诺华新型口服铁螯合剂Jadenu获美国FDA批准上市
Jadenu是Exjade的一种新口服配方,是首个可直接吞服的每天1次口服铁螯合剂。Exjade则是一种分散片,必须在液体中混合并在饭前至少30min空腹服用。Jadenu则在有无便餐的情况下均可直接吞服,从而大大简化了慢性铁过载(CIO)的治疗管理。Jadenu的上市,对于需要定期服用铁螯合剂治疗以清除体内过量铁的广大患者而言,是一个大好消息
批准日期：2015年4月2日  公司：诺华 Novartis
JADENU（地拉罗司 deferasirox）片剂，用于口服使用
美国初步批准：2005年
警告：
死亡，死亡和胃肠道异物请参阅完整的处方信息以获得完整的盒装警告。
JADENU可能造成严重和致命：
肾毒性，包括失败
肝毒性，包括失败
胃肠道出血
JADENU治疗需要密切的患者监测，包括肾脏和肝脏功能的实验室测试。
近期主要变化
剂量和管理，管理 10/2015
警告和注意事项，过敏 8/2016
警告和注意事项，严重皮肤反应 8/2016
作用机制
JADENU（deferasirox）是一种对铁有选择性的口服活性螯合剂（如Fe3+）。 它是以高比例以2:1的比例结合铁的三齿配体。 虽然地拉罗司对锌和铜具有非常低的亲和力，但是在施用地拉罗司之后，这些痕量金属的血清浓度存在可变的减少。 这些减少的临床意义是不确定的。
适应症和用法
JADENU是一种铁螯合剂，用于治疗2岁及以上患者输血引起的慢性铁超负荷。该指征在加速批准下基于肝铁浓度和血清铁蛋白水平的降低而得到批准。这种适应症的持续批准可能取决于在验证性试验中临床获益的验证和描述。
JADENU用于治疗10岁及以上患有非输血依赖性地中海贫血（NTDT）综合征和具有至少5mg Fe每克的肝脏铁（Fe）浓度（LIC）的患者的慢性铁超负荷干重（Fe/gdw）和血清铁蛋白大于300mcg/L。该指示在加速批准下基于肝铁浓度（小于5mg Fe/gdw）和血清铁蛋白水平的降低而得到批准。这种适应症的持续批准可能取决于在验证性试验中临床获益的验证和描述。
使用限制
尚未进行JADENU在骨髓增生异常综合征（MDS）和由于输血的慢性铁超负荷的患者中的受控临床试验。
JADENU与其他铁螯合疗法一起使用时的安全性和有效性尚未确定。
剂量和给药
转移铁超负荷：初始剂量14mg/kg（计算为最接近的整片），每天一次。
NTDT综合征：初始剂量7mg/kg（计算为最接近的整片），每天一次。
每月监测血清铁蛋白，并相应调整剂量。
每6个月监测LIC，并相应调整剂量。
服用空腹或低脂肪餐。
将中度（Child-Pugh B）肝损伤的剂量减少50％。避免在严重（Child-Pugh C）肝损伤的患者。
在肾损伤患者中减少剂量50％（ClCr 40-60mL/min）。
剂量形式和强度
片剂：90mg，180mg，360mg。
禁忌症
血清肌酐大于正常上限（ULN）或肌酐清除率（ClCr）的2倍以上小于40mL /min。
性能状态差的患者。
高危骨髓增生异常综合征（MDS）患者。
患有晚期恶性肿瘤的患者。
血小板计数小于50×109 / L的患者。
已知对地拉罗司或JADENU的任何组分的超敏反应。
警告和注意事项
骨髓抑制：中性粒细胞减少，粒细胞缺乏症，恶化贫血和血小板减少症，包括致命事件;在JADENU治疗期间监测血细胞计数。中毒治疗。
增加老年人的毒性：密切监测毒性。
超敏反应：停止JADENU的严重反应，并进行医疗干预。
严重的皮肤反应，包括史蒂文斯 - 约翰逊综合征（SJS）：停止JADENU。
不良反应
在输血性铁超负荷的患者中，最常发生（大于5％）的不良反应是腹泻，呕吐，恶心，腹痛，皮疹和血清肌酐升高。在地拉罗司治疗的NTDT综合征患者中，最常见的（大于5％）不良反应是腹泻，皮疹和恶心。
要报告可疑的不良反应，请联系诺华制药公司1-888-669-6682或FDA 1-800-FDA-1088或www.fda.gov/medwatch。
药物相互作用
由于JADENU的作用机制，避免使用JADENU与含铝抗酸制剂。
地拉罗司增加CYP2C8底物瑞格列奈的暴露。考虑使用瑞格列奈的剂量降低和监测血糖水平。
避免使用JADENU与CYP1A2底物茶碱作为茶碱水平可以增加。
在特定人群中使用
怀孕：根据动物研究，可能导致胎儿伤害。
哺乳：停止药物或母乳喂养，考虑到药物对母亲的重要性。

完整处方资料附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fee89140-fff1-4443-9f42-24ac004fcda1
Jadenu (deferasirox)
Drug SummaryNovartis Pharmaceuticals Corporation
Jadenu
(deferasirox)
BOXED WARNING
May cause acute renal failure and death, particularly in patients w/ comorbidities and those in the advanced stages of their hematologic disorders. Measure SrCr and determine CrCl in duplicate prior to initiation of therapy and monitor renal function at least monthly thereafter. Monitor creatinine weekly for the 1st month, then at least monthly for patients w/ baseline renal impairment or increased risk of acute renal failure. Consider dose reduction, interruption, or discontinuation based on increases in SrCr. May cause hepatic injury, including hepatic failure and death. Measure serum transaminases and bilirubin prior to initiating treatment, every 2 weeks during the 1st month, and at least monthly thereafter. Avoid in patients w/ severe (Child-Pugh C) hepatic impairment and reduce dose w/ moderate (Child-Pugh B) hepatic impairment. May cause GI hemorrhages, which may be fatal, especially in elderly who have advanced hematologic malignancies and/or low platelet counts. Monitor patients and d/c therapy if GI ulceration or hemorrhage is suspected.
View FDA-Approved Full Prescribing Information for Jadenu
THERAPEUTIC CLASS
Iron-chelating agent
DEA CLASS
RX
ADULT DOSAGE & INDICATIONS
Chronic Iron Overload
Transfusional Iron Overload:
Only consider when a patient has evidence of chronic transfusional iron overload, which should include the transfusion of at least 100mL/kg of packed RBCs (eg, at least 20 U of packed RBCs for a 40kg person or more in individuals weighing >40kg), and a serum ferritin consistently >1000mcg/L
Initial: 14mg/kg qd; calculate doses (mg/kg/day) to the nearest whole tab
Maint: May adjust dose every 3-6 months based on serum ferritin trends. Make dose adjustments in steps of 3.5 or 7mg/kg and tailor adjustments to individual response and therapeutic goals. If inadequately controlled w/ doses of 21mg/kg (eg, serum ferritin levels persistently >2500mcg/L and not showing a decreasing trend over time), doses of up to 28mg/kg may be considered. Consider temporarily interrupting therapy if serum ferritin falls consistently <500mcg/L.
Max: 28mg/kg
In Non-Transfusion-Dependent Thalassemia (NTDT) Syndromes:
Only consider in a patient w/ a liver iron concentration (LIC) of at least 5mg of iron per gram of liver dry weight (mg Fe/g dw) and a serum ferritin >300mcg/L
Initial: 7mg/kg qd; calculate doses (mg/kg/day) to the nearest whole tab. Consider increasing dose to 14mg/kg/day after 4 weeks if baseline LIC is >15mg Fe/g dw.
Maint: Interrupt treatment when serum ferritin is <300mcg/L and obtain an LIC to determine whether LIC has fallen to <3mg Fe/g dw. After 6 months of therapy, if LIC remains >7mg Fe/g dw, increase dose to a max of 14mg/kg/day. If after 6 months of therapy, LIC is 3-7mg Fe/g dw, continue treatment at no more than 7mg/kg/day. When LIC is <3mg Fe/g dw, interrupt treatment and continue to monitor LIC. Restart treatment when LIC rises again to >5mg Fe/g dw.
Max: 14mg/kg/day
Conversions
Converting from Exjade to Jadenu:
Jadenu dose should be about 30% lower, rounded to nearest whole tab
Transfusion-Dependent Iron Overload:
Initial: 14mg/kg/day (for 20mg/kg/day Exjade)
Titration Increments: 3.5-7mg/kg (for 5-10mg/kg Exjade)
Max: 28mg/kg/day (for 40mg/kg/day Exjade)
NTDT Syndromes:
Initial: 7mg/kg/day (for 10mg/kg/day Exjade)
Titration Increments: 3.5-7mg/kg (for 5-10mg/kg Exjade)
Max: 14mg/kg/day (for 20mg/kg/day Exjade)
Transfusional Iron Overload:
Only consider when a patient has evidence of chronic transfusional iron overload, which should include the transfusion of at least 100mL/kg of packed RBCs (eg, at least 20 U of packed RBCs for a 40kg person or more in individuals weighing >40kg), and a serum ferritin consistently >1000mcg/L≥2 Years:
Initial: 14mg/kg qd; calculate doses (mg/kg/day) to the nearest whole tab
Maint: May adjust dose every 3-6 months based on serum ferritin trends. Make dose adjustments in steps of 3.5 or 7mg/kg and tailor adjustments to individual response and therapeutic goals. If inadequately controlled w/ doses of 21mg/kg (eg, serum ferritin levels persistently >2500mcg/L and not showing a decreasing trend over time), doses of up to 28mg/kg may be considered. Consider temporarily interrupting therapy if serum ferritin falls consistently <500mcg/L.
Max: 28mg/kg
In NTDT Syndromes:
Only consider in a patient w/ an LIC of at least 5mg Fe/g dw and a serum ferritin >300mcg/L
≥10 Years:
Initial: 7mg/kg qd; calculate doses (mg/kg/day) to the nearest whole tab. Consider increasing dose to 14mg/kg/day after 4 weeks if baseline LIC is >15mg Fe/g dw.
Maint: Interrupt treatment when serum ferritin is <300mcg/L and obtain an LIC to determine whether LIC has fallen to <3mg Fe/g dw. After 6 months of therapy, if LIC remains >7mg Fe/g dw, increase dose to a max of 14mg/kg/day. If after 6 months of therapy, LIC is 3-7mg Fe/g dw, continue treatment at no more than 7mg/kg/day. When LIC is <3mg Fe/g dw, interrupt treatment and continue to monitor LIC. Restart treatment when LIC rises again to >5mg Fe/g dw.
Max: 14mg/kg/day
Conversions
Converting from Exjade to Jadenu:
Jadenu dose should be about 30% lower, rounded to nearest whole tab
Transfusion-Dependent Iron Overload:
Initial: 14mg/kg/day (for 20mg/kg/day Exjade)
Titration Increments: 3.5-7mg/kg (for 5-10mg/kg Exjade)
Max: 28mg/kg/day (for 40mg/kg/day Exjade)
NTDT Syndromes:
Initial: 7mg/kg/day (for 10mg/kg/day Exjade)
Titration Increments: 3.5-7mg/kg (for 5-10mg/kg Exjade)
Max: 14mg/kg/day (for 20mg/kg/day Exjade)
DOSING CONSIDERATIONS
Concomitant Medications
Bile Acid Sequestrants/Potent UDP-Glucuronosyltransferase (UGT) Inducers:
Avoid w/ bile acid sequestrants (eg, cholestyramine, colesevelam, colestipol) or potent UGT inducers (eg, rifampicin, phenytoin, phenobarbital, ritonavir).
If concomitant use is necessary w/ 1 of these agents, consider increasing initial deferasirox dose by 50%, and monitor serum ferritin levels and clinical responses for further dose modification.
Renal Impairment
Baseline Renal Impairment:
CrCl 40-60mL/min: Reduce initial dose by 50%
SrCr >2X ULN or CrCl <40mL/min: Contraindicated
Increases in SrCr During Therapy:
All Patients: D/C therapy for SrCr >2X the age-appropriate ULN or for CrCl <40mL/min
Transfusional Iron Overload:
2-15 Years: Reduce dose by 7mg/kg if SrCr increases to >33% above the average baseline measurement and greater than the age-appropriate ULN
≥16 Years: If SrCr increases by ≥33% above the average baseline measurement, repeat SrCr w/in 1 week, and if still elevated by ≥33%, reduce dose by 7mg/kg
NTDT Syndromes:
10-15 Years: Reduce dose by 3.5mg/kg if SrCr increases to >33% above the average baseline measurement and greater than the age-appropriate ULN
≥16 Years: If SrCr increases by ≥33% above the average baseline measurement, repeat SrCr w/in 1 week, and if still elevated by ≥33%, interrupt therapy if the dose is 3.5mg/kg, or reduce by 50% if the dose is 7 or 14mg/kg
Hepatic Impairment
Baseline Hepatic Impairment:
Mild (Child-Pugh A): No dose adjustment necessary
Moderate (Child-Pugh B): Reduce initial dose by 50%
Severe (Child-Pugh C): Avoid therapy
Elderly
Start at lower end of dosing range
ADMINISTRATION
Oral route
Swallow tab w/ water or other liquids, preferably at the same time each day.
May be taken on an empty stomach or w/ a light meal (containing <7% fat content and approx 250 calories).
For patients who have difficulty swallowing whole tabs, may crush tabs and mix w/ soft foods (eg, yogurt, applesauce) immediately prior to use; dose should be immediately and completely consumed and not stored for future use. Avoid commercial crushers w/ serrated surfaces for crushing a single 90mg tab.
HOW SUPPLIED
Tab: 90mg, 180mg, 360mg
CONTRAINDICATIONS
SrCr >2X the age-appropriate ULN or CrCl <40mL/min, poor performance status, high-risk myelodysplastic syndrome (MDS), advanced malignancies, platelet counts <50 x 109/L, known hypersensitivity to deferasirox or any component of this medication.
WARNINGS/PRECAUTIONS
Renal tubular damage including Fanconi's syndrome reported, most commonly in children and adolescents w/ β-thalassemia and serum ferritin levels <1500mcg/L. Intermittent proteinuria reported; monitor for proteinuria monthly. Hepatic toxicity appears to be more common in patients >55 yrs of age. Hepatic failure was more common in patients w/ significant comorbidities, including liver cirrhosis and multiorgan failure. Consider dose modifications or interruption of treatment for severe or persistent elevations in serum transaminases and bilirubin. Patients w/ mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic toxicity. Nonfatal upper GI irritation, ulceration, and hemorrhage reported. There have been reports of ulcers complicated w/ GI perforation (including fatal outcome). Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events, reported; risk may increase w/ preexisting hematologic disorders. Interrupt treatment in patients who develop cytopenias until the cause has been determined. Increased risk of toxicity in elderly; monitor more frequently. May cause serious hypersensitivity reactions (eg, anaphylaxis, angioedema); d/c and institute appropriate medical intervention if reactions are severe. Do not reintroduce in patients who have experienced previous hypersensitivity reactions on deferasirox products. Severe skin reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and erythema multiforme, reported. Cannot exclude risk of other skin reactions (eg, drug reaction w/ eosinophilia and systemic symptoms). D/C immediately and do not reintroduce if severe skin reactions are suspected. Rashes may occur; interrupt treatment in severe cases and may consider reintroduction at a lower dose w/ escalation after resolution of rash. Auditory and ocular disturbances reported. Perform auditory and ophthalmic testing every 12 months; monitor more frequently if disturbances are noted and consider dose reduction or interruption. Measure serum ferritin monthly for possible overchelation of iron for patients w/ transfusional iron overload. For patients w/ NTDT, measure serum ferritin monthly and measure LIC by liver biopsy or by using an FDA-cleared/approved method for monitoring patients receiving therapy every 6 months on treatment.
ADVERSE REACTIONS
Transfusional Iron Overload: Abdominal pain, N/V, diarrhea, skin rashes, increases in SrCr.
NTDT Syndromes: Nausea, rash, diarrhea.
DRUG INTERACTIONS
See Dosing Considerations. Avoid w/ aluminum-containing antacid preparations. May induce CYP3A4, resulting in a decrease in CYP3A4 substrate concentration; closely monitor for signs of reduced effectiveness w/ drugs metabolized by CYP3A4 (eg, cyclosporine, fentanyl, quetiapine). Inhibits CYP2C8 and CYP1A2, resulting in an increase in CYP2C8 (eg, repaglinide, paclitaxel) and CYP1A2 (eg, duloxetine, theophylline, tizanidine) substrate concentration; closely monitor for signs of exposure-related toxicity. Consider decreasing the dose of repaglinide and monitor blood glucose levels carefully. Avoid w/ theophylline or other CYP1A2 substrates w/ a narrow therapeutic index (eg, tizanidine); monitor theophylline concentrations and consider theophylline dose modification if theophylline must be coadministered. Increased risk of GI hemorrhage w/ drugs that have ulcerogenic or hemorrhagic potential (eg, NSAIDs, corticosteroids, oral bisphosphonates, anticoagulants).
PREGNANCY AND LACTATION
Pregnancy: There are no adequate or well-controlled studies in pregnant women. Administration to animals during pregnancy and lactation resulted in decreased offspring viability and an increase in renal anomalies in male offspring at exposures that were less than the recommended human exposure. Use during pregnancy only if potential benefit justifies the potential risk to the fetus.
Lactation: Not for use in nursing.
MECHANISM OF ACTION
Iron-chelating agent; a tridentate ligand that binds iron w/ high affinity in a 2:1 ratio.
PHARMACOKINETICS
Absorption: Absolute bioavailability (tab for oral sus: 70%, tab: 36% greater than tab for oral sus); Tmax=1.5-4 hrs (median). Distribution: Vd=14.37L (adults); plasma protein binding (99%). Metabolism: Glucuronidation via UGT1A1 (major) and UGT1A3 (minor) followed by deconjugation in the intestine and reabsorption (enterohepatic recycling); oxidation via CYP450 (minor). Elimination: Feces (84%), urine (8%); T1/2=8-16 hrs.
ASSESSMENT
Assess for high-risk MDS, performance status, renal/hepatic impairment, advanced malignancies, hematological disorders, comorbidities, hypersensitivity to the drug, pregnancy/nursing status, and possible drug interactions. Perform baseline auditory and ophthalmic examinations. Obtain baseline SrCr in duplicate, serum transaminases, bilirubin, and blood counts. Determine CrCl (Cockcroft-Gault method). In patients w/ transfusional iron overload, obtain baseline serum ferritin level. In patients w/ iron overload in NTDT syndromes, obtain LIC by liver biopsy or by an FDA-cleared/approved method for identifying patients for treatment w/ deferasirox therapy, and obtain baseline serum ferritin level on at least 2 measurements 1 month apart.
MONITORING
Monitor for acute renal failure, hepatic failure, GI ulceration/hemorrhage, neutropenia, agranulocytosis, worsening anemia, thrombocytopenia, hypersensitivity reactions, rashes, SJS, TEN, erythema multiforme, and other adverse reactions. Monitor blood counts. Perform auditory and ophthalmic tests every 12 months. Monitor closely for efficacy and adverse reactions that may require dose titration in patients w/ mild or moderate hepatic impairment. Monitor serum transaminases and bilirubin every 2 weeks during the 1st month of therapy and at least monthly thereafter. Monitor SrCr weekly during the 1st month after initiation or modification of therapy and at least monthly thereafter. Monitor SrCr and/or CrCl more frequently if creatinine levels are increasing. Monitor serum ferritin and for proteinuria monthly. In patients w/ iron overload in NTDT syndromes, monitor LIC every 6 months. Monitor elderly more frequently for toxicity.
PATIENT COUNSELING
Instruct to take ud. Instruct not to take the medication simultaneously w/ aluminum-containing antacids. Inform of the importance of auditory and ophthalmic testing before starting treatment and thereafter at regular intervals. Caution patients experiencing dizziness to avoid driving or operating machinery. Inform about drug interactions including potential for GI ulcers/bleeding and loss of effectiveness due to drug interactions. Advise that blood tests will be performed every month or more frequently if patient is at increased risk of complications. Inform that severe kidney and liver problems, blood disorders, stomach hemorrhage, and death have been reported. Inform that skin rash and serious allergic reactions have been reported; advise to d/c therapy and contact physician immediately if severe reactions occur.
STORAGE
25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture.
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产地国家： 美国
原产地英文商品名:
Jadenu 90MG/TAB 30TABS/bottle 
原产地英文药品名:
DEFERASIROX
中文参考商品译名:
Jadenu片 90毫克/片 30片/瓶
中文参考药品译名:
地拉罗司斯
生产厂家中文参考译名:
诺华公司
生产厂家英文名:
Novartis Pharma 
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产地国家：美国
原产地英文商品名:
Jadenu 180MG/TAB 30TABS/bottle 
原产地英文药品名:
DEFERASIROX
中文参考商品译名:
Jadenu片 180毫克/片 30片/瓶
中文参考药品译名:
地拉罗司斯
生产厂家中文参考译名:
诺华公司
生产厂家英文名:
Novartis Pharma 
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产地国家： 美国
原产地英文商品名:
Jadenu 360MG/TAB 30TABS/bottle 
原产地英文药品名:
DEFERASIROX
中文参考商品译名:
Jadenu片 360毫克/片 30片/瓶
中文参考药品译名:
地拉罗司斯
生产厂家中文参考译名:
诺华公司
生产厂家英文名:
Novartis Pharma