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[Drug Name] Aubajie (Teriflunomide Tablets)
[Suitable for u2002 symptoms] It is suitable for the treatment of relapsing multiple sclerosis.
[Usage and Dosage] The doctor should guide the patient to use this product according to the severity of the patient's condition and tolerance (please pay attention to the relevant content of [Pharmacokinetics] for details). It is recommended to take 7 mg or 14 mg orally once a day. It can be taken before meals, after meals or with meals.
Safety Monitoring
Before starting treatment with teriflunomide tablets, transaminase and bilirubin level data should be obtained within 6 months. After starting to take teriflunomide tablets, ALT levels should be monitored at least once a month for 6 months (see [Precautions] Hepatotoxicity).
Before starting to take teriflunomide tablets, obtain a complete blood count (CBC) within 6 months. Further monitor for signs and symptoms of infection (see [Precautions] Myeloid Effects/Suppression of Disease in Rabbits/Infections).
Before starting to take teriflunomide tablets, patients with latent tuberculosis infection should be screened for latent tuberculosis infection using a tuberculin skin test or blood test (see [Precautions] Bone marrow effects in immunosuppression/infection).
Pregnancy should be ruled out in women of childbearing potential before starting treatment with teriflunomide tablets (see [Precautions] Teratogenicity).
Check your blood pressure when you start taking teriflunomide tablets, and check regularly thereafter (see [Precautions] Increased blood pressure). [Ingredients] The main ingredient is teriflunomide
Chemical name: (Z)-2-oxy-3-hydroxy-2-butene-(4-trifluoromethyl-phenyl) acyl waste
Molecular formula: C12HF3N2O2
Molecular weight: 270.21
[Properties] This product is a film-coated tablet, which appears white or off-white after the coating is removed.
[Notes]
1. Hepatotoxicity: Leflunomide is used to treat rheumatoid arthritis, and there have been reports of severe hepatotoxicity, including fatal liver failure, in patients treated with leflunomide. Because the recommended doses of teriflunomide and leflunomide produce similar ranges of teriflunomide plasma concentrations, it is expected that similar risks may exist with teriflunomide. Patients with pre-existing liver disease may be at increased risk of developing serum aminotransferase elevations when taking this product. Patients with acute or chronic liver disease or serum alanine aminotransferase (ALT) levels greater than 2 times the upper limit of normal (ULN) before initiating treatment generally should not receive teriflunomide. Teriflunomide is contraindicated in patients with severe hepatic impairment (see Contraindications). In placebo-controlled trials, 61/1045 (5.8%) and 62/1002 (6.2%) of patients who received 7 mg and 14 mg of this product during treatment had ALT higher than 3 times UILN, respectively, compared with 38/997 (3.8%) of patients in the placebo group. Most of these increases occur during the first year of treatment. Half of the cases return to normal values without discontinuing medication. In clinical trials, if ALT is higher than 3 times the ULN in two consecutive tests, the drug will be discontinued and the accelerated elimination program will be entered (see [Precautions] Accelerated elimination program). In controlled trials of patients who underwent discontinuation and accelerated elimination procedures, half of the patients returned to normal or near-normal levels within two months. One patient in the controlled trial developed ALT as high as 32 times the ULN and developed jaundice 5 months after starting treatment with this product (14 mg). The patient was hospitalized for 5 weeks and recovered after plasmapheresis and accelerated cholestyramine elimination procedures. Hepatic injury induced by this product cannot be ruled out in this patient. Before initiating treatment with this product, serum aminotransferase and bilirubin level data should be obtained within 6 months. ALT levels should be monitored at least once a month for 6 months after starting this product. Further monitoring should be considered when this product is administered concomitantly with other potentially hepatotoxic drugs. If repeated tests confirm an increase in serum aminotransferase (greater than or equal to 3 times the ULN), this product should be discontinued. When using this product for treatment, pay attention to monitoring serum aminotransferase and heme levels, especially when the patient has symptoms of liver insufficiency, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia or jaundice and yellow-red urine. If this product-induced liver injury is suspected, this product should be discontinued and an accelerated elimination program should be entered (see [Precautions] Accelerated elimination program), and liver test results should be monitored weekly until normalization returns. If other possible causes of the disease are found and it is believed that the liver injury induced by this product is unlikely, resumption of treatment with this product may be considered.
2. Teratogenicity: This product may cause fetal harm when administered to pregnant women. Teratogenicity and embryo-fetal death have occurred in animal reproduction studies in multiple species at plasma teriflunomide exposures similar to or below the maximum recommended human dose (MHRD) of 14 mg/day (see Use in Pregnant and Lactating Women). Pregnant women and women of childbearing age who are not using effective contraceptive measures are prohibited from using this product (see [Contraindications] and [Precautions] for accelerated elimination procedures).
3． Teriflunomide Accelerated Elimination Procedure: Teriflunomide is slowly eliminated from the plasma (see Pharmacokinetics). Without accelerated elimination procedures, it would take an average of 8 months for the plasma concentration to drop below 0.02mg/L. Due to individual differences in drug elimination, some individuals may take up to 2 years. The accelerated elimination procedure may be used at any time after discontinuation of this product. Elimination can be accelerated by any of the following procedures: 8 g of cholestyramine should be given every 8 hours for 1 day. If the dose of 8 cholestyramine is not tolerated, 4 g of cholestyramine can be given three times a day. Take 50g of activated charcoal powder orally every 12 hours for 11 days. If all the above elimination procedures are not tolerated well, continuous daily treatment is not necessary. Unless rapid achievement of low teriflunomide blood concentrations is required. At the end of day 11, both regimens could successfully accelerate the elimination of teriflunomide, reducing the plasma concentration of teriflunomide by more than 98%. If a patient responds to treatment with this product, accelerated elimination procedures may activate disease.
4. Myeloid Effects in Immunosuppression/Infections: Myeloid Effects: In placebo-controlled trials, patients treated with 7 mg and 14 mg of this product experienced an approximate mean decrease in white blood cell (WBC) count of 15% (mainly neutrophils and lymphocytes) and platelet count of approximately 10% relative to baseline. The decrease in mean WBC count occurred in the first 6 weeks, and WBC counts continued to be low throughout the study. In placebo-controlled studies, 12% and 16% of patients treated with 7 mg and 14 mg of this product, respectively, had neutrophil counts <1.5x10°L, compared with 7% in the placebo group; 10% and 12% of patients treated with 7 mg and 14 mg of this product, respectively, had lymphocyte counts <0.8x10^9/L, compared with 6% in the placebo group. No cases of severe pancytopenia have been reported in premarketing studies of leflunomide, but rare cases of pancytopenia and agranulocytosis have been reported in postmarketing studies of leflunomide. It is speculated that this product may have similar risks (see [Pharmacokinetics]). Cases of thrombocytopenia, including rare cases of platelet counts less than 50,000 m3, have been reported after marketing. Before starting treatment with this product, a complete blood count (CBC) should be obtained within 6 months. Further monitoring should be based on signs and symptoms of myelosuppression. Tuberculosis screening for risk of infection: Patients with acute active or chronic infection should not start treatment until the infection is controlled. If a patient develops a serious infection, consideration should be given to suspending treatment with this product or using accelerated elimination procedures. Benefits and risks need to be reassessed before restarting treatment. Patients who are receiving this product should be informed to promptly report symptoms of infection to their physician. This product is not recommended for use in patients with severe immunodeficiency, bone marrow disease, or severe uncontrolled infections. Medications like this product may be potentially immunosuppressive, making patients susceptible to infections, including opportunistic infections. In placebo-controlled studies of this product, there was no overall increase in the risk of serious infection in the 7 mg (2.2%) or 14 mg (2.7%) group compared with the placebo group (2.2%). However, one patient who took 14 mg of this product for 1.7 years developed Klebsiella pneumoniae sepsis and died. There have been reports of fatal infections, particularly Pneumocystis jiroveci pneumonia and aspergillosis, in patients receiving leflunomide in post-marketing studies. In most of these reports, the cause cannot be determined because of concomitant immunosuppressive therapy and/or comorbid conditions (other than rheumatoid disease) that predispose the patient to infection. Reactivation of cytomegalovirus hepatitis has been observed in clinical studies with this product. Cases of tuberculosis have been observed in clinical studies using this product. Screen patients for latent tuberculosis infection with a tuberculin skin test or blood test before starting treatment with this product. This product has not been studied in patients with positive tuberculosis screening results, and the safety of this product in individuals with latent tuberculosis infection is unknown. Patients who screen positive for tuberculosis should be treated in accordance with standard medical practice before receiving teriflucan. Vaccination: There are no clinical data on the efficacy and safety of this product in patients vaccinated with live vaccines. However, live vaccines are not recommended. If you wish to receive a live vaccine after discontinuing this product, you should take into account the longer half-life of this product. Malignant diseases: The risk of malignant diseases, especially lymphoproliferative diseases, is increased when some immunosuppressive drugs are used. This product can potentially induce immunosuppressive reactions. In the clinical trials of this product, there were no reports of a significant increase in the incidence of malignant diseases and lymphoproliferative diseases, but large-scale long-term studies are needed to determine whether this product will cause an increase in the incidence of malignant diseases and lymphoproliferative diseases.
5. Hypersensitivity and severe skin reactions: This product can cause anaphylaxis and severe allergic reactions (see Contraindications). Signs and symptoms include difficulty breathing, urticaria, and angioedema (including lips, eyes, throat, and tongue). Cases of serious skin reactions have been reported with this product, including cases of Stevenson-Johnson syndrome (SJS) and fatal cases of toxic epidermal necrolysis (TEN). Very rare cases of drug-responsive eosinophilia and systemic symptoms (DRESS) have also been reported in patients treated with the parent compound leflunomide. Patients should be informed of the signs and symptoms of anaphylaxis and angioedema and of signs and symptoms that may signal a serious skin reaction. Inform patients that fever associated with other organ system involvement (e.g., rash, lymphadenopathy, or abnormal hepatic function tests) may be drug-related. If these signs and symptoms occur, instruct patients to discontinue use of this product and seek immediate medical attention. Unless the reaction is clearly not drug-related, discontinue use of this product and begin an accelerated elimination procedure immediately (see [Precautions] Accelerated elimination procedures). In this situation, patients should not be re-exposed to teriflunomide (see Contraindications).
6. Peripheral neuropathy: In placebo-controlled studies, peripheral neuropathy, including polyneuropathy and single neuropathy (e.g., carpal tunnel syndrome), occurred more frequently in patients taking this product than in patients taking placebo. The incidence of peripheral neuropathy confirmed by nerve conduction testing was 1.4% (13 patients) and 1.9% (17 patients) in the 7 mg and 14 mg groups, respectively, compared with 0.4% (4 patients) in the placebo group. 0.7% (8 patients) of patients with confirmed peripheral neuropathy discontinued treatment (3 patients received 7 mg of EGFR and 5 patients received 14 mg of EGFR). Five of the patients recovered after treatment was terminated. Not all cases of peripheral neuropathy resolve with continued medication. Peripheral neuropathy has also occurred in patients receiving leflunomide. Age over 60 years, concomitant use of neurotoxic drugs, and diabetes increase the risk of peripheral neuropathy. If a patient taking this product develops symptoms of peripheral neuropathy, such as bilateral numbness or numbness or tingling in the hands or feet, discontinuation of this product and accelerated elimination procedures (see [Precautions] Accelerated elimination procedures) should be considered.
7． Increased blood pressure: In placebo-controlled studies, the mean changes in systolic blood pressure from baseline to the end of the study were +2.3 mmHg and +2.7 mmHg in patients taking 7 mg and 14 mg of teriflunomide, respectively, and 0.6 mmHg in the placebo group. The changes in diastolic blood pressure from baseline in patients taking 7 mg and 14 mg of teriflunomide were +1.4 mmHg and +1.9 mmHg, respectively, and -0.3 mmHg in the placebo group. The adverse event of hypertension occurred in 3.1% and 4.3% of patients taking 7 mg and 14 mg of this product, respectively, compared with 1.8% in the placebo group. Check your blood pressure before starting treatment with this product and regularly thereafter. Elevated blood pressure should be properly managed during treatment with Triclofluor Film.
8． Effects on the Respiratory System: Interstitial lung disease (including acute interstitial pneumonia) has been reported after taking this product after marketing. Interstitial lung disease and exacerbation of interstitial lung disease have been reported during treatment with leflunomide. Interstitial lung disease can be fatal, and acute interstitial lung disease can occur at any time during treatment and has variable clinical manifestations. New onset or worsening of pulmonary symptoms, such as cough, dyspnea, with or without associated fever, may be a consideration for discontinuation of drug therapy and further investigation may be warranted as appropriate. If discontinuation of the drug is necessary, consideration should be given to initiating an accelerated elimination procedure (see [Precautions] Accelerated elimination procedures).
9． Concomitant Use with Immunosuppressive or Immunosuppressive Therapies: Concomitant use with antineoplastic agents or immunosuppressive therapies has not been evaluated in the treatment of multiple sclerosis. In safety studies, this product was used concomitantly with other immunomodulatory therapies (interferon beta, glatiramer acetate) for up to 1 year, and no special safety considerations were found. The long-term safety of combination therapy for multiple sclerosis has not been established. In any case, when the decision is made to abandon this product in favor of another drug with known hematodepressant properties, the hematological toxicity must be carefully monitored because there may be overlap in systemic exposure of the two compounds. The use of accelerated elimination procedures can reduce this risk, but may lead to disease reactivation in patients who have already responded to treatment with this product (see [Precautions] Accelerated elimination procedures).