teriflunomide after interferon beta or glatiramer acetate or when initiating therapy with interferon beta or glatiramer acetate after teriflunomide.
Due to the long half-life of natalizumab, when therapy with teriflunomide begins for 2-3 months after discontinuation of natalizumab, simultaneous exposure and, consequently, simultaneous exposure of these drugs to the immune system can occur. Therefore, precautions should be taken when switching from natalizumab therapy to teriflunomide.
Taking into account the half-life of phylogenide for eliminating from the organism of its circulating metabolites, a 6-week interval without therapy is necessary. After the termination of reception финголимода for returning of quantity of lymphocytes to norm it is required from 1 till 2 months. Therefore, precautions should be taken when switching from phylogolimide therapy to teriflunomide. This can lead to a combined effect on the immune system.
Influence on the ability to drive and use machinery
Teriflunomide does not have or has little effect on the ability to drive or use machinery. However, if there are undesirable phenomena from the nervous system, for example dizziness, you should refrain from driving and other potentially hazardous activities.