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2012年2月17日，美国食品药品管理局(FDA)已经批准将Korlym(米非司酮)用于合并2型糖尿病或葡萄糖不耐受，以及不适合做手术或手术治疗无效的成人内源性库欣综合征患者，控制由皮质醇增多症引起的高血糖症。Korlym是皮质醇受体阻断剂，其常规剂量为1300 mg的片剂、每日服用1片。 商品名：Korlym 适应证和用途 Korlym(米非司酮[mifepristone])是一种皮质醇受体阻断剂适用于有2型糖尿病或葡萄糖耐受不良和有手术失败或不是手术备选者患内源性库欣氏综合征成年患者中继发于皮質醇增多症[hypercortisolism]中控制高血糖。 使用重要限制 与内源性库欣氏综合征无关的2型糖尿病治疗不要使用。 剂量和给药方法 （1）与进餐每天1次口服给药 （2）推荐开始剂量是300 mg每天1次 （3）肾受损：不要超过600 mg每天1次. （4）轻-至-中度肝受损：不要超过600 mg每天1次。严重肝受损中不要使用. 根据临床反应和耐受性，剂量可能增加300 mg增量至最大1200 mg每天1次。不要超过20 mg/kg每天 剂型和规格 300 mg/片 禁忌证 （1）妊娠 （2）使用辛伐他汀[simvastatin]或洛伐他汀[lovastatin]和有狭窄治疗范围CYP 3A底物 （3）同时长期皮质甾体使用 （4）有不能解释的阴道出血史妇女 （5）妇女有内膜增生有异型或内膜癌 警告和注意事项 （1）肾上腺机能不全：应严密监视患者肾上腺机能不全的体征和症状 （2）低钾血症：治疗前应纠正低钾血症和治疗期间监视 （3）阴道出血和子宫内膜变化：妇女可能经受内膜增厚或非期望阴道出血。如患者还有出血性疾病或使用抗凝治疗慎用 （4）QT间期延长：避免使用 QT间期延长药物，或在有钾通道变异体患者中导致长QT间期 （5）强CYP3A抑制剂的使用：同时使用可能明显增加米非司酮血浆水平。只在需要时使用和限制米非司酮剂量至300 mg 不良反应 在库欣氏综合征中最常见(≥ 20%)不良反应：恶心，疲乏，头痛，血钾减低，关节痛，呕吐，周边水肿，高血压，头晕，食欲减退，内膜肥厚。 药物相互作用 （1）被代谢药物CYP3A：当使用Korlym时给予在最低剂量的被CYP3A代谢药物 （2）CYP3A抑制剂：当Korlym与强CYP3A抑制剂使用应谨慎。与强CYP3A抑制剂使用时限制米非司酮剂量至300 mg每天 （3）CYP3A诱导剂：Korlym不要与CYP3A诱导剂使用 （4）被代谢药物CYP2C8/2C9；当与Korlym使用时，用最低剂量CYP2C8/2C9底物 （5）被代谢药物CYP2B6：与安非他酮[bupropion]和依非韦伦[efavirenz]使用时，Korlym使用应谨慎 （6）激素避孕药：不要与Korlym使用
——FDA批准首个内源性库欣综合征治疗药Korlym（米非司酮） 近日，FDA批准Korlym（米非司酮）用于控制成人内源性库欣综合征的高血糖症（血糖水平过高），该药物的适应症是具有2型糖尿病或者葡萄糖耐受不良，已行手术但血糖仍然偏高，或者不适合做手术的库欣综合征病人。这是首个被批准用于治疗该疾病的药物。 内源性库欣综合征是一种抑制性和少见的多系统性疾病，主要影响年龄介于25岁至40岁之间。该疾病是由过高的皮质醇激素水平引起的，皮质醇是一种甾体激素，由肾上腺产生，可以增高血糖水平。FDA在2007批准米非司酮为罕见病药物，通过阻滞皮质醇和其受体结合而起作用，大约有5000名病人适合使用米非司酮治疗。尽管这种治疗方式并不能减少皮质醇的量，但确实能减轻皮质醇的过多副作用，如增高的血糖水平。 在一项包括50名内源性库欣综合征病人的试验中，研究者正在研究评估米非司酮的安全性和药效。更多的科学文献，安全性药理学研究，药物间相互作用的研究都为FDA批准米非司酮提供了依据。米非司酮改善了受试者血糖的控制，其中一些受试者减少了胰岛素的需要量。 药物最常见的副作用是呕吐，头晕，头痛，食欲减低，关节痛，四肢肿胀，疲劳，和恶心。其他一些副作用包括阴道流血，低钾血症，和可能的心脏传导异常。对临床工作者来说，考虑药物间的相互作用，及避免一些药物和米非司酮联合使用或者调整剂量是至关重要的，因为一些特定的药物和米非司酮联合使用时，可能会增高米非司酮的水平。尽管由于过高的皮质醇具有抑制女性生殖功能的作用，患有库欣综合征的女性很少怀孕，但也不建议怀孕的女性服用米非司酮。米非司酮在包装盒上标有提醒病人和临床工作者的警示：米非司酮会终止妊娠。根据FDA的报告，米非司酮治疗内源性库欣综合征的作用价值优于其带来的风险。 在考虑了若干因素之后，FDA做出上述结论：在美国，有可能使用米非司酮的临床工作者数量会相对较少，但都很专业。他们熟知米非司酮用于内源性库欣综合征的风险因素，在治疗期间将会经常检测病人的疾病情况。由于没有其它被批准治疗库欣综合征的药物，如果米非司酮出现治疗问题，病情较重的病人会遭受巨大的痛苦。据估计，大约只有5000名库欣综合征病人适合使用米非司酮治疗。在开了米非司酮的处方后，其治疗的风险将由医生和病人共同承担。不仅如此，在病人的药物指南中也需强调米非司酮相关的风险因素。
KORLYM Manufacturer:Corcept Therapeutics Pharmacological Class:Cortisol receptor blocker. Active Ingredient(s):Mifepristone 300mg; tabs. Indication(s):To control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing’s syndrome who have type 2 diabetes or glucose intolerance and have failed surgery or are not candidates for surgery. Pharmacology:Korlym blocks the glucocorticoid receptor type II (GR-II) to which cortisol normally binds. By blocking this receptor, Korlym inhibits the effects of excess cortisol in Cushing’s syndrome patients. Clinical Trials:An uncontrolled, open-label, 24-week, multicenter clinical study was conducted to evaluate the safety and efficacy of Korlym in the treatment of endogenous Cushing’s syndrome. Patients belonged to one of two cohorts: a “diabetes” cohort (29 patients, 26 with type 2 diabetes and 3 with glucose intolerance), and a “hypertension” cohort (21 patients). Efficacy was evaluated separately in the two cohorts. Korlym was started in all patients at a dose of 300mg once a day. The study protocol allowed an increase in dose to 600mg after 2 weeks, and then by additional 300mg increments every 4 weeks to a maximum of 900mg/day for patients <60kg, or 1200mg/day for patients >60kg, based on clinical tolerance and clinical response. Patients in the diabetes cohort underwent standard oral glucose tolerance tests at baseline and periodically during the trial. The primary efficacy analysis for the diabetes cohort was an analysis of responders. A responder was defined as a patient who had a ≥25% reduction from baseline in glucose AUC. Mean HbA1c was 7.4% in the 24 patients with HbA1c values at baseline and Week 24. For these 24 patients mean reduction in HbA1c was 1.1% (95% CI -1.6, -0.7) from baseline to the end of the trial. There were no changes in mean systolic and diastolic blood pressures at the end of the trial relative to baseline in the modified intent-to-treat group (n=21). Legal Classification:Rx Adults:Swallow whole. Take with a meal. Initially 300mg once daily; may increase in 300mg increments every 2–4 weeks to max 1200mg once daily; do not exceed 20mg/kg/day. If interrupted, re-start at 300mg and titrate to dose lower than the one that resulted in treatment interruption. Renal or mild to moderate hepatic impairment: max dose 600mg. Severe hepatic impairment: not recommended. Concomitant strong CYP3A inhibitors (see Interactions): max 300mg/day. Children:Not recommended. Contraindication(s):Pregnancy (Cat.X). Concomitant simvastatin, lovastatin, CYP3A substrates with narrow therapeutic ranges (eg, cyclosporine, ergots, fentanyl, pimozide, quinidine, sirolimus, tacrolimus). Concomitant systemic corticosteroids for serious medical conditions or illnesses (eg, immunosuppression after organ transplantation). History of unexplained vaginal bleeding. Endometrial hyperplasia with atypia or endometrial carcinoma. Warnings/Precautions:Pregnancy must be excluded before initiating therapy and if treatment is interrupted for >14 days in females of reproductive potential. Prevent pregnancy during and for 1 month after stopping treatment (use non-hormonal contraceptive). Monitor for adrenal insufficiency; if suspected, discontinue treatment immediately and give glucocorticoids; may resume at a lower dose after resolution. Correct hypokalemia prior to initiating therapy; measure serum potassium 1–2 weeks after starting or increasing dose, then periodically. Women with hemorrhagic disorders or are receiving concurrent anticoagulant therapy. Autoimmune disorders. Heart failure. Coronary vascular disease. Monitor for Pneumocystis jiroveci infection. Nursing mothers: not recommended. Interaction(s):Potentiated by strong CYP3A inhibitors (eg, ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir, boceprevir, clarithromycin, conivaptan, lopinavir, nefazodone, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole). Caution with moderate CYP3A inhibitors (eg, amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil). Avoid concomitant CYP3A inducers (eg, rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, St. John’s wort). May potentiate drugs metabolized by CYP2C8/2C9 (eg, fluvastatin, NSAIDs, warfarin, repaglinide); monitor, use smallest effective dose. May potentiate drugs metabolized by CYP2B6 (eg, bupropion, efavirenz). Antagonizes hormonal contraceptives. Adverse Reaction(s):Nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, endometrial hypertrophy; QT prolongation, hypokalemia, reduced HDL-C, elevated TSH. How Supplied:Tabs—28, 280 Last Updated:5/15/2012 |
