固定剂量复方制剂Orkambi(lumacaftor/ivacaftor)-为囊性纤维化针对有两个疾病原因特异性突变拷贝人们治疗的第一个药物 首款囊性纤维化新药Lumacaftor/Ivacaftor组成的固定剂量复方制剂（商品名 ORKAMBI）获FDA已批准用于治疗6至11岁有双F508del突变儿童出现的囊性纤维化。 药品评价和研究中心新药室主任John Jenkins，M.D.说：“FDA鼓励制造商为严重的罕见病像囊性纤维化开发新和创新治疗，” “今天的批准显著地扩展对致囊性纤维化特异性缺陷靶向治疗的可利用性。”突破性治疗指，优先审评和孤儿药物指定。 批准日期：2015年7月2日；公司：Vertex制药 ORKAMBI™(lumacaftor/ivacaftor)片/固定剂量复方制剂 ，为口服使用 美国初次批准：2015 药理作用 CFTR蛋白是一个氯化物通道存在于多器官表皮细胞表面。F508del突变导致蛋白错误折叠，引起靶向蛋白降解细胞处置和运输中缺陷和因此减低在细胞表面CFTR的量。小量F508del-CFTR到达细胞表面是稳定性较低和与野生型CFTR蛋白比较具有低通道开放概率(有缺陷的门控活动)。 Lumacaftor改善F508del-CFTR的构象稳定性，导致成熟蛋白至细胞表面处置和运输增加。依伐卡托是一个CFTR增强剂通过增强通道-打开概率(或门控)促进在细胞表面CFTR蛋白的氯化物运输。在体外研究曾显示lumacaftor和依伐卡托两者在原代人支气管表皮培养和窝藏F508del-CFTR突变其他细胞系中直接地作用在CFTR蛋白增加在细胞表面处F508del-CFTR 的量，稳定性，和功能，导致氯化物离子运输增加。在体外反应不一定相当于在体内药效动力学反应或临床获益。 适应证和用途 ORKAMBI是lumacaftor和依伐卡托的组合复方，一个囊性纤维化跨膜电导调节(CFTR)增强剂，适用为的治疗囊性纤维化(CF)在年龄12岁和以上是对在CFTR基因中F508del突变纯合子患者。如患者的基因型是未知，应当用一个FDA批准的CF突变试验检测CFTR基因的两个等位基因上突变F508del的存在。 使用的限制: 尚未确定在有CF以外那些对F508del突变纯合子患者中ORKAMBI的疗效和安全性。 剂量和给药方法 ⑴年龄12岁和以上和儿童患者：两片(各含lumacaftor 200mg/依伐卡托 125mg)每12小时口服服用。 ⑵ 在有中度或严重肝受损患者中减低剂量。 ⑶在服用强CYP3A抑制剂患者当开始ORKAMBI，对治疗头一周减低ORKAMBI剂量。 剂型和规格 片：lumacaftor 200mg和依伐卡托 125mg。 禁忌证 无。 警告和注意事项 ⑴ 在有晚期肝病患者中使用：在这些患者中ORKAMBI应被慎用和仅是如获益胜过风险。如在这些患者中使用ORKAMBI，治疗开始后应被严密监视和剂量应减低。 ⑵ 肝相关事件：在有些病例中曾观察到升高的转氨酶(ALT/AST)伴随升高的胆红素。开始ORKAMBI治疗前第一年期间每3个月和其后每年测量血清转氨酶和胆红素。对有ALT，AST，或胆红素升高史患者，应被考虑更频。在有ALT或AST >5 × 正常上限(ULN)，或ALT或AST >3 × ULN与胆红素 >2×ULN患者中中断给药。解决后，考虑恢复给药获益和风险。 ⑶ 呼吸事件：ORKAMBI的开始期间更常观察到胸部不适，呼吸困难，和呼吸异常。预测的FEV1(ppFEV1) <40临床经验患者%是受限，和治疗的开始期间建议另外监视这些患者。 ⑷ 药物相互作用：使用有敏感CYP3A底物或有一个狭窄治疗指数CYP3A底物可能减低医药产品的全身暴露和建议不共同给药。激素避孕药不应被依赖作为避孕有效方法和它们的使用伴随月经-相关不良反应增加。与强CYP3A诱导剂使用可能减低依伐卡托的暴露，可能减低其有效性；因此，建议不共同给药。 ⑸ 白内障：儿童患者用依伐卡托治疗， ORKAMBI的一种组分曾报道非-先天性晶体混账/白内障。建议儿童患者开始ORKAMBI检查基线和随访。 不良反应 对ORKAMBI最常见不良反应(发生≥5%有CF在CFTR基因对F508del突变纯合子患者)是呼吸困难，鼻咽炎，恶心，腹泻，上呼吸道感染，疲乏，呼吸异常，血肌酸磷酸激酶增高，皮疹，胀气，鼻漏，流感。 药物相互作用 对完整清单见完整处方资料。 包装规格/贮存和处置 ORKAMBI(lumacaftor 200mg/依伐卡托125mg)是以粉红色，椭圆形片供应；各片含200 mg的lumacaftor和125 mg的依伐卡托，在一侧用黑墨汁印有“2V125”和另一侧平坦，和被包装如下： 112–计数片盒含一个4-周供应(每周4盒7每天泡罩带有4片每条)。NDC 51167-809-01 贮存在20-25°C(68-77°F)；外出允许至15-30°C(59-86°F)[见USP控制室温]。 IMPORTANT SAFETY INFORMATION FOR ORKAMBI™ (lumacaftor/ivacaftor) Use in Patients With Advanced Liver Disease • Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported in some patients with CF while receiving ORKAMBI. Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced Liver-related Events • Serious adverse reactions related to elevated transaminases have been reported in patients with CF receiving ORKAMBI. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin • It is recommended that ALT, AST, and bilirubin be assessed prior to initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Patients who develop increased ALT, AST, or bilirubin should be closely monitored until the abnormalities resolve • Dosing should be interrupted in patients with ALT or AST greater than 5 x upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations greater than 3 x ULN when associated with bilirubin elevations greater than 2 x ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing Respiratory Events • Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of ORKAMBI compared to those who received placebo. Clinical experience in patients with percent predicted FEV1 (ppFEV1) <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy Drug Interactions Substrates of CYP3A • Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI (lumacaftor/ivacaftor) may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended. Consider an alternative to midazolam and triazolam. Avoid the use of ORKAMBI with cyclosporine, everolimus, sirolimus, and tacrolimus • ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular (27% in women using hormonal contraceptives compared with 3% in women not using hormonal contraceptives). Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI Strong CYP3A Inducers • Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers (e.g., rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, St. John's wort) is not recommended Cataracts • Cases of non-congenital lens opacities have been reported in pediatric patients treated with ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with ORKAMBI Adverse Reactions • Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients • The most common adverse reactions in Phase 3 trials occurring in ≥5% of patients treated with ORKAMBI (N=369) compared to placebo (N=370) were dyspnea (13% vs 8%), nasopharyngitis (13% vs 11%), nausea (13% vs 8%), diarrhea (12% vs 8%), upper respiratory tract infection (10% vs 5%), fatigue (9% vs 8%), respiration abnormal (9% vs 6%), blood creatine phosphokinase increased (7% vs 5%), rash (7% vs 2%), flatulence (7% vs 3%), rhinorrhea (6% vs 4%), and influenza (5% vs 2%) Potential Additional Drug Interactions • ORKAMBI has the potential to affect other drugs including CYP2B6 and CYP2C substrates, digoxin and other P-gp substrates, anti-allergics and systemic corticosteroids, antibiotics, antifungals, anti-inflammatories, antidepressants, hormonal contraceptives, oral hypoglycemics, acid reducing drugs, and warfarin. For additional information regarding drug interactions, see full Prescribing Information INDICATIONS AND USAGE ORKAMBI is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene. Limitations of Use The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation. ORKAMBI Rx Pharmacological Class: Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator. Active Ingredient(s): Lumacaftor, ivacaftor 200mg/125mg; tabs. Company Vertex Pharmaceuticals Indication(s): Treatment of cystic fibrosis (CF) in patients ≥12yrs who are homozygous for the F508del mutation in the CFTR gene. Limitations of use: efficacy and safety not established in patients with CF other than those homozygous for the F508del mutation. Pharmacology: Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. In vitro studies have demonstrated that both lumacaftor and ivacaftor act directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport. Clinical Trials: The efficacy of Orkambi in patients with CF who are homozygous for the F508del mutation in the CFTR gene was evaluated in two randomized, double-blind, placebo-controlled, 24-week clinical trials (Trials 1 and 2) in 1108 clinically stable patients with CF of whom 369 patients received Orkambi twice daily. Trial 1 evaluated 549 patients with CF who were ≥12 years (mean age 25.1 years) with ppFEV1 at screening between 40–90 [mean ppFEV1 60.7 at baseline (range: 31.1–94.0)]. Trial 2 evaluated 559 patients ≥12 years (mean age 25.0 years) with ppFEV1 at screening between 40–90 [mean ppFEV1 60.5 at baseline (range: 31.3–99.8)]. Patients in both trials were randomized 1:1:1 to receive either Orkambi (lumacaftor 400mg q12h/ivacaftor 250mg q12h; or lumacaftor 600mg once daily/ivacaftor 250mg q12h) or placebo. Patients took the study drug with fat-containing food for 24 weeks in addition to their prescribed CF therapies (eg, bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). The primary efficacy endpoint in both trials was change in lung function as determined by absolute change from baseline in ppFEV1 at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24. In both trials, treatment with Orkambi resulted in a statistically significant improvement in ppFEV1. The treatment difference between Orkambi and placebo for the mean absolute change in ppFEV1 from baseline at Week 24 was 2.6 percentage points [95% CI (1.2, 4.0)] in Trial 1 (P=0.0003) and 3.0 percentage points [95% CI (1.6, 4.4)] in Trial 2 (P<0.0001). For more clinical trial data, see full labeling. Legal Classification: Rx Adults: Take with fat-containing food (eg, eggs, avocados, nuts, butter, peanut butter, cheese pizza, whole-milk dairy products). 2 tabs every 12hrs. Currently taking strong CYP3A inhibitors (eg, itraconazole, ketoconazole, posaconazole, voriconazole, telithromycin, clarithromycin): initially 1 tab once daily for 1st week then continue with recommended daily dose. Hepatic impairment (moderate): 2 tabs in the AM and 1 tab in the PM; (severe): 1 tab in the AM and 1 tab in the PM, or less; use with caution. Children: Not established. Warnings/Precautions: If genotype is unknown, use an FDA cleared CF mutation test to detect the presence of the F508del mutation on both alleles of the CFTR gene. Advanced hepatic impairment. Assess ALT/AST and bilirubin levels prior to initiating therapy, every 3 months during the first year of treatment, and annually thereafter. If ALT/AST or bilirubin levels increased, monitor closely until resolved. Interrupt dosing if ALT/AST is >5XULN or if ALT/AST is >3XULN with bilirubin elevations >2XULN; after resolution, consider restarting. Monitor for respiratory events during treatment initiation. Perform baseline and follow-up eye exams. Severe renal impairment (CrCl ≤30mL/min) or ESRD. Pregnancy (Cat.B). Nursing mothers. Interaction(s) See Adults. Concomitant strong CYP3A inducers (eg, rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, St. John’s wort): not recommended. Concomitant sensitive CYP3A substrates or those with a narrow therapeutic index (eg, midazolam, triazolam, cyclosporine, everolimus, sirolimus, tacrolimus): not recommended. May affect CYP2B6, CYP2C8, CYP2C9, CYP2C19, P-gp substrates. Monitor digoxin. May antagonize montelukast, systemic corticosteroids (eg, prednisone, methylprednisolone), ibuprofen, citalopram, escitalopram, sertraline, omeprazole, esomeprazole, lansoprazole, ranitidine; dose adjustment may be needed. May antagonize clarithromycin, erythromycin, telithromycin; consider alternatives (eg, ciprofloxacin, azithromycin, levofloxacin). Concomitant itraconazole, ketoconazole, posaconazole, voriconazole: not recommended; if necessary, monitor closely or consider alternatives (eg, fluconazole). May antagonize repaglinide or affect sulfonylureas; dose adjustment may be needed. Concomitant warfarin; monitor INR. May reduce effectiveness of hormonal contraceptives and increase menstruation abnormality events; avoid. Adverse Reaction(s) Dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, abnormal respiration, increased blood creatinine phosphokinase, rash, flatulence, rhinorrhea, influenza. How Supplied: Tabs—112 LAST UPDATED: 9/11/2015