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药品名称：特立氟胺
英文名称：Aubagio
适应症：Aubagio(特立氟胺)用于治疗成人复发性多发性硬化症。
成分：特立氟胺是免疫调制剂(immunomodulatory drug)，通过抑制二氢乳清酸脱氢酶(dihydroorotate dehydrogenase)来阻断嘧啶的源合成(de novo synthesis)。特立氟胺是来氟米特(Leflunomide)的体内代谢物。特立氟胺由Sanofi Aventis开发，商品名Aubagio。
结构式：特立氟胺的结构相对简单，其合成有三条不同的路线。
路线1，对三氟甲基苯胺
(1)和酰氯2缩合得到来氟米特(Leflunomide)，来氟米特在碱性条件下开环得到特立氟胺。
路线2，对三氟甲基苯胺(1)和羧酸3在缩合剂DIC(N,N′-Diisopropylcarbodiimide)作用下成酰胺4,4用NaH脱亚甲基的酸性质子后与乙酰氯反应得到特立氟胺。
路线3，对三氟甲基苯胺(1)和乙酰乙酸乙酯(5)高温下缩合得到6,酰胺6的酸性亚甲基溴化后与氰化钠在DMSO中发生SN2反应得到特立氟胺。
FDA批准新药Aubagio(特立氟胺)用于治疗成人复发性多发性硬化症。Aubagio为片剂，用法为每日1片。
FDA药品评价与研究中心神经产品部主任Russell Katz博士称：“在一项临床试验中，使用Aubagio的病人复发率比安慰剂组低约30%。多发性硬化症可以对患者运动、感觉和思维方面造成损伤，因此给病人提供多种治疗选择很重要。”
多发性硬化症是一种慢性、炎性、自身免疫性中枢神经系统疾病，这种疾病扰乱了大脑和身体其他部分的通讯联系。多发性硬化症是造成青壮年神经损伤的最常见原因之一，而女性发病率至少是男性的两倍。对于患有多发性硬化的病人，功能恶化发作（复发期）后首先伴随着恢复期（缓解期）。随着时间的推移，恢复期可能症状不能完全恢复，导致神经功能的渐进性低下。
临床试验中，使用Aubagio最常见的副作用包括腹泻、肝功能异常、恶心和脱发。Aubagio被黑框警告，以提醒处方医生和患者注意本药有引起肝脏问题（包括死亡）、出生缺陷方面的风险。内科医生应该在病人服用Aubagio前和治疗期间，定期对患者进行血液学检查以检测肝功能。该黑框警告还提醒，基于动物试验的结果，Aubagio可能会引起胎儿损害。因此，Aubagio被标示为怀孕类别X，意味着育龄期妇女在服药前必须为妊娠检测结果呈阴性，并且在治疗期间采取有效的避孕措施。
Aubagio包装中将包含患者用药指南文件，提供了关于这种药物使用方法和药品安全的重要信息。
AUBAGIO (Teriflunomide) is an FDA approved once-daily oral tablet developed by Genzyme, A Sanofi Company for relapsing forms of Multiple Sclerosis (MS).
MS is a chronic, inflammatory, autoimmune disease of the central nervous system that disrupts communication between the brain and other parts of the body. It is among the most common causes of neurological disability in young adults and occurs at least twice as frequently in women as in men. For most people with MS, episodes of worsening function (relapses) are initially followed by recovery periods (remissions). Over time, recovery periods may be incomplete, leading to progressive decline.
AUBAGIO is a disease-modifying therapy (DMT) that offers an effective alternative for patients suffering from Relapsing Multiple sclerosis (RMS)
AUBAGIO was extensively tested in several clinical trials and has one of the most robust clinical development programs. The FDA approved after reviewing data from the trials covering more than 1,000 patients in a 2-year study. When compared to placebo, AUBAGIO 14mg showed a significant improvement in the 3 measures of MS activity:
•Relapse Rate
•Disability progression
•MRI brain lesions
Aubagio is the only marketed oral DMT to be studied successfully in Clinical Isolated Syndrome (CIS).
Pharmacological Class:
Pyrimidine synthesis inhibitor.
Active Ingredient(s):
Teriflunomide 7mg, 14mg; tablets.
Company
Genzyme Corporation
Indication(s):
Relapsing forms of multiple sclerosis (MS).
Pharmacology:
Teriflunomide, an immunomodulatory agent with anti-inflammatory properties, inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. The mechanism by which teriflunomide exerts its therapeutic effect is unknown but may involve a reduction in the number of activated lymphocytes in CNS.
Clinical Trials:
The efficacy of teriflunomide was demonstrated in Study 1, a double-blind, placebo-controlled study that eva luated patients with relapsing forms of multiple sclerosis (RMS) over 108 weeks. A total of 1088 patients with RMS were randomized to receive 7mg (n=366) or 14mg (n=359) of teriflunomide or placebo (n=363). The primary endpoint was the annualized relapse rate (ARR). The ARR was significantly reduced in patients treated with either 7mg or 14mg of teriflunomide compared to patients who received placebo (0.370, 0.369 vs. 0.539, respectively).
The time to disability progression sustained for 12 weeks (as measured by at least a 1-point increase from baseline Expanded Disability Status Scale (EDSS) ≤ 5.5 or a 0.5 point increase for those with a baseline EDSS > 5.5) was statistically significantly reduced only in the teriflunomide 14mg group compared to placebo. The change in total lesion volume from baseline was significantly lower in the 7mg and 14mg groups than in the placebo group. Patients in both teriflunomide groups had significantly fewer gadolinium-enhancing lesions per T1-weighted scan than those in the placebo group.
The effect of teriflunomide on MRI activity was also demonstrated in Study 2. The mean number of unique active lesions per brain MRI scan during the 36-week treatment period was lower in patients treated with teriflunomide 14mg (0.98) and 7mg (1.06) as compared to placebo (2.69), the difference being statistically significant for both (P=0.0052 and P=0.0234, respectively).
Legal Classification:
Rx
Adults:
7mg or 14mg once daily.
Children:
Not established.
Contraindication(s):
Severe hepatic impairment. Pregnancy (Category X), women of childbearing potential not using reliable contraception. Co-administration with leflunomide.
Warnings/Precautions:
Perform accelerated elimination procedure (see literature) after drug discontinuance. Severe liver injury may be possible; obtain transaminase and bilirubin levels within 6 months before starting, monitor ALT at least monthly for 6 months after starting. Discontinue if drug-induced liver injury suspected; monitor liver tests weekly until normalized. Pre-existing liver disease: increased risk of developing elevated serum transaminases. Obtain CBCs within 6 months prior to starting. Severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections: not recommended. Screen for latent TB; do not start therapy until infection resolved. Monitor BP before starting and periodically. Diabetes, >60 years: increased risk of peripheral neuropathy. Monitor for new onset or worsening pulmonary symptoms, discontinue if interstitial lung disease suspected. Male patients: undergo elimination procedure before fathering child. Nursing mothers: not recommended.
Interaction(s)
See Contraindications. Live vaccines: not recommended. Risk of liver injury with hepatotoxic drugs. Risk of peripheral neuropathy with neurotoxic drugs. Potentiates drugs metabolized by CYP2C8 (eg, repaglinide, paclitaxel, pioglitazone, rosiglitazone), oral contraceptives. Antagonizes drugs metabolized by CYP1A2 (eg, duloxetine, alosetron, theophylline, tizanidine). Monitor INR. Concomitant immunosuppressives, immunomodulators: not eva luated.
Adverse Reaction(s)
ALT increased, alopecia, diarrhea, influenza, nausea, paresthesia; bone marrow suppression, immunosuppression potential, infection (consider suspending therapy), peripheral neuropathy; hyperkalemia, acute renal failure (check K+ levels); possible severe skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis; discontinue if occurs), respiratory effects.
How Supplied:
Tabs—5, 28
LAST UPDATED:
11/5/2012
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