药物名称： 来氟米特
　　
药物别名： 爱若华、妥抒 　
　
英文名称： Leflunomide 　
　
说　明： 本品为白色薄膜衣片，除去簿膜衣呈白色。储藏温度25℃：允许范围15～30℃，避光。
　
功用作用： 来氟米特是一个具有抗增生活生的异饿恶唑类免抑制剂其作用机理主要是抑制二氢乳清酸脱氢酶的活性，从而影响活化淋巴细胞的嘧啶合成。体内外试验表明本品具有抗炎作用。来氟米特的体内活性主要通过其活性代谢产物而产生。成人活动性类风湿性关节炎。

用法用量： 每日一次，每次2片。最初三天给予负荷剂量(50mg／日)，之后给予维持剂量20mg／天。
　　
注意事项：
1．临床试验发现来氟米特可引起一过性的SGPT升高和白细胞下降，服药初始阶段应定期检查SGPT和白细胞。检查间隔视病人情况而定。 　
2．严重肝脏损害和明确的乙肝或丙肝血清学指标的患者慎用。用药前及用药后每月检查SGPT，检测时间间隔视病人具体情况而定。 　　
3．免疫缺陷、未控制的感染、活动性胃肠道疾病、肾功能不全、骨髓发育不良的患者慎用。 　　
4．准备生育的男性应该考虑中断治疗，同时服药消胆胺。5．如果剂量过大或出现毒性时，可给予消胆胺或活性炭快速降低M1浓度。

【原产地英文商品名】ARAVA 10MG/TAB 30TABS/BOX
【原产地英文药品名】LEFLUNOMIDE 10MG/TAB 30TABS/BOX
【中文参考商品译名】
注：以下产品不同的规格和不同的价格，购买时请咨询为准
·爱若华 10毫克/片 30片/盒 （安万特公司）
·爱若华 10毫克/片 30片/盒
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·爱若华仿制药 20毫克/片 30片/盒 （爱若华仿制药）
·爱若华仿制药 10毫克/片 30片/盒（爱若华仿制药）
【中文参考药品译名】来氟米特 10毫克/片 30片/盒
【生产厂家中文参考译名】安万特公司
【生产厂家英文名】SANOFI AVENTIS US

DRUG DESCRIPTION
ARAVA® (leflunomide) is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4´-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C12H9F3N2O2, a molecular weight of 270.2.ARAVA is available for oral administration as tablets containing 10, 20, or 100 mg of active drug. Combined with leflunomide are the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, starch, talc, titanium dioxide, and yellow ferric oxide (20 mg tablet only).
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INDICATIONS
ARAVA is indicated in adults for the treatment of active rheumatoid arthritis (RA):
1.to reduce signs and symptoms
2.to inhibit structural damage as evidenced by X-ray erosions and joint space narrowing
3.to improve physical function.

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DOSAGE AND ADMINISTRATION
Loading Dose
Due to the long half-life in patients with RA and recommended dosing interval (24 hours), a loading dose is needed to provide steady-state concentrations more rapidly. It is recommended that ARAVA therapy be initiated with a loading dose of one 100 mg tablet per day for 3 days.
Elimination of the loading dose regimen may decrease the risk of adverse events. This could be especially important for patients at increased risk of hematologic or hepatic toxicity, such as those receiving concomitant treatment with methotrexate or other immunosuppressive agents or on such medications in the recent past.
Maintenance Therapy
Daily dosing of 20 mg is recommended for treatment of patients with RA. A small cohort of patients (n=104), treated with 25 mg/day, experienced a greater incidence of side effects; alopecia, weight loss, liver enzyme elevations. Doses higher than 20 mg/day are not recommended. If dosing at 20 mg/day is not well tolerated clinically, the dose may be decreased to 10 mg daily. Due to the prolonged half-life of the active metabolite of leflunomide, patients should be carefully observed after dose reduction, since it may take several weeks for metabolite levels to decline.
Monitoring
Hematology parameters and liver enzymes should be monitored.
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HOW SUPPLIED
ARAVA Tablets in 10 and 20 mg strengths are packaged in bottles. ARAVA Tablets 100 mg strength are packaged in blister packs.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
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SIDE EFFECTS
Adverse reactions associated with the use of leflunomide in RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. In the controlled studies at one year, the following adverse events were reported, regardless of causality.
Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.
In addition, the following adverse events have been reported in 1% to < 3% of the RA patients in the leflunomide treatment group in controlled clinical trials.
Body as a Whole: abscess, cyst, fever, hernia, malaise, pain, neck pain, pelvic pain;
Cardiovascular: angina pectoris, migraine, palpitation, tachycardia, varicose vein, vasculitis, vasodilatation;
Gastrointestinal: cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, stomatitis (or aphthous stomatitis), tooth disorder;
Endocrine: diabetes mellitus, hyperthyroidism;
Hemic and Lymphatic System: anemia (including iron deficiency anemia), ecchymosis;
Metabolic and Nutritional: creatine phosphokinase increased, hyperglycemia, hyperlipidemia, peripheral edema;
Musculo-Skeletal System: arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon rupture;
Nervous System: anxiety, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorder, sweating increased, vertigo;
Respiratory System: asthma, dyspnea, epistaxis, lung disorder;
Skin and Appendages: acne, contact dermatitis, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster, maculopapular rash, nail disorder, skin discoloration, skin disorder, skin nodule, subcutaneous nodule, ulcer skin;
Special Senses: blurred vision, cataract, conjunctivitis, eye disorder, taste perversion;
Urogenital System: albuminuria, cystitis, dysuria, hematuria, menstrual disorder, prostate disorder, urinary frequency, vaginal moniliasis.
Other less common adverse events seen in clinical trials include: 1 case of anaphylactic reaction occurred in Phase 2 following rechallenge of drug after withdrawal due to rash (rare); urticaria; eosinophilia; transient thrombocytopenia (rare); and leukopenia < 2000 WBC/mm³ (rare).
Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.
In post-marketing experience, the following have been reported rarely:
Body as a whole: opportunistic infections, severe infections including sepsis that may be fatal;
Gastrointestinal: pancreatitis;
Hematologic: agranulocytosis, leukopenia, neutropenia, pancytopenia, thrombocytopenia;
Hypersensitivity: angioedema;
Hepatic: hepatitis, jaundice/cholestasis, severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal;
Respiratory: interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal;
Nervous system: peripheral neuropathy;
Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis.
Adverse Reactions (Pediatric Patients)
The safety of ARAVA was studied in 74 patients with polyarticular course juvenile rheumatoid arthritis ranging in age from 3-17 years (47 patients from the active-controlled study and 27 from an open-label safety and pharmacokinetic study). The most common adverse events included abdominal pain, diarrhea, nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia, rash, headache, and dizziness. Less common adverse events included anemia, hypertension, and weight loss. Fourteen pediatric patients experienced ALT and/or AST elevations, nine between 1.2 and 3-fold the upper limit of normal, five between 3 and 8-fold the upper limit of normal.
Drug Abuse And Dependence
ARAVA has no known potential for abuse or dependence.
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DRUG INTERACTIONS
Cholestyramine and Charcoal
Administration of cholestyramine or activated charcoal in patients (n=13) and volunteers (n=96) resulted in a rapid and significant decrease in plasma M1 (the active metabolite of leflunomide) concentration .
Hepatotoxic Drugs
Increased side effects may occur when leflunomide is given concomitantly with hepatotoxic substances. This is also to be considered when leflunomide treatment is followed by such drugs without a drug elimination procedure. In a small (n=30) combination study of ARAVA with methotrexate, a 2- to 3-fold elevation in liver enzymes was seen in 5 of 30 patients. All elevations resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. A > 3-fold increase was seen in another 5 patients. All of these also resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. Three patients met “ACR criteria” for liver biopsy (1: Roegnik Grade I, 2: Roegnik Grade IIIa). No pharmacokinetic interaction was identified .
NSAIDs
In in vitro studies, M1 was shown to cause increases ranging from 13 - 50% in the free fraction of diclofenac and ibuprofen at concentrations in the clinical range. The clinical significance of this finding is unknown; however, there was extensive concomitant use of NSAIDs in clinical studies and no differential effect was observed.
Tolbutamide
In in vitro studies, M1 was shown to cause increases ranging from 13 - 50% in the free fraction of tolbutamide at concentrations in the clinical range. The clinical significance of this finding is unknown.
Rifampin
Following concomitant administration of a single dose of ARAVA to subjects receiving multiple doses of rifampin, M1 peak levels were increased (~40%) over those seen when ARAVA was given alone. Because of the potential for ARAVA levels to continue to increase with multiple dosing, caution should be used if patients are to be receiving both ARAVA and rifampin.
Warfarin
Increased INR (International Normalized Ratio) when ARAVA and warfarin were co-administered has been rarely reported.
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WARNINGS
Hepatotoxicity
Severe liver injury, including fatal liver failure, has been reported in some patients treated with ARAVA. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) > 2xULN before initiating treatment, should not be treated with ARAVA. Use caution when ARAVA is given with other potentially hepatotoxic drugs. Monitoring of ALT levels is recommended at least monthly for six months after starting ARAVA, and thereafter every 6-8 weeks. If ALT elevation > 3 fold ULN occurs, interrupt ARAVA therapy while investigating the probable cause of the ALT elevation by close observation and additional tests. If likely leflunomide-induced, start cholestyramine washout and monitor liver tests weekly until normalized . If leflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of ARAVA therapy may be considered.
In addition, if ARAVA and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing monthly.
In clinical trials, ARAVA treatment as monotherapy or in combination with methotrexate was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild ( ≤ 2-fold ULN) and usually resolved while continuing treatment. Marked elevations ( > 3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 8 shows liver enzyme elevations seen with monthly monitoring in clinical trials US301 and MN301. It was notable that the absence of folate use in MN302 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate.
Immunosuppression Potential/Bone Marrow Suppression
ARAVA is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. In the event that a serious infection occurs, it may be necessary to interrupt therapy with ARAVA and administer cholestyramine or charcoal . Medications like leflunomide that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis. Severe infections including sepsis, which may be fatal, have been reported in patients receiving ARAVA, especially Pneumocystis jiroveci pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection.
There have been rare reports of pancytopenia, agranulocytosis and thrombocytopenia in patients receiving ARAVA alone. These events have been reported most frequently in patients who received concomitant treatment with methotrexate or other immunosuppressive agents, or who had recently discontinued these therapies; in some cases, patients had a prior history of a significant hematologic abnormality.
Patients taking ARAVA should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6- to 8 weeks thereafter. If used with concomitant methotrexate and/or other potential immunosuppressive agents, chronic monitoring should be monthly. If evidence of bone marrow suppression occurs in a patient taking ARAVA, treatment with ARAVA should be stopped, and cholestyramine or charcoal should be used to reduce the plasma concentration of leflunomide active metabolite.
In any situation in which the decision is made to switch from ARAVA to another anti-rheumatic agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. ARAVA washout with cholestyramine or charcoal may decrease this risk, but also may induce disease worsening if the patient had been responding to ARAVA treatment.
Skin Reactions
Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients receiving ARAVA. If a patient taking ARAVA develops any of these conditions, ARAVA therapy should be stopped, and a drug elimination procedure is recommended.
Malignancy
The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppression medications. There is a potential for immunosuppression with ARAVA. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the clinical trials of ARAVA, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with ARAVA.
Use in Women of Childbearing Potential
There are no adequate and well-controlled studies evaluating ARAVA in pregnant women. However, based on animal studies, leflunomide may increase the risk of fetal death or teratogenic effects when administered to a pregnant woman . Women of childbearing potential must not be started on ARAVA until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with ARAVA, patients must be fully counseled on the potential for serious risk to the fetus.
The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the blood level of the active metabolite by instituting the drug elimination procedure described below at the first delay of menses may decrease the risk to the fetus from ARAVA.
Upon discontinuing ARAVA, it is recommended that all women of childbearing potential undergo the drug elimination procedure described below. Women receiving ARAVA treatment who wish to become pregnant must discontinue ARAVA and undergo the drug elimination procedure described below which includes verification of M1 metabolite plasma levels less than 0.02 mg/L (0.02 μg/mL). Human plasma levels of the active metabolite (M1) less than 0.02 mg/L (0.02 μg/mL) are expected to have minimal risk based on available animal data.
Drug Elimination Procedure
The following drug elimination procedure is recommended to achieve non-detectable plasma levels (less than 0.02 mg/L or 0.02 μg/mL) after stopping treatment with ARAVA:
1.Administer cholestyramine 8 grams 3 times daily for 11 days. (The 11 days do not need to be consecutive unless there is a need to lower the plasma level rapidly.)
2.Verify plasma levels less than 0.02 mg/L (0.02 μg/mL) by two separate tests at least 14 days apart. If plasma levels are higher than 0.02 mg/L, additional cholestyramine treatment should be considered.
Without the drug elimination procedure, it may take up to 2 years to reach plasma M1 metabolite levels less than 0.02 mg/L due to individual variation in drug clearance.