Approval date: March 06, 2007
Revision date: Mar. 20, 2009
Revision date: October 01, 2010
Modification date: December 01, 2015
Date of modification.
Leflunomide Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
warning: embryo-fetal toxicity and hepatotoxicity
For full black box warning information refer to the full instructional information.
Embryo-fetal toxicity
Teratogenicity and embryonic lethality have occurred in animals receiving leflunomide.
Exclude pregnancy prior to treatment with Leflunomide.
● Women of childbearing potential are advised to use effective contraception during treatment and during drug elimination.
● If patient becomes pregnant, discontinue leflunomide and initiate the washout process.
Hepatotoxicity
● Severe liver injury and fatal liver failure have been reported.
● Leflunomide is contraindicated in patients with pre-existing liver disease or alanine aminotransferase (ALT) above 2 times the upper limit of normal.
● Use caution when combining Leflunomide with other potentially hepatotoxic drugs.
● Monitor ALT levels. If ALT is elevated more than 3 times the upper limit of normal, interrupt leflunomide therapy. If a leflunomid-induced ALT elevation may occur, initiate a washout process and monitor liver function weekly until normal. Drug Name]
Generic name: Leflunomide Tablets
Trade name: Airova
English name: Leflunomide Tablets
Hanyu Pinyin: Laifumite Pian
Ingredients
The main ingredient of this product is Leflunomide.
Chemical name: α,α,α-trifluoro-5-methyl-isoxazole-N-acyl-p-toluidine.
Chemical structure formula.
Molecular formula: C12H9F3N2O2
Molecular weight: 270.2
Properties
This product is a film-coated tablet, which appears white after removing the coating.
Indications
(1)It is suitable for adults with rheumatoid arthritis, and has the effect of improving the condition. (2) Lupus nephritis.
Specification
10mg 【Dosage】 (1)Adult rheumatoid arthritis: Oral. Due to the long half-life of Leflunomide, it is recommended to administer the drug at 24-hour intervals. For rapid achievement of steady-state blood concentration, a loading dose of 50mg a day is recommended for the first three days of treatment, followed by a maintenance dose of 10mg or 20mg a day depending on the condition.
(2) Lupus nephritis: take orally. Select the appropriate dose according to the condition. The recommended dose is 20-40mg once a day, and the dose is reduced appropriately after the condition is in remission. It can be used in combination with glucocorticosteroids, or as prescribed by the doctor.
Adverse reactions
(1)Used in the treatment of rheumatoid arthritis
As reported in foreign literature.
Safety overview
The most commonly reported adverse reactions to leflunomide are: mild increase in blood pressure, leukopenia, abnormal sensation, headache, dizziness, diarrhea, nausea, vomiting, oral mucosal disease (e.g., aphthous stomatitis, oral ulcers), abdominal pain, increased hair loss, eczema, rash (including maculopapular rash), pruritus, dry skin, tenosynovitis, increased CPK (phosphocreatine kinase), anorexia, weight loss (usually not significant), weakness, mild allergic reactions, and elevated liver parameters [transaminases (especially alanine aminotransferase ALT) and, less commonly, gamma-GT (glutamyl transpeptidase), alkaline phosphatase, bilirubin].
Expected incidence grading.
Very common (≥10%), common (1% to 10% with 1%), occasional (0.1% to 1% with 0.1%), rare (0.01% to 0.1% with 0.01%), very rare (<0.01%); unknown (cannot be estimated from available data).
Among the groups by frequency, adverse reactions were listed in descending order according to severity.
Infections and Infectious Diseases
Rare.
Severe infections, including potentially fatal sepsis
As with other immunosuppressive drugs, leflunomide may increase susceptibility to infections, including opportunistic infections (see [Precautions]). As a result, the overall incidence of infections may be increased (especially rhinitis, bronchitis, and pneumonia).
Benign, malignant and tumors of unknown nature (including cystic and polypoid)
The use of certain immunosuppressive drugs can lead to an increased risk of malignant tumors, especially lymphoproliferative disorders.
Blood and lymphatic system disorders
Common: leukopenia (white blood cells > 2 x 109/L)
Occasionally: anemia, mild thrombocytopenia (platelets<100×109/L)
Rare: holocytopenia (probably caused by antiproliferative mechanisms), leukopenia (leukocytes<2×109/L), eosinophilia
Very rare: granulocyte deficiency
Recent, combined or continuous use of potentially myelotoxic drugs may result in a higher risk of hematologic reactions.
Immune system disorders
Common: Mild allergic reactions
Very rare: severe rapid-onset allergic/rapid-onset anaphylactic reactions, vasculitis, including cutaneous necrotizing vasculitis
Metabolic and nutritional disorders
Common: elevated CPK
Occasional: hypokalemia, hyperlipidemia, hypophosphatemia
Rare: elevated LDH (lactate dehydrogenase)
Unknown: hypouricemia
Psychiatric
Occasional: anxiety
All types of neurological disorders
Common: sensory confusion, headache, dizziness, peripheral neuropathy
Heart organ disorders
Common: Mildly elevated blood pressure
Rare: Severe elevation of blood pressure
Respiratory, thoracic and mediastinal disorders
Rare: interstitial lung disease (including interstitial pneumonia), potentially fatal
Unknown: pulmonary hypertension
Diseases of the gastrointestinal system
Common: colitis (including microscopic colitis, e.g., lymphatic colitis), collagenous colitis, diarrhea, nausea, vomiting, oral mucosal disease (e.g., aphthous stomatitis, oral ulcers), abdominal pain
Occasionally: taste abnormalities
Very rare: pancreatitis
Hepatobiliary disorders
Common: elevated liver parameters (transaminases [especially ALT], gamma-GT, alkaline phosphatase, bilirubin less common)
Rare: hepatitis, jaundice/cholestasis
Very rare: severe liver injury (e.g., liver failure) and acute hepatic necrosis, which may be fatal
Skin and subcutaneous tissue disorders
Common: increased hair loss, eczema, rash (including maculopapular rash), pruritus, dry skin
Occasional: urticaria
Very rare: toxic epidermolysis bullosa, Stevens-Johnson syndrome, erythema multiforme
Unknown: cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis, drug reactions with eosinophilia and systemic symptoms (DRESS)
Various musculoskeletal and connective tissue disorders
Common: tenosynovitis
Occasionally: tendon rupture
Renal and urological disorders
Unknown: renal failure
Reproductive system and breast disorders
Unknown: critical (reversible) decline in sperm concentration, total sperm count, and rapid progressive motility
Systemic diseases and various reactions at the drug administration site
Common: anorexia, weight loss (usually not significant), malaise
Reports of suspected adverse reactions
It is important to report suspected adverse reactions after obtaining marketing authorization for a drug. This allows for continued monitoring of the drug benefit/risk balance.
(2) Use in the treatment of lupus nephritis
Data from domestic clinical trials showed that among 108 patients with active proliferative lupus nephritis treated with leflunomide, a total of 43 experienced adverse reactions possibly related/associated with the trial drug during the first 6 months (20-40 mg/day), with an incidence of 39.81%; during the treatment period, adverse events with an incidence of ≥3% included: alopecia, elevated blood pressure, herpes zoster, elevated transaminases, diarrhea/dilute stool decreased white blood cells, skin rash, menstrual irregularities, palpitations, abdominal pain; adverse events with an incidence of <3% included: nausea/vomiting, upper respiratory tract infection, decreased platelets, malaise, heartburn, anorexia, fever, periodontal pain, visual abnormalities, urinary tract infection, sore throat, cytomegalovirus infection, weight loss, hirsutism, and lung infection. During 7-72 months of treatment (10-30 mg/day), 52 patients were followed up, and a total of 12 had adverse reactions possibly related/associated with the test drug, with an incidence of 23.08%. Adverse events with an incidence of ≥3% included: decreased white blood cells, elevated transaminases, and thrombocytopenia; adverse events with an incidence of <3% included: upper respiratory tract infection, alopecia, herpes zoster, menstrual disorders, and Urinary tract infection.
Contraindications
Patients with hypersensitivity to the active ingredient, the major active metabolite teriflunomide, or to lactose, corn starch, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, polyethylene glycol, hydroxypropylmethyl cellulose, talc, titanium dioxide, or any of the excipients (especially if Stevens-Johnson syndrome, toxic epidermolysis bullosa, erythema multiforme have occurred previously).
● Patients with impaired liver function.
● Patients in a state of severe immunodeficiency, such as AIDS (AIDS).
●Patients with severely impaired bone marrow function or severe anemia, leukopenia, neutropenia, or thrombocytopenia due to causes other than rheumatoid arthritis.
● Patients with severe infection (see [Precautions]).
● Patients with moderate to severe renal insufficiency due to lack of experience with clinical use in this patient group.
●Patients with severe hypoproteinemia, such as those with nephrotic syndrome.
● Pregnant women or women of childbearing age who are not using reliable contraception during leflunomide treatment and thereafter during periods when plasma active metabolite levels are above 0.02 mg/L (see [Pregnancy and Lactation]). Pregnancy must be excluded prior to initiation of treatment with leflunomide.
●Females of lactating age (see [Dosage for Pregnant and Lactating Women]).
Precautions]
As reported in foreign literature.
Combination with disease-modifying anti-rheumatic drugs (DMARD) with hepatotoxic or hematotoxic properties (e.g., methotrexate) is not recommended.
The active metabolite of leflunomide, teriflunomide, has a long half-life, usually 1 to 4 weeks. Serious adverse effects (e.g., hepatotoxicity, hematotoxicity, or allergic reactions) may occur even after leflunomide has been discontinued. Therefore, if such toxicity occurs or if for any other reason there is a need for rapid removal of teriflunomide from the body, a washout procedure must be followed. This procedure may be repeated as clinically indicated.
For information on the purging process and other recommended measures in case of planned or unplanned pregnancy, see [Pregnancy and Lactation].
Hepatic Reactions
Rare cases of severe liver injury, including death, have been reported during leflunomide treatment. Most cases occurred within the first 6 months of treatment. Most cases exist in combination with other hepatotoxic drugs. Strict adherence to monitoring recommendations is essential.
ALT (SGPT) must be checked before starting leflunomide and tested regularly (every two weeks) for the first 6 months of treatment, along with a complete blood count, and every 8 weeks thereafter.
When ALT (SGPT) is elevated to 2 to 3 times the upper limit of normal, a dose reduction from 20 mg to 10 mg may be considered and must be monitored weekly. If the ALT (SGPT) elevation exceeds 2 times the upper limit of normal and persists, or if the ALT elevation exceeds 3 times the upper limit of normal, then leflunomide must be discontinued and a washout procedure initiated. Continued monitoring of liver enzymes after discontinuation of treatment with leflunomide is recommended until liver enzyme levels return to normal.
Because of the potential for superimposed hepatotoxic effects, abstinence from alcohol during leflunomide therapy is recommended.
Because the active metabolite of leflunomide, teriflunomide, has a high protein binding rate and is cleared by hepatic metabolism and biliary secretion, elevated plasma teriflunomide levels would be expected in patients with hypoproteinemia. Leflunomide is contraindicated in patients with severe hypoproteinemia or impaired hepatic function (see [Contraindications]).
Hematologic Reactions
ALT and complete blood count (including white blood cell sorting count and platelet count) are measured prior to initiation of treatment with Leflunomide, every 2 weeks for the first 6 months of treatment, and every 8 weeks thereafter.
There is an increased risk of hematologic abnormalities in patients with pre-existing anemia, leukopenia and/or thrombocytopenia and in patients with impaired bone marrow function or at risk of bone marrow suppression. If such reactions occur, consideration should be given to washout (see “Washout Procedure” below) to reduce plasma levels of teriflunomide.
In the event of a severe hematologic reaction (including complete cytopenia), leflunomide and other concomitant myelosuppressive therapy must be discontinued and the leflunomide washout process initiated.
Combination with other therapeutic agents
To date, the combination of leflunomide with antimalarials (e.g., chloroquine and hydroxychloroquine), intramuscular or oral gold, D-penicillamine, azathioprine, and other immunosuppressive agents (including tumor necrosis factor alpha inhibitors) has not been adequately studied in randomized trials in patients with rheumatic diseases (except methotrexate, see [Drug Interactions]). Therefore the risks associated with combination dosing (particularly in long-term therapy) are not known. Because the combination of this product with other DMARDs (e.g., methotrexate) may result in superimposed or enhanced toxicity (e.g., hepatotoxicity or hematotoxicity), the combination of the two is not recommended.
Co-administration of teriflunomide with leflunomide is not recommended because leflunomide is the parent compound of teriflunomide.
Conversion to other treatments
Leflunomide is present in the body for a long time and therefore the potential for additional risks (kinetic interactions, organ toxicity) is increased if switching to another DMARD (e.g., methotrexate) without purging, even long after the switch.
Similarly, recent treatment with hepatotoxic or hematotoxic drugs (e.g., methotrexate) may lead to increased side effects; therefore, initiation of leflunomide therapy requires careful consideration of these benefit/risk scenarios and close monitoring is recommended at the beginning of the switch.
Skin reactions
Leflunomide should be discontinued if ulcerative oral mucositis occurs.
Very rare reactions to Stevens-Johnson syndrome, toxic epidermolysis bullosa, and drug reactions with eosinophilia and systemic symptoms (DRESS) have been reported in patients treated with Leflunomide. Once skin and/or mucosal reactions suspected of such severe reactions are observed, leflunomide and any other potentially relevant therapeutic agents must be discontinued and leflunomide cleansing must be performed immediately. In such cases, a complete cleansing process must be used and reintroduction of Leflunomide is prohibited (see [Contraindications]).
Pustular psoriasis and worsening of psoriasis were reported after the use of Leflunomide.
Considering the patient’s condition and past history, discontinuation of the drug may be considered.
Infections
Immunosuppressive drugs (e.g., leflunomide) are known to cause patients to be more susceptible to infections (including opportunistic infections). Infections may be more severe in nature and therefore may require early and vigorous treatment. If severe uncontrollable infections occur, it may be necessary to interrupt leflunomide therapy and perform a washout procedure as described below.
Rare cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving leflunomide and other immunosuppressive agents.
Prior to initiating treatment, all patients should be evaluated for active and inactive (“latent”) TB disease according to local guidelines. This includes medical history, previous contact with TB patients and/or appropriate screening (e.g., lung x-ray, tuberculin test and/or interferon-gamma release test, if applicable). Alert prescribers about the risk of false-negative tuberculin skin test results, especially in those patients who are severely or immunocompromised. Patients with a history of tuberculosis should be monitored closely because of the possibility of reactivation of infection.
Respiratory reactions
Cases have been reported of interstitial lung disease during leflunomide therapy, as well as rare pulmonary hypertension (see [Adverse Reactions]). Patients with a history of interstitial lung disease may be at increased risk of developing this reaction. Interstitial lung disease is a potentially fatal disease that may flare up acutely during treatment. Pulmonary symptoms (e.g., cough and dyspnea) may lead to interruption of treatment and intensive examination depending on the condition.
Peripheral neuropathy
Peripheral neuropathy has been reported in patients treated with leflunomide. Most patients experienced improvement in symptoms after discontinuation of leflunomide. However, the final outcome varied considerably: in some patients the neuropathy became remitted, while in others the symptoms persisted. Patients older than 60 years of age with a combination of neurotoxic medications and diabetes may be at increased risk of developing peripheral neuropathy. If peripheral neuropathy develops in patients taking leflunomide, it is recommended that leflunomide therapy be discontinued and a drug clearance process be implemented.
Colitis
Colitis (including microscopic colitis) has been reported in patients treated with Leflunomide. Appropriate diagnosis should be made in the event of unexplained chronic diarrhea in patients treated with leflunomide.
Blood pressure
Blood pressure must be checked prior to initiation of leflunomide therapy and periodically thereafter.
Fertility (recommendations for men)
Male patients should be aware of the possibility of male-mediated fetal toxicity and ensure reliable contraception during treatment with Leflunomide.
Specific data on male-mediated fetal toxicity are not available. To reduce all possible risks, men who are ready to have children should consider discontinuing leflunomide and taking either 8 g of cloacenamide (abciximide) three times a day for 11 consecutive days or 50 g of activated charcoal powder four times a day for 11 consecutive days.
For both of these options, the teriflunomide plasma concentration is first measured, after which the teriflunomide plasma concentration must be measured again at an interval of at least 14 days. If both plasma concentrations are below 0.02 mg/L and after waiting at least 3 months, the risk of fetal toxicity will be very low.
Washing process
Take 8g of kolefenamide per dose, 3 times a day. Or 50g of activated charcoal powder per dose, 4 times per day. A complete washout period is usually 11 days. The washout period can be changed according to clinical or laboratory needs.
Lactose
This product contains lactose. It should not be administered to patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption disorders.
Interference with the determination of ionized calcium levels
Depending on the type of ionized calcium analyzer used (e.g. blood gas analyzer), determination of ionized calcium levels may incorrectly show a decrease in values under treatment with leflunomide and/or teriflunomide (the active metabolite of leflunomide). Therefore, the possibility of a decrease in ionized calcium levels observed in patients treated with leflunomide or teriflunomide is questionable. In case of doubtful measurements, determination of total albumin radiolucent serum calcium concentration is recommended.
[For pregnant and lactating women].
According to foreign literature.
Pregnancy
The active metabolite of leflunomide, teriflunomide, is suspected to cause serious birth defects when given during pregnancy. Leflunomide is contraindicated during pregnancy (see [Contraindications]).
Women of childbearing potential must use effective contraception for 2 years after treatment (see “Waiting Period” below) or for 11 days after treatment (see “Washout Period” below).
Patients must be informed that if pregnancy is suspected by delayed menstruation or for any other reason, the physician must be notified immediately for a pregnancy test, and if the pregnancy test is positive, the physician and patient must discuss the risks of pregnancy. Administering the drug clearance process described below at the time of first delayed menstruation has the potential to rapidly reduce blood levels of active metabolites to reduce the risk of leflunomide to the fetus.
In a small prospective study, the overall incidence of major structural defects (5.4%) was not significantly different (p=0.13) in unintended pregnant women (n=64) who took leflunomide followed by a drug elimination procedure within 3 weeks of pregnancy compared to either control group (4.2% in the disease-matched group [n=108] and 4.2% in the group of healthy pregnant women [n=78]).
For women treated with leflunomide and planning a pregnancy, one of the following procedures is recommended to ensure that the fetus is not exposed to toxic concentrations of teriflunomide (target concentrations below 0.02 mg/L).
Waiting period
Plasma levels of teriflunomide can be expected to be above 0.02 mg/L for a prolonged period of time. it is expected that this concentration can be reduced to less than 0.02 mg/L approximately 2 years after discontinuation of haloflunomide.
After a 2-year waiting period, the first measurement of teriflunomide plasma concentrations is taken. Thereafter, teriflunomide plasma concentrations must be measured again at intervals of at least 14 days. If both plasma concentrations are below 0.02 mg/L, no teratogenic risk is expected.
Cleaning process
After discontinuation of treatment with teriflunomide.
● 8 g of colesevelamer given 3 times daily for 11 consecutive days.
●or, 50 g of activated carbon powder given 4 times daily for 11 consecutive days.
However, after either washout procedure, a minimum of 14 days is required for verification by 2 independent trials and a one-and-a-half month wait for conception after the first occurrence of plasma concentrations below 0.02 mg/L.
Women of childbearing age should be informed that they need to wait 2 years after stopping treatment before conceiving. If reliable contraception is not available for 2 years, an earlier cleansing process is recommended.
Both koleenamine and activated charcoal powder may affect the absorption of estrogen and progesterone, so the reliability of the contraceptive effect of oral contraceptives may not be guaranteed during cleansing with koleenamine or activated charcoal powder. The use of other contraceptive methods is recommended.
Lactation
Leflunomide should not be administered to women who are breastfeeding.
[Pediatric use].
Leflunomide is not recommended for use in patients under 18 years of age because the efficacy and safety of this product has not been demonstrated in patients with juvenile rheumatoid arthritis (JRA) (see [Pharmacokinetics]). Geriatric Use]
Pharmacokinetic data in the elderly (> 65 years of age) are limited, but are consistent with those in younger adults.
[Drug Interactions].
As reported in foreign literature.
Interaction studies have been conducted in adults only.
The occurrence of side effects may be increased if the patient has recently or concurrently used hepatotoxic or hematotoxic drugs, or if such drugs are not used after a washout period following leflunomide treatment (see [Precautions]). Therefore, close monitoring of hepatic enzymes and hematologic parameters is recommended in the initial period after drug switching.
Methotrexate
In a small study (n=30) of leflunomide (10-20 mg/day) in combination with methotrexate (10-25 mg/week), a 2- to 3-fold increase in liver enzymes was seen in 5 of 30 patients. All liver enzyme elevations resolved, including two patients with continued use of both drugs and three patients with discontinuation of leflunomide. In the other 5 patients, liver enzyme elevations of more than 3-fold were seen. All elevations resolved, including two patients with continuation of both drugs and three patients with discontinuation of flumet.
No pharmacokinetic interactions were seen between leflunomide (10-20 mg/day) and methotrexate (10-25 mg/week) in patients with rheumatoid arthritis.
Vaccination
There are no clinical data on the efficacy and safety of vaccination with the use of Leflunomide. However, vaccination with live attenuated vaccines is not recommended with the use of this product. The long half-life of leflunomide should be considered when vaccinating with live attenuated vaccines after discontinuation of leflunomide.
Warfarin and other coumarin-based anticoagulants
Prolonged prothrombin time has been reported with the coadministration of leflunomide and warfarin. Clinical pharmacology studies have found a pharmacokinetic interaction between teriflunomide and warfarin. Therefore, close follow-up and monitoring of the international normalized ratio (INR) is recommended when this product is co-administered with warfarin or other coumarin-based anticoagulants.
NSAIDS/Corticosterone
Patients may continue to use non-steroidal anti-inflammatory drugs (NSAIDs) and/or corticosterone if they were already using these drugs prior to starting treatment with Leflunomide.
Effects of other drugs on Leflunomide.
Colesevelam and activated charcoal
Patients treated with leflunomide should not take colesevelam or powdered activated charcoal because this causes a rapid and significant decrease in plasma teriflunomide (the active metabolite of leflunomide; see [Pharmacokinetics]) concentrations. The mechanism of action is the interruption of enterohepatic circulation and/or gastrointestinal dialysis of teriflunomide.
CYP450 Inhibitors and Inducers
Results of in vitro inhibition studies in human liver microsomes suggest the involvement of cytochrome P450 (CYP) 1A2, 2C19 and 3A4 in the metabolism of leflunomide. In vivo interaction studies with leflunomide and cimetidine, a non-specific weak cytochrome P450 (CYP) inhibitor, showed no significant change in teriflunomide exposure. The combination of multiple doses of rifampicin (a non-specific cytochrome P450 inducer) and a single dose of rifamet in patients resulted in an approximately 40% increase in peak concentrations of teriflunomide without a significant change in AUC. The mechanism of action of this effect is unclear.
Effects of Leflunomide on other drugs.
Oral contraceptives
In a study of healthy female volunteers taking leflunomide in combination with a triphasic oral contraceptive containing 30 µg of ethinyl estradiol, there was no decrease in contraceptive activity of the pill and the teriflunomide pharmacokinetics were within the expected range. There were pharmacokinetic interactions between teriflunomide and oral contraceptives (see “Effects on Oral Contraceptives” below).
The following pharmacokinetic and pharmacodynamic interaction studies were performed with teriflunomide, the primary active metabolite of leflunomide. Similar drug interactions cannot be ruled out for leflunomide at the recommended doses and therefore the following findings and recommendations should be considered when patients use leflunomide.
Effects on Repaglinide (CYP2C8 substrate)
Repeated administration of teriflunomide resulted in an increase in mean Cmax and AUC of repaglinide (1.7 and 2.4-fold, respectively), suggesting that teriflunomide is a CYP2C8 inhibitor in vivo. Therefore, monitoring is recommended for patients using both this product and drugs metabolized by CYP2C8 (e.g., repaglinide, paclitaxel, pioglitazone, or rosiglitazone are recommended) due to their higher exposure.
Effects on caffeine (CYP1A2 substrate)
Repeated administration of teriflunomide reduced the mean Cmax and AUC of caffeine (CYP1A2 substrate) by 18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2 in vivo. Therefore, drugs metabolized by CYP1A2 (e.g., duloxetine, alosetron, theophylline, and tizanidine) should be used with caution during treatment with this product, as they may result in reduced efficacy of these drugs.
Effects on organic anion transporter 3 (OAT3) substrates
The mean Cmax and AUC of cefaclor increased after repeated administration of teriflunomide (1.43 and 1.54-fold, respectively), indicating that teriflunomide is an OAT3 inhibitor in vivo. Therefore, caution should be exercised in combining this product with OAT3 substrates (e.g., cefaclor, benzylpenicillin, ciprofloxacin, indomethacin, ketoprofen, furosemide, cimetidine, methotrexate, zidovudine).
Effect on BCRP (breast cancer resistance protein) and/or organic anion transporting polypeptide B1 and B3 (OATP1B1/B3) substrates
Repeated administration of teriflunomide increased the mean Cmax and AUC of resulvastatin (2.65 and 2.51-fold, respectively). However, increased plasma risuvastatin exposure had no significant effect on HMG-CoA reductase activity. If combined, the dose of rosuvastatin should not exceed 10 mg once daily. Combinations of other BCRP substrates (e.g., methotrexate, topotecan, lorazepam, rosmarinic acid, doxorubicin) and OATP family drugs, particularly HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, repaglinide, rifampin), should be administered with caution. Patients should be closely monitored for signs and symptoms of overexposure and dose reductions of these drugs should be considered.
Effects on oral contraceptives (0.03 mg ethinylestradiol and 0.15 mg levonorgestrel)
Repeated administration of teriflunomide resulted in an increase in mean Cmax and AUC0-24 for ethinylestradiol (1.58 and 1.54-fold, respectively) and levonorgestrel (1.33 and 1.41-fold, respectively). Although this interaction is not expected to adversely affect the efficacy of oral contraceptives, the type of oral contraceptive should be considered.
Effects on warfarin (CYP2C9 substrate)
Repeated administration of teriflunomide had no effect on S-warfarin pharmacokinetics, indicating that teriflunomide is not an inhibitor or inducer of CYP2C9. However, when teriflunomide was coadministered with warfarin, a 25% reduction in peak international normalized ratio (INR) was observed compared to warfarin alone. Therefore, when co-administered with warfarin, close follow-up and monitoring of the INR is recommended.
[Drug overdose].
As reported in foreign literature.
Symptoms
Long-term overdoses of leflunomide in patients with daily doses up to 5 times the recommended daily dose have been reported, as well as acute overdoses in adults and children. No adverse events have been reported in the vast majority of overdose cases. Adverse events consistent with the safety profile of leflunomide were: abdominal pain, nausea, diarrhea, elevated liver enzymes, anemia, leukopenia, pruritus and rash.
Treatment
In the event of an overdose or toxic reaction, accelerated elimination with either kolefenamide or activated charcoal is recommended. 3 healthy volunteers given 8 g of kolefenamide orally 3 times a day over 24 hours had an approximately 40% reduction in plasma levels of teriflunomide over 24 hours and 49%-65% over 48 hours.
It has been demonstrated that administration of activated charcoal (powder made into a suspension) by oral or nasogastric tube (50 g every 6 hours over a 24-hour period) reduces teriflunomide plasma levels by 37% over 24 hours and by 48% over 48 hours.
This cleansing process can be repeated as clinically indicated.
The results of hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) studies indicate that teriflunomide, the major metabolite of leflunomide, is not dialyzable.
[Clinical trials].
The phase III clinical trial of leflunomide for lupus nephritis in China was a multicenter, randomized, parallel-controlled clinical study. A total of 184 patients were enrolled, including 108 patients in the trial group (leflunomide) and 76 patients in the control group (cyclophosphamide).
Patient inclusion criteria: age 18-65 years; lupus nephritis renal biopsy pathology type III, IV or with V; active disease, SLEDAI lupus activity score ≥ 8; persistent proteinuria (≥ 1g/24h), microscopic hematuria; no use of cytotoxic drugs such as CTX within 3 months.
Treatment regimen: trial group: oral leflunomide tablets, 0.8-1.0 mg/Kg/day for 3 days at the beginning of the trial and 20-40 mg/day for maintenance thereafter. Control group: intravenous cyclophosphamide at a dose of 0.8-1.0g/month, once a month. Combination hormone: oral prednisone at a dose of 0.8mg/Kg/day (usually at 40-60mg/day), changed to 0.5mg/Kg/day after 1 month, then gradually reduced (2.5-5mg every 2 weeks) to a maintenance dose of 5-10mg/day. The duration of treatment is 6 months.
Efficacy criteria: complete remission: 24-hour urine protein quantification less than 0.3g, and urine sediment (RBC <5/HP, WBC <5/HP), serum albumin, serum SCr and CCr tests are normal. Partial remission: 24-hour urine protein quantification between 0.3-3g with ≥50% decrease, and serum albumin ≥30g/L, and stable renal function. Treatment failure: 24-hour urine protein quantification decreased <50%; or 24-hour urine protein quantification between 0.3-3g, but serum albumin <30g/L; or serum SCr increased and CCr decreased more than 15% of the basal value.
Efficacy.
Comprehensive efficacy evaluation: after 6 months of treatment, complete remission was 22.22% and partial remission was 59.60% in the test group; 18.84% and 62.32% in the control group, respectively; after 6 months of treatment, compared with baseline levels, both the test and control groups significantly reduced SLEDAI scores, reduced 24-hour urine protein, increased serum albumin, reduced SCr, increased C3, and reduced ds- DNA positivity rate.
The pathological types of the biopsies of the cases enrolled in the trial were type III, IV, or with type V of lupus nephritis. Fifteen of the cases in the trial group underwent repeat renal biopsies after 6 months of treatment. The results showed that the activity of lupus nephritis was reduced and the acute activity index decreased in 13 patients after treatment with leflunomide. Among them, 7 patients had types III and IV before treatment, and all of them were converted to type II with milder pathological types after treatment with leflunomide.
Adverse effects.
The incidence of adverse reactions that may be related/associated with the drug was 39.81% in the test group and 55.26% in the control group. Adverse events with an incidence of ≥3% in the trial group included alopecia, elevated blood pressure, herpes zoster, elevated transaminases, diarrhea/dilute stools, decreased white blood cells, rash, menstrual irregularities, palpitations, and abdominal pain; adverse events with an incidence of <3% included nausea/vomiting, upper respiratory tract infection, decreased platelets, malaise, burning stomach, anorexia, fever, periodontal pain, visual abnormalities, urinary tract infection, sore throat, giant cell virus infection, weight loss, hypertrichosis, and lung infection.
At the end of the phase III clinical trial, 52 patients in the trial group voluntarily continued to take the trial drug at doses of 10-30 mg/day; after 9 months of treatment, the dose was reduced to 10-20 mg/day in 90% of patients. The mean follow-up time was 32.7±18.2 months, and the longest observation time was 72 months; at 6 months of treatment, the complete remission rate was 36.5% and partial remission rate was 44.2% in 52 patients; after 7-72 months of continued treatment, the complete remission rate was 59.6% and partial remission rate was 30.6%. During the clinical observation period, a total of 12 patients experienced adverse reactions that may be related/associated with the test drug, with an incidence of 23.08%. Adverse events with an incidence of ≥3% included: leukocyte drop, transaminase elevation, thrombocytopenia; adverse events with an incidence of <3% included: upper respiratory tract infection, alopecia, herpes zoster, menstrual disorders, urinary tract infection.
Pharmacology and Toxicology
Pharmacological effects
Leflunomide is an isoxazole immunosuppressant with anti-proliferative activity, mainly inhibiting the activity of dihydroorotic acid dehydrogenase and thus affecting pyrimidine synthesis in activated lymphocytes. Some in vitro and in vivo tests have shown that it has anti-inflammatory effects.
Toxicological studies
Genotoxicity
Leflunomide was not found to be mutagenic in the Ames assay, the in-process DNA synthesis assay, the HGPRT gene mutation assay, the in vivo mouse micronucleus assay, or the in vivo genetic assay in Chinese hamster bone marrow cells. The trace metabolite of leflunomide, 4-trifluoromethylaniline (TFMA), showed mutagenicity in the Ames test and the HGPRT mutation test, and mutagenicity was induced in the in vitro chromosomal aberration test in Chinese hamster cells; TFMA was not mutagenic in the in vivo mouse micronucleus test and the in vivo genetic test in Chinese hamster bone marrow cells.
Reproductive toxicity
No effects on fertility or reproductive capacity were observed in male and female rats when leflunomide was given orally at 4.0 mg/kg (approximately 1/30th of the in vivo exposure to human teriflunomide in terms of AUC).
Carcinogenicity
In a 2-year rat test, no carcinogenicity was observed with oral administration of leflunomide at a maximum tolerated dose of 6 mg/kg (approximately 1/40th of the maximum human in vivo exposure to teriflunomide in terms of AUC). In a 2-year mouse test, an increased incidence of lymphoma was seen in male mice given the highest dose of 15 mg/kg of leflunomide (1.7 times the in vivo exposure of human teriflunomide in terms of AUC); in female mice given doses starting at 1.5 mg/kg (approximately 1/10th of the exposure of human teriflunomide in terms of AUC), drug-related bronchoalveolar adenocarcinoma and bronchial A dose-related increase in the incidence of alveolar adenocarcinoma of the lung was observed. The relevance of the mouse findings to the clinical application of the drug is unknown.
[Pharmacokinetics].
As reported in foreign literature.
Leflunomide is rapidly converted to the active metabolite teriflunomide through a first-pass effect (ring opening) in the intestinal wall and liver. In a radiolabeled 14C-leflunomide study, the prototype drug of leflunomide was not detected in the plasma, urine or feces of three healthy volunteers. In other studies, plasma levels of the prototype leflunomide drug were rarely detected, but plasma levels were at the ng/ml level. The only plasma radiolabeled metabolite detected was teriflunomide. This metabolite is the primary source of all in vivo activity of leflunomide.
Absorption
Excretion data from the 14C study indicate that at least about 82% – 95% of the dose is absorbed. The time to peak blood concentrations of teriflunomide is highly variable; peak plasma concentrations occur between 1 and 24 hours after a single dose. Leflunomide can be taken with meals, as it is absorbed to a comparable extent in the fed and fasted states. Because of the long half-life of teriflunomide (approximately 2 weeks), a loading dose of 100 mg for 3 consecutive days in clinical studies resulted in rapid achievement of steady-state levels of teriflunomide. In the absence of a loading dose, it is estimated that steady-state plasma concentrations are reached after approximately 2 months of administration. In multi-dose studies in patients with rheumatoid arthritis, the pharmacokinetic parameters of teriflunomide were linear over the 5-25 mg dose range. In these studies, clinical efficacy was strongly correlated with teriflunomide plasma concentrations and daily doses of leflunomide. The mean steady-state plasma concentration of teriflunomide given as a 20 mg daily dose was approximately 35 µg/ml. Steady-state plasma levels accumulated approximately 33-35 times compared to a single dose.
Distribution
In human plasma, teriflunomide is extensively bound to proteins (albumin). The unbound fraction of teriflunomide is approximately 0.62%. Binding of teriflunomide is linear over the therapeutic concentration range. In plasma from patients with rheumatoid arthritis or chronic renal insufficiency, the protein binding of teriflunomide appears to be slightly lower and more variable. The extensive protein binding of teriflunomide may lead to substitution with other highly bound drugs. However, in vitro plasma protein binding interaction studies with clinically relevant concentrations of warfarin showed no interaction. Similar results showed that ibuprofen and diclofenac did not displace teriflunomide, however, the unbound fraction of teriflunomide increased 2-3 fold in the presence of tosylbutazone. Teriflunomide replaced ibuprofen, diclofenac, and tosylbutazone, but the unbound fraction of these drugs increased by only 10%-50%. There is no indication that these effects are clinically significant. Consistent with extensive protein binding, teriflunomide has a low apparent volume of distribution (~11 L). There is no preferential erythrocyte uptake.
Biotransformation
Leflunomide is metabolized to a major (teriflunomide) and many minor metabolites, including TFMA (4-trifluoromethylaniline). The metabolism of leflunomide to teriflunomide and the subsequent biotransformation of teriflunomide metabolism is not controlled by a single enzyme and has been shown to occur in the microsomal and cytoplasmic cell fractions. Interaction studies with cimetidine (a non-specific cytochrome P450 inhibitor) and rifampicin (a non-specific cytochrome P450 inducer) have shown that the CYP enzymes in vivo are involved in the metabolism of leflunomide only to a lesser extent.
Elimination
The elimination of teriflunomide is slow, with an apparent clearance of approximately 31 ml/h. The elimination half-life in patients is approximately 2 weeks. Following administration of radiolabeled leflunomide, radioactivity is excreted in moderate amounts in the feces (possibly through biliary elimination) and urine. Teriflunomide was still detectable in urine and feces 36 days after a single dose. The major metabolites in urine were the leflunomide glucosinolate product (mainly in 0-24 hour samples) and the aniline carbonyl acid derivative of teriflunomide. The major component in feces is teriflunomide.
In humans it has been demonstrated that administration of activated charcoal powder or koleleneamine oral suspension results in a rapid and significant increase in the rate of teriflunomide elimination and a decrease in plasma concentrations (see [Drug Overdose]). This is thought to be achieved by gastrointestinal dialysis mechanisms and/or interruption of the enterohepatic circulation.
Renal damage
A single oral dose of 100 mg of leflunomide was administered to three patients on hemodialysis and three patients on continuous peritoneal dialysis (CAPD). The pharmacokinetics of teriflunomide in CAPD subjects were similar to those of healthy volunteers. Faster elimination of teriflunomide was observed in hemodialysis patients, which was not due to extraction of the drug from the dialysate.
Liver Injury
No data are available on the treatment of patients with hepatic injury. The active metabolite teriflunomide is extensively bound to proteins and is cleared by hepatic metabolism and biliary secretion. These processes may be affected by hepatic dysfunction.
Geriatric population
Pharmacokinetic data in the elderly (> 65 years of age) are limited, but are consistent with those in younger adults.
Storage】Store in a dry place under shade and seal.
Package】Packaged in laminated aluminum foil, 10 tablets/plate×1 plate/box; 10 tablets/plate×2 plate/box; 8 tablets/plate×2 plate/box; 8 tablets/plate×4 plate/box; 8 tablets/plate×6 plate/box.
【Validity】18 months
【Execution standard
【Approval number】State Drug Administration H20000550
[Marketing authorization holder
Company Name: Suzhou Changzheng-Xinkai Pharmaceutical Co.
Production Address: No. 567, Liufeng Road, Hedong Industrial Park, Wuzhong Economic Development Zone, Suzhou, Jiangsu Province, China
Manufacturer
Company Name: Suzhou Changzheng-Xinkai Pharmaceutical Co.
Production Address: No. 567, Liufeng Road, Hedong Industrial Park, Wuzhong Economic Development Zone, Suzhou, Jiangsu Province
Postal Code: 215124
Phone Number：800-820-5615（call from landline）400-820-5615（call from mobile）0512-66981208 0512-66981100
Fax number：0512-66980737
Web Address: http://www.cinkate.net