爱必妥(西妥昔单抗注射液)说明书
西妥昔单抗注射液Cetuximab-详细说明书与重点
西妥昔单抗注射液Cetuximab商品名：爱必妥英文名：Cetuximab Solution for Infusion汉语拼音：Xi Tuo Xi Dan Kang Zhu She Ye【警示语】警告：严重的输液反应。
在大约3%的患者中发生了严重的输液反应，其中一些为致命性的。
注意：因本品目前尚缺乏中国人应用的安全性、有效性数据，故必须在有相关产品应用经验的三级以上医院内（建议在国家临床肿瘤研究基地使用) ，与伊立替康联合用药试用于治疗表达表皮生长因子受体(EGFR) 、经含伊立替康细胞毒治疗失败后的转移性结直肠癌；本品必须在有经验医师的指导下使用。
【成份】本品每20ml溶液含：活性成分：西妥昔单抗100mg其他成分：氯化钠116.88mg，甘氨酸150.14mg，聚山梨酯80 2mg，一水合柠檬酸42.02mg，氢氧化钠（1M）调节pH值至5.5，注射用水加至20ml。
【性状】本品为注射用无色、澄清、透明溶液。
【适应症】西妥昔单抗用于治疗表达表皮生长因子受体(EGFR) 、RAS基因野生型的的转移性结直肠癌：与伊立替康联合用于经含伊立替康治疗失败后的患者。
西妥昔单抗联合FOLFOX（奥沙利铂+亚叶酸钙+5-氟尿嘧啶[5-FU]）或FOLFIRI（伊立替康+亚叶酸钙+5-FU）一线治疗RAS野生型（wt）转移性结直肠癌（mCRC）患者、或联合伊立替康（irinotecan）用于对伊立替康化疗无效的患者。
与铂类和氟尿嘧啶化疗联合，用于一线治疗复发和/或转移性头颈部鳞癌。
【规格】100mg(20ml)/瓶【用法用量】西妥昔单抗必须在有使用抗癌药物经验的医师指导下使用。
在用药过程中及用药结束后1小时内，需密切监测患者的状况，并必须配备复苏设备。
在首次滴注本品之前至少1小时，患者必须接受抗组胺药物和皮质类固醇药物的预防用药。
建议在在后续治疗中,每次使用本品之前都对患者进行上述预防用药。
本品每周给药一次。
爱必妥作用机制及不良反应处理
50-90% 14-91% 35-70% 40-63% 31-48%
Salomon (1995); Yoshida (1997)
Klijn (1992); Bucci (1997); Walker (1999)
Bartlett (1996); Fischer-Colbrie (1997)
Salomon (1995); Watanabe (1996); Rieske (1998)
• 如果患者出现重度（3～4级）超敏反应，应立 即并永久性的停用爱必妥，对患者进行急救
.
皮肤反应
• 80% 以上的患者可能出现皮肤反应
• 痤疮样皮疹 • 皮肤干燥症 • 指甲病变 • 毛发改变
.
皮肤反应—— 分级
皮疹/ 脱屑
1级
2级
3级
4级
斑疹/丘疹/红斑 斑疹/丘疹/红斑 有瘙痒 等相关症状 有/无相关症状 局限性脱屑或其它皮损
剂量和给药
初始剂量400 mg/m2 每周剂量250 mg/m2 输注
初始剂量输注120分钟以上 每周剂量输注60分钟以上 每周给药
双周方案 500 mg/m2 每两周给药一次
贮存条件
• 药品应贮存在2℃- 8℃的冷柜中，不能冰冻!
• 未开封的药品保质期为2年，在25℃条件下 产品稳定性可保持20小时
对于这部分患者在今后的输注过程中应始终采用较慢的滴速?如果患者出现重度34级超敏反应应立即并永久性的停用爱必妥对患者进行急救kuangshu20103皮肤反应?80以上的患者可能出现皮肤反应?痤疮样皮疹?皮肤干燥症?指甲病变?毛发改变kuangshu20103皮肤反应?80以上的患者可能出现皮肤反应主要表现为痤疮样皮疹其中约15症状严重?皮疹多于治疗的前3周内出现在停药后能自行消退且不留疤痕?痤疮样皮疹常出现在脸部上胸部和背部?皮疹的发生频率呈剂量依赖性kuangshu20103皮肤反应分级1级2级3级4级皮疹脱屑斑疹丘疹红斑有无相关症状斑疹丘疹红斑有瘙痒等相关症状局限性脱屑或其它皮损50皮肤区域严重广泛斑丘疹或椭圆形皮疹脱屑皮损50皮肤区域广泛皮肤剥脱溃疡或大疱性皮炎皮疹痤疮样皮疹无需处理需要处理有相关症状疼痛容貌受损畸形溃疡脱屑瘙痒轻微局限严重广泛影响日常生活皮肤干燥无症状有症状但不影响日常生活影响日常生活ctcaev30kuangshu20103皮肤反应痤疮样皮疹?爱必妥用药后导致的皮肤反应主要表现为痤疮样皮疹6080?机制
分子靶向药物 爱必妥
爱必妥【中文名称】：西妥昔单抗注射液【功效主治】本品单用或与伊立替康(irinotecan)联用于表皮生长因子(EGF)受体过度表达的，对以伊立替康为基础的化疗方案耐药的转移性直肠癌的治疗。
【禁忌】已知对西妥昔单抗有严重超敏反应(3级或4级)的患者禁用本品。
伊立替康的有关禁忌，请参阅其使用说明书。
【用法用量】1、西妥昔单抗必须在有使用抗癌药物经验的医师指导下使用在用药过程中及用药结束后一小时内必须密切监察患者的状况并必须配备复苏设备. 首次注滴本品之前患者必须接受抗组胺药物治疗建议在随后每次使用本品之前都对患者进行这种治疗3 初次给药时建议滴注时间为分钟。
【不良反应】1西妥昔单抗的安全性不会受到伊立替康的影响反之亦然与伊立替康合用时本品的其它一些不良反应为已知的伊立替康的不良反应(包括腹泻%恶心%呕吐%粘膜炎如口腔炎等%发热%白细胞减少症%和脱发%)因此请同时参阅伊立替康的使用说明书3 轻中度反应包括发热寒战恶心皮疹和呼吸困难等症状严重的超敏反应(级或级)多发于初次滴注过程中或初次滴注结束小时内症状包括急性气道阻塞(如支气管痉挛喘鸣嘶哑说话困难)风疹和/或低血压症状极少见。
【临床操作流程】1、严格遵医嘱配制药液。
2、用输血皮条静滴。
3、使用前应予克敏2.5mg口服，5%GS20ml+地塞米松5mg静推，预防反应。
4、每次用药前均应使用心电血压监护并记录。
5、使用前需测基础生命体征，开始输注时滴速在50滴/分左右，每隔5分钟复测心电血压，重复3次，15分钟后如无不适症状，以60滴/分左右静滴30分钟以上，无不适症状后可输注第二瓶，匀速直至结束。
6、静滴结束后用NS100ml冲管后拔出。
西妥昔单抗
Phase I Study of Anti–Epidermal Growth Factor Receptor Antibody Cetuximab in Combination With Radiation Therapy in Patients With Advanced Head and Neck Cancer By Francisco Robert,Mark P.Ezekiel,Sharon A.Spencer,Ruby F.Meredith,James A.Bonner,M.B.Khazaeli, Mansoor N.Saleh,Delicia Carey,Albert F.LoBuglio,Richard H.Wheeler,Michael R.Cooper,and Harlan W.WaksalPurpose:To evaluate the safety,pharmacokinetics, and efficacy of a chimeric anti–epidermal growth factor receptor monoclonal antibody,cetuximab,in combina-tion with radiation therapy(RT)in patients with ad-vanced squamous cell carcinoma of the head and neck. Patients and Methods:We treated16patients infive successive treatment schedules.A standard dose esca-lation procedure was used;three patients entered onto the study at each dose level of cetuximab received conventional RT(70Gy,2Gy/d),and thefinal three patients received hyperfractionated RT(76.8Gy,1.2Gy bid).Cetuximab was delivered as a loading dose of100 to500mg/m2,followed by weekly infusions of100to 250mg/m2for7to8weeks.Circulating levels of cetuximab during therapy were determined using a biomolecular interaction analysis core instrument.Hu-man antichimeric antibody response was evaluated with a double-antigen radiometric assay.The recom-mended phase II/III dose was defined as the optimal cetuximab dose level based on the pharmacologic pa-rameters and adverse events.Results:The most commonly reported adverse events were fever,asthenia,transaminase elevation,nausea, and skin toxicities(grade1to2in most patients).Skin toxicity outside of the RTfield was not strictly dose-dependent;however,grade2or higher events were observed in patients treated with higher dose regimens. There was one grade4allergic reaction.Most acute adverse effects were associated with RT(xerostomia, mucositis,and local skin toxicity).No antibodies against cetuximab were detected.All patients achieved an objec-tive response(13complete and two partial remissions). Conclusion:Cetuximab can be safely administered with RT.The recommended dose for phase II/III studies is a loading dose of400to500mg/m2and a mainte-nance weekly dose of250mg/m2.J Clin Oncol19:3234-3243.©2001by American Society of Clinical Oncology.R ADIATION THERAPY(RT)is the mainstay of treat-ment for locally advanced,unresectable squamous cell carcinoma of the head and neck(SCCHN).However, with conventional fractionation of1.8to2.0Gy per fraction for a total dose of60to75Gy,the rate of relapse-free survival is approximately25%,and the majority of patients die from locoregional disease.1,2Tumor cell repopulation during treatment,tumor hypoxia,and intrinsic radioresis-tance represent biologic barriers implicated as causes of treatment failure after primary RT.3-5Numerous attempts to improve local control and long-term survival in advanced SCCHN have been undertaken,such as altered fractionated regimens,combined RT and chemotherapy,radiation sensitizers,and hyperbaric oxy-gen.6-11Although some of these therapeutic approaches have shown encouraging results,not all of them have shown an unequivocal survival benefit,and the treatments often are associated with significant toxicity.Thus,there is a need for newer therapies that produce long-term local control and less toxicity.One novel approach to treatment has been the develop-ment of new agents that target specific growth factors and growth factor receptors.One particular growth factor recep-tor and signal transduction system that has been shown to play an important role in the pathogenesis of SCCHN is the epidermal growth factor receptor(EGFR)and its li-gand.12-14The EGFR system represents a promising thera-peutic target because it is commonly overexpressed in these tumors.15-17Tumor levels of EGFR and its ligand,trans-forming growth factor alpha,have been shown to be significant predictors of tumor staging and clinical out-come.17,18In addition,several studies have reported that repopulation of epithelial tumor cells after exposure to radiation is related to the activation and expression of EGFR.19,20Thesefindings suggest that EGFR blockade may be important in reducing tumor cell repopulation by modulation of cellular proliferation and enhancement of tumor radioresponse.From the Division of Hematology/Oncology,Department of Radia-tion Oncology,Comprehensive Cancer Center,University of Alabamaat Birmingham,and Birmingham Veterans Administration,Birming-ham,AL;University of Utah Medical Center,Salt Lake City,UT;andImClone Systems,Inc,Somerville,NJ.Submitted December12,2000;accepted March29,2001.Supported by grant no.5U01CA743392from the National Institutesof Health,Bethesda,MD.Address reprint requests to Francisco Robert,MD,University ofAlabama at Birmingham,Comprehensive Cancer Center,WallaceTumor Institute,Rm230,1824Sixth Ave South,Birmingham,AL35294-3300;email:pacorobertuab@.©2001by American Society of Clinical Oncology.0732-183X/01/1913-32343234Journal of Clinical Oncology,Vol19,No13(July1),2001:pp3234-3243Inhibition of the EGFR-induced signal transduction path-ways,either by higher than physiologic concentrations of epidermal growth factor or by monoclonal antibodies (mAbs)directed at the EGFR,has been shown to inhibit the growth of EGFR-expressing human cancer cells.21-23One such antibody is cetuximab (C225;ImClone Systems,Inc,Somerville,NJ),a mouse-human chimeric anti-EGFR mAb that binds with high affinity to the receptor,blocks ligand-induced activation of receptor tyrosine kinase,and induces dimerization and downregulation of the EGFR,which prevents further receptor binding and activation by the ligands.24-28In addition,cetuximab has been shown to inhibit the proliferation of a variety of cultured human tumor cell lines that overexpress EGFR and to enhance the antitumor activity of several chemotherapeutic agents in xenograft models.27,28-30Furthermore,we and others have shown that cetuximab enhanced the radioresponse of EGFR-expressing A431tumor cells in vitro and in tumor xenografts.31,32Given the correlation of EGFR expression with poor prognosis and the fact that preclinical studies identified cetuximab as a radiosensitizer,a phase I study was under-taken to assess the interaction of cetuximab and RT in patients with locally advanced,unresectable SCCHN.The purposes of this study were to establish a safety profile of cetuximab administered over a range of dose levels during RT and to determine the dose-dependent pharmacokinetics and human immune response to the antibody.PATIENTS AND METHODSThis single-center,phase I,open-label study evaluated different dose levels of cetuximab with concomitant RT in patients with locally advanced SCCHN.Five treatment groups (Table 1)with at least three assessable patients were considered for this study to determine the recommended phase II/III dose.Patients received eight to nine weekly infusions of cetuximab.The initial infusion was a loading dose of either 100,200,400,or 500mg/m 2administered over 60to 120minutes.Subsequent infusions of cetuximab consisted of 100-,200-,or 250-mg/m 2maintenance doses administered over 60minutes.Single daily fractions or twice-daily hyperfractionated RT was started on day 8(week 2)of the treatment course and continued for approximately 7weeks.The protocol was approved by the institutional review board,and all patients gave written informed consent before they were entered onto the study.Patient EligibilityPatients enrolled onto this study were at least 18years old and had a histologically confirmed diagnosis of SCCHN.The inclusion criteria were as follows:all sites of the head and neck except the nasopharynx,stage III or IV 33disease or recurrent disease that was not resectable for curative intent,no evidence of metastatic disease,and no history of prior RT or chemotherapy.In addition,patients had a Karnofsky performance status of at least 60%and preserved hematologic param-eters (absolute neutrophil count Ն1,500/L,platelet count Ն100,000/L,and hemoglobin level Ն9gm/dL),liver function (alkaline phosphatase Ͻ2.6times the normal limit,AST level Ͻ2.6times the normal limit,and total bilirubin Ͻ1.5times the normal limit),and normal renal function (creatinine Ͻ 1.5times the normal limit).Exclusion criteria were pregnancy or lactation,prior murine mAb or cetuximab therapy,significant comorbid conditions,or investigational therapy for diseases within 1month of study entry.Representative tumor tissue (paraffin tumor blocks)for EGFR assessment was obtained before the start of the study,but a positive result was not required as a prestudy parameter because of the high reported expression levels in SCCHN.17,18The presence of the EGFR was determined in a two-step immunostaining process,which involved,first,the binding of a murine anti-EGFR antibody (M225)to the receptor and,second,the detection and visualization of bound antibody by application of an enzyme chromogenic reagent.Tumors were considered to overexpress EGFR if positive cytoplasmic rimming was observed in 10%or more of the cells.All patients were evaluated initially by a multidisciplinary team that consisted of radiation oncologists,otolaryngologists,and medical oncologists.The stage of the tumor was determined on the basis of a physical examination,chest x-ray,and computed tomography or magnetic resonance imaging of the head and neck.A routine blood chemical analysis,complete blood count,and urinalysis were per-formed within 2weeks before enrollment.Dental evaluation was performed in each patient,and at least 10days were allowed for healing gingivae after extraction.DefinitionsDose-limiting toxicity (DLT)was defined as grade 3or higher toxicity as determined by the Cancer and Leukemia Group B expanded common toxicity criteria and the Radiation Therapy Oncology GroupTable 1.Study DesignTreatment Group No.of PatientsRTCetuximab Loading Dose (mg/m 2)Cetuximab Loading Infusion Time (min)Cetuximab Maintenance Dose(mg/m 2)Cetuximab Maintenance Infusion Time (min)13qd 10060100q 1wk ϫ76024*qd 20060200q 1wk ϫ76033qd 400120200q 1wk ϫ76043qd 500120250q 1wk ϫ76053bid 400120250q 1wk ϫ760Abbreviations:qd,single daily fraction,bid,twice-daily fractions;q 1wk,once a week.*One patient was replaced because of a grade 4allergic reaction during the initial infusion of cetuximab.3235CETUXIMAB PLUS RT IN HEAD-NECK CANCER(RTOG)acute radiation morbidity scoring criteria.Excluded from thedefinition of DLT were allergic reactions,asthenia,grade3mucositis, and grade3skin toxicity(within and outside of the RTfields).The definition of grade3skin toxicity outside of the RTfield was expanded to include confluence,pain,and erosion of the skin.Grade4skin toxicity was defined as exfoliative or ulcerating generalized dermatitis. Any patients who experienced a grade4allergic reaction were removed from the study and replaced in the same treatment group.The maximum-tolerated dose was defined as the highest dose level at which zero of three or one offive patients experienced a DLT.The recommended phase II/III dose was defined as the optimal cetuximab dose level based on pharmacologic parameters and adverse events. Investigational AgentCetuximab(C225)was provided by ImClone Systems as an inject-able solution in either10-mL or50-mL vials that contained2mg/mL of the antibody.Before infusion,cetuximab wasfiltered with a 0.22-m protein-sparingfilter.Treatment PlanPatients were enrolled sequentially ontofive treatment groups that comprised at least three assessable patients in each group,with all patients at the preceding dose level having received at least two doses of cetuximab(Table1).Dose escalation proceeded in the absence of a study drug–related DLT.If,at any dose level,one of the three patients experienced a DLT,two additional patients were to be enrolled at that dose level.Patients received eight to nine weekly cetuximab infusions with an initial loading dose on day1that ranged from100to500mg/m2 administered intravenously over60or120minutes(Table1).Subse-quent infusions of cetuximab consisted of100-,200-,and250-mg/m2 maintenance doses administered over60minutes.Patients received a test dose of cetuximab(20mg)over10minutes before the initial loading dose.They received the remainder of their infusion after completion of the observation period(30minutes).Patients were premedicated with diphenhydramine(50mg intravenously)and an H2 blocker before the test dose.All treatments were given in the outpatient setting.Vital-sign measurements were obtained before administration of cetuximab,midway through the infusion,and every15minutes during the1-hour observation period after administration of the antibody therapy.The weekly doses of cetuximab were scheduled for Mondays and were administered before RT.An additional weekly infusion of cetuximab(ninth dose)was given to patients who required RT breaks.If a patient experienced a grade1or2allergic reaction,premedita-tion with50mg of diphenhydramine and an H2receptor antagonist was administered before each treatment with cetuximab.The duration of the remaining and subsequent infusions was increased,but it did not exceed4hours.Concurrent treatment with oral diphenhydramine and a topical antibiotic was considered for skin toxicity grades1through3. In addition,cetuximab dose reduction and/or dose delays were required for grade3skin toxicity.In the event of a grade4skin toxicity or grade 4allergic reaction,the patient was removed from the study.RT began on day8(week2).Patients in four initial treatment groups received once-daily RT that consisted of2.0Gy per fraction,five fractions per week,for a total dose of70Gy in7weeks.After administration of50Gy,boostfields to the primary tumor and gross nodal disease with margin were given with photons or electrons in the 4-to20-MeV range.The entire neck and supraclavicular regions were irradiated to a dose of at least44Gy.Patients in the last treatment group received RT bid that consisted of1.2Gy per fraction,10fractions per week,for a total of76.8Gy in7weeks.After administration of45.6 Gy,boostfields to the primary tumor and gross nodal disease with margin were given with photons or electrons in the4-to20-MeV range. The entire neck and supraclavicular regions were irradiated to a dose of at least45.6Gy.Treatment breaks because of confluent mucositis (gradeՆ3)were allowed,but they were restricted to5days. Surgical treatment was used only after the completion of therapy. Neck dissection was permitted for any patient with residual cervical adenopathy or as a planned treatment for any nodal disease with an initial diameter of3cm or more.Pharmacokinetics and Whole-Body Retention DataSerum samples for analysis of circulating cetuximab were obtained during each treatment at the following time intervals:before the infusion of cetuximab and at1,24,48,72,and96hours after infusion with doses1,4,and8.Samples were collected before infusion and1 hour after infusion with doses2,3,5,6,and7.Serum concentrations of cetuximab were determined using a Bio-sensor(Pharmacia,Uppsala,Sweden)biomolecular interaction analysis core instrument,which measures changes in surface plasmon reso-nance.In this method,a serum sample that contains the antibody is flowed over a dextran-coated foldfilm to which EGFR has been conjugated.The binding of cetuximab to the immobilized EGFR produces a change in the angle of light reflected from the goldfilm,and from this relationship,a standard curve can be created to express the concentration of cetuximab in the serum sample.In addition,whole-body probe counts were performed after radiola-beled antibody infusion in patients in treatment groups1through4 only.For each dose,approximately1mg of cetuximab was radiola-beled with10mCi of iodine-131(131I)and was administered intrave-nously over2to3minutes after the infusion of thefirst(loading dose) and last maintenance dose of unlabeled cetuximab.Radiolabeling was performed under aseptic conditions using standard iodogen methodol-ogy.Quality control of the radiolabeled product was monitored by immunoreactivity,high-performance liquid chromatography analy-sis,limulus amebocyte lysate assay,and sterility testing.To block uptake of131I by the thyroid,patients received a saturated solution of potassium iodide,beginning48hours before the administration of 131I-cetuximab and continuing for14days.Serial total-body sodium iodide probe counts were measured to determine whole-body retention data from each patient during thefirst andfinal131I-cetuximab infusions.The residence time(area under the curve of a percentage of the injected dose)was calculated using a trapezoidal integration method.The biologic half-life(T1/2)for131I-cetuximab also was derived from a monoexponential regressionfit of whole-body count data.Human Antichimeric Antibody ResponsePatients were monitored to determine whether the administration of cetuximab resulted in the production of human antichimeric antibodies (HACAs).Sera obtained before thefirst infusion and throughout the subsequent treatment period were analyzed with a double-antigen radiometric assay specific for cetuximab.34,35The results are expressed as nanograms per milliliter of bound antibody.A positive response is greater than10ng/mL antibody bound and greater than two times the preinfusion levels.3236ROBERT ET ALCriteria for Toxicity and ResponseSystemic and local adverse events were graded in accordance with the Cancer and Leukemia Group B expanded common toxicity criteria and the RTOG morbidity scoring criteria.Safety was assessed by physical examination and laboratory evaluations(complete blood count,chemical profile,and urinalysis)for the duration of the treatment and follow-up.The initial tumor response assessment was performed4to6weeks after treatment was completed.Tumor response was determined by physical examination and imaging studies(computed tomography or magnetic resonance imaging).Extended follow-up was performed at approximately3-month intervals.A complete response was defined as resolution of all evidence of measurable and assessable disease.A partial response was defined as a50%or greater reduction in the sum of the products of the longest perpendicular diameters of measurable lesions,with no new lesion development.Progressive disease was defined as a greater than25%increase of the sum of the products of the maximum diameters of the measurable lesions or the appearance of a new lesion.In addition to analyzing tumor response,we analyzed several clinical events,including the time to progression,actuarial locoregional progression-free survival,and overall survival.These data were analyzed using the Kaplan-Meier method.36The Student’s t test was used for the comparison of the resident time and biologic T1/2 between thefirst and last radiolabeled antibody infusions.RESULTSPatient CharacteristicsA total of16patients were enrolled onto this study between April1997and August1998.Table2outlines thecharacteristics of the patients.The median age was55years (range,34to72years).Fifteen patients were treatment-naı¨ve,and one patient with recurrent disease had been treated previously with surgery.The majority of patients (81%)had stage IV disease.Nodal metastases were present in81%of the patients,and six patients had N2disease.Of a total of15patients tested for tumor EGFR expression, only two were negative.Of the16patients,15received the planned cetuximab infusions and RT,with minimal interruption or delay. One patient in the second treatment group developed a reversible grade4anaphylactic reaction approximately5 minutes into thefirst infusion,which required his re-moval from the study.ToxicityA total of125cetuximab infusions were administered, with a mean of eight infusions per patient.Treatment with cetuximab and RT was well tolerated.The adverse events encountered in the present study for all patients and by treatment group are listed in Tables3and4,respectively. The most common adverse experiences thought to be related to the antibody therapy were asthenia,fever,nausea, and skin toxicities.Skin toxicities included acneiform-follicular rashes(mainly on the scalp,face,and truck)and maculopapular eruptions.The onset of these cutaneous manifestations usually occurred during thefirst3weeks of therapy,with complete resolution or stabilization with continued therapy.Only one patient(treatment group4) developed grade3skin toxicity related to cetuximab(out of the RTfield),which was characterized by symptomatic (pruritic)generalized maculopapular eruption after thefirst antibody infusion.The incidence of skin toxicity outside of the RTfields was not strictly dose-dependent;however, grade2and higher skin eruptions were observed only in patients treated with higher-dose regimens(treatment groups4and5).Four patients experienced allergic reactions during the first infusion(Table3).Two of these patients had a grade3 or higher reaction;one patient with reversible anaphylactic reaction(grade4)was removed from the study.Patients with allergic reactions lower than grade4received subse-quent infusions with premedication(diphenhydramine and H2-receptor antagonists),and the time of infusions was increased.No further allergic manifestations were observed in these patients after these treatment alterations.Most of the acute grade2and higher adverse events observed during treatment were associated with standardTable2.Patient CharacteristicsCharacteristicNo.of Patients(Nϭ16) Age,yearsMedian55 Range34-72 SexMale12 Female4 Performance status90%3 80%7 70%6 Primary siteOral cavity3 Oropharynx9 Larynx2 Hypopharynx2 AJCC stageIII3IV13 Tumor stageT23T36T47 Nodal stageN04N16N26 Abbreviation:AJCC,American Joint Committee on Cancer.3237CETUXIMAB PLUS RT IN HEAD-NECK CANCERaggressive irradiation,ie,xerostomia,mucositis,odynopha-gia,and local skin toxicity in the radiotherapyfields(Table 4).The incidence of confluent mucositis and local skin toxicity was virtually the same in all of the treatment groups.Long-term effects of treatment included mild to moderate xerostomia in the great majority of the patients and one case of soft tissue necrosis with exposure of bone. Pharmacokinetics and Whole-Body Retention DataThe cetuximab concentration-versus-time data during treatment for thefive treatment groups are shown in Fig1. Visual inspection of the individual concentration versus time curves indicates that circulating cetuximab peak and trough levels increased progressively in patients treated with loading doses of100to500mg/m2and maintenance weekly doses of100to250mg/m2.The mean serum peak levels in thefirst four treatment groups were358,656, 1,291,and1,478nmol/L.Mean serum trough levels in the same treatment groups were39,202,504,and772nmol/L.It is obvious that the interpatient variability with thesefixed regimens is high,especially at higher doses of cetuximab. The mean Km(the concentration of the antibody at which its elimination is half of its maximum)for this group of patients was482nmol/L.The inadequacy of thefirst two dosing regimens is readily apparent.The concentrations of cetuximab generated with these two dosing regimens per-sistently fell below the population Km,which indicates that within this dose range,saturation of drug clearance was not achieved.A complete analysis of the pharmacokinetic data will be presented in a separate report.The sodium iodide probe count data from thefirst and last infusion of cetuximab for thefirst four treatments groups is shown in Fig2.The mean value for the residence time in the first infusion was85.3hours,as compared with83.7hours for the last infusion(Pϭ.69;t test).The mean biologic T1/2 was94.5hours with thefirst infusion and89.6hours with the last infusion.Individual patient data indicate a trend in the residence time and biologic T1/2with increased doses of cetuximab.HACA ResponseThe sera of14patients who completed therapy were analyzed for the presence of HACAs.None of these patients developed an immune response to cetuximab.Clinical ResponsesFifteen patients were assessable for response and locore-gional control.Thirteen patients achieved a complete re-Table3.Adverse Events During Therapy*EventGradeTotal No. 1234Allergic reaction†11114 Asthenia703010 Chills10001 Fever380011 Injection site reaction20002 Anorexia12003 Diarrhea21003 Xerostomia†2130015 Odynophagia†0411015 Nausea1440018 Vomiting41005 Mucositis†0411015 Skin toxicity outside RTfields‡1031014 Skin toxicity within RTfields§195015 Arthralgia13004 Myalgia21003 Paresthesia10001 Alopecia10001 Conjunctivitis10001 Anemia1200012 Leukopenia90009 Thrombocytopenia40004 Creatinine elevation10001 Alkaline phosphataseelevation60006 AST elevation80008*Number of adverse events during the administration of125cetuximab infusions plus RT.†Worst toxicity during therapy.‡Worst cetuximab-related skin toxicity during therapy.§Worst RT-induced skin toxicity.Table4.Adverse Events by Treatment GroupToxicity GradeNo.of Patients by Treatment Group12345 Mucositis100000211011322322400000 Odynophagia100000211110322223400000 Xerostomia100011233322300000400000 Skin,infield100001232121301211400000 Skin,outside of the RTfield1233112000123000104000003238ROBERT ET ALsponse,and two patients achieved a partial response (Table 5).One of the partial responders,a patient with a T3N2cMo tumor,underwent bilateral neck dissection after completion of RT for persistent disease and has remained free of disease for more than 22months.The median duration of response for all patients was 28months.The median follow-up of surviving patients was 36months (range,23to 42months).Six patients had relapsed,with a median time to progression of 8months (range,4.5to 31months).All recurrences were at the locoregionalsites.Five of these patients died from progressive disease,and the cause of death of one patient is unknown.The actuarial 1-and 2-year disease-free survival rates were 73%and 65%,respectively.The median survival of these pa-tients has not been reached.DISCUSSIONThe combination of cetuximab and RT was well tolerated in this group of patients with advanced SCCHN.The most common reported cetuximab-related adverse eventswereFig 1.Serum levels of cetux-imab during therapy shown on a semilogarithmic plot scale at dose levels of (A)100/100mg/m 2,(B)200/200mg/m 2,(C)400/200mg/m 2,(D)500/250mg/m 2,and (E)400/250mg/m 2loading and maintenance regimens.3239CETUXIMAB PLUS RT IN HEAD-NECK CANCERfever,asthenia,transaminase elevation,nausea,and skin toxicities.These adverse events were grades 1and 2in the majority of the patients and were not related to the dose level of the antibody therapy.Only one patient experienced grade 3skin toxicity (a follicular/maculopapular rash)outside of the RT fields.Otherwise,the majority of the grade 2and 3skin toxicities were within the RT fields and not necessarily related to cetuximab therapy.In addition to the skin toxicity,one patient experienced a grade 4anaphy-lactic reaction shortly after the initiation of the first cetux-imab infusion,which was completely reversible.The re-mainder of the grade 2and 3antibody-related local/systemic toxicities were of little consequence and required no cetuximab dose modification or RT delays.In recent studies of hyperfractionated RT alone or com-bined RT and chemotherapy,the most common grade 3adverse event was acute mucositis in 67%to 77%of patients.11,37,38In the first report of RTOG 9003,the incidence of grade 3or worse acute mucositis was 25%for standard fractionation and 43%for altered fractionation RT.9In that study,the incidence of grade 3or higher skin toxicity was 7%for standard fractionation and 9%for altered fractionation RT.In our study,the incidence of grade 3mucositis was 73%,and the incidence of grade 3in-field skin toxicity was 33%.An important relevant issue is whether cetuximab increases the local toxicity of RT.Our data suggest some enhanced toxicity,which implies a biologic interaction between the antibody and RT.How-ever,a definite conclusion cannot be reached at this time because of the small number of patients in this study.A critical issue in clinical studies with an anti-EGFR mAb is definition of the optimal biologic dose and schedule.The hypothesis that has driven the clinical development of cetuximab is that complete saturation of EGFR binding might require saturation of the mechanism(s)responsible for the antibody’s elimination from the body.Indeed,it is likely that a major route for cetuximab clearance involves the binding of the antibody to EGFR on hepatocytes,with subsequent internalization of the cetuximab-EGFR com-plex.On the basis of this hypothesis,the optimal biologic dose is the lowest dose of cetuximab required to continu-ously maintain zero-order antibody elimination.Analysis of the pharmacokinetic data of previous phase I studies has shown that cetuximab displayed nonlinear phar-macokinetics,with antibody doses in the range of 200to 400mg/m 2associated with complete saturation of systemic clearance.39On the basis of these findings,therecom-Fig 2.Whole-body retention data after 131I-cetuximab admin-istration during the first and last infusions at different dose levels (100/100mg/m 2,patient nos.1to 3;200/200mg/m 2,patient nos.4,6,and 7;400/200mg/m 2,patient nos.8to 10;and 500/250mg/m 2,patient nos.11to 13).(A)Residence time;(B)biologic T 1/2.Table 5.Clinical Response and DurationPatient No.Treatment GroupPrimary Site TNM/StageClinical ResponseDuration of Response (months)11Base of tongue T3N1M0/III CR 621Tonsil T3N0M0/III CR 39ϩ31TonsilT2N2BM0/IV CR 37ϩ42Base of tongue T3N2BM0/IV CR 33ϩ52Tonsil T3N0M0/III CR 2862LarynxT4N1M0/IV CR 373Retromolar trigone T4N2BM0/IV CR 28ϩ83Oral tongue T4N1M0/IV CR 393Hypopharynx T4N0M0/IV CR 5ϩ104TonsilT2N2BM0/IV CR 30ϩ114Floor of mouth T4N0M0/IV PR 3124TonsilT4N1M0/IV CR 25ϩ135Soft palate T2N2CM0/IV CR 11145Tonsil T3N1M0/IV CR 24ϩ155Larynx T3N2CM0/IV PR 21ϩAbbreviations:TNM,AJCC primary tumor,nodal status,and distant metastases staging system;CR,complete response;PR,partial response.3240ROBERT ET AL。
爱必妥2
爱必妥(西妥昔单抗)——爱必妥2006-07-03 11:19:53 作者：来源：中国新药网浏览次数：2512 文字大小：【大】【中】【小】简介：爱必妥™(西妥昔单抗)是一种IgG1单克隆抗体，能与表皮生长因子受体(EGFR)特异性结合，阻断内源性配体介导的EGFR信号传导通路，从而抑制肿瘤的生长。
目前大量临床研究显示，爱必妥™用于转移性结直 ...关键字：爱必妥西妥昔单抗Erbitux cetuximab直肠癌爱必妥™(西妥昔单抗)是一种IgG1单克隆抗体，能与表皮生长因子受体(EGFR)特异性结合，阻断内源性配体介导的EGFR信号传导通路，从而抑制肿瘤的生长。
目前大量临床研究显示，爱必妥™用于转移性结直肠癌以及头颈部鳞状细胞癌等多种实体肿瘤的治疗取得了良好的疗效。
自2003年12月在瑞士上市以来，爱必妥™已在全球50余个国家注册并上市。
2005年12月，中国SFDA批准爱必妥™联合伊立替康用于治疗经含伊立替康方案化疗失败且表达表皮生长因子受体的转移性结直肠癌。
2006年7月，爱必妥™在中国成功上市。
爱必妥™以带橡皮塞和铝封的无色玻璃瓶包装，每瓶含有50ml注射液，每毫升注射液含2mg西妥昔单抗有效成分。
本品为静脉输注使用。
爱必妥™为处方药，须在专业医师的指导下使用。
爱必妥（西妥昔单抗）——大肠癌生物靶向治疗新药★第一个获准上市的靶向单克隆抗体，治疗转移性结直肠癌。
★靶向的生物导弹，精确打击肿瘤细胞而很少伤及正常细胞。
★阻断肿瘤细胞信号传导，抑制癌细胞增殖，透导肿瘤细胞凋亡。
★爱必妥与FOLFOX-4联合应用达到最高缓解率（81%）。
”★耐受性好，不良反应轻。
药品名称:爱必妥注射 (Erbitux)通用名:西妥昔单抗英文名: cetuximab制造商: 德国默克勃林格殷格翰性状本品除活性成分外，还含有以下成分：磷酸二氢钠20 mg、磷酸氢二钠66 mg、氯化钠424 mg、注射用水加至50 mL。
西妥昔单抗
靶向疗法，西妥昔单抗可能会帮助提高头颈部癌患者的放疗效果。
与单独使用放疗相比，西妥昔单抗与放疗联用几乎能够将肿瘤尚未向身体其它部位转移的某种头颈部癌患者的中位存活期提高一倍。
不过对于西妥昔单抗与放疗联用的效果是否优于目前临床的标准疗法（用顺铂化疗）还有待于进一步的研究。
西妥昔单抗的副作用之一是有可能引发严重的类痤疮斑疹。
西妥昔单抗（cetuximab，商品名为爱必
妥）为嵌合单克隆抗体，属于表皮生长因子受体抑制剂，静注用于转移性结肠直肠癌及头颈部癌症的治疗。
该药由ImClone Systems开发，在北美地区，由ImClone及施贵宝公司合作推广，在全球其它地区销售权归德国Merck KgaA 所有。
FDA在2004年批准了该药用于结肠直肠癌的治疗。
研究人员认为西妥昔单抗是通过与表达EGFR 的所有细胞，其中也包括亚组“癌细胞”的EGFR 的胞外片断结合，抑制腺病毒结合和受体的激活，由此抑制EGFR的下游信号转导，从而使细胞生长和复制功能受损。
另外西妥昔单抗也在研究中表现出介导抗体依赖性细胞毒的作用。
目前西妥昔单抗正面临严峻的竞争挑战，FDA在2006年11月批准了安进公司的帕尼单抗（panitumumab，Vectibix）。
这两种药物的主要差别是前者为IgG 1抗体，而后者为IgG 2抗体。
目西妥昔单抗
关键词：首个在中国上市的靶向单克隆抗体。
利妥昔单抗注射液Rituximab-详细说明书与重点
利妥昔单抗注射液Rituximab【成份】本品主要活性成分为利妥昔单抗辅料：枸橼酸钠、聚山梨酯80、氯化钠、盐酸（37%）和注射用水【性状】无色或淡黄色澄明液体【适应症】复发或耐药的滤泡性中央型淋巴瘤（国际工作分类B、C和D亚型的B细胞非霍奇金淋巴瘤）的治疗。
先前未经治疗的CD20阳性III-IV期滤泡性非霍奇金淋巴瘤，患者应与化疗联合使用。
CD20阳性弥漫大B细胞性非霍奇金淋巴瘤（DLBCL）应与标准CHOP化疗（环磷酰胺、阿霉素、长春新碱、强的松）8个周期联合治疗。
【规格】100mg/10ml/瓶【用法用量】用法和使用说明：在无菌条件下抽取所需剂量的利妥昔单抗，置于无菌无致热原的含0.9%生理盐水或5%葡萄糖溶液的输液袋中，稀释到利妥昔单抗的浓度为1mg/ml。
轻柔的颠倒注射袋使溶液混合并避免产生泡沫。
由于本品不含抗微生物的防腐剂或抑菌制剂，必须检查无菌技术。
静脉使用前应观察注射液有无微粒或变色。
利妥昔单抗稀释后通过独立的不与其他药物混用的输液管静脉滴注，适用于不卧床患者的治疗。
利妥昔单抗的治疗应在具有完备复苏设备的病区内进行，并在有经验的肿瘤医师或血液科医师的直接监督下进行。
对出现呼吸系统症状或低血压的患者至少监护24小时。
每名患者均应被严密监护，监测是否发生细胞因子释放综合征（见【注意事项】）。
对出现严重反应的患者，特别是有严重呼吸困难，支气管痉挛和低氧血症的患者应立即停止滴注。
还应该评估患者是否出现肿瘤溶解综合征，例如可以进行适当的实验室检查。
预先存在肺功能不全或肿瘤肺浸润的患者必须进行胸部X线检查。
所有的症状消失和实验室检查恢复正常后才能继续滴注，此时滴注速度不能超过原滴注速度的一半。
如再次发生相同的严重不良反应，应考虑停药。
利妥昔单抗绝不能未稀释就静脉滴注，制备好的注射液也不能用于静脉推注。
滤泡性非霍奇金淋巴瘤：每次滴注利妥昔单抗前应预先使用解热镇痛药（例如扑热息痛）和抗组胺药（例如苯海拉明）。
分子靶向药物
分子靶向药物类首页上一页1下一页尾页页次：1/1页100篇文章/页找了一下之前孙燕院士的靶向治疗文章中对靶向药物的总结：1、信号转导: TK酶抑制剂—吉非替尼、厄洛替尼、伊马替尼、达沙替尼、尼罗替尼、索拉非尼、舒尼替尼、凡德他尼、埃克替尼2、新生血管: 小分子化合物—恩度；单克隆抗体—贝伐单抗3、调控基因: 曲妥珠单抗4、EGFR受体: 小分子化合物—TKIs；单克隆抗体—西妥昔单抗、尼妥珠单抗、帕尼单抗5、表面受体: 利妥昔单抗因为这个是2010年总结的药物，过了1年多，所以里面肯定不全，先将这些慢慢的进行整理，后面再逐步添加新的。
吉非替尼商品名：易瑞沙英文名：Gefitinib Tablet 、Iressa、ZD1839结构式：适应症及作用机制：吉非替尼( gefitinib)是第一个批准用于治疗晚期非小细胞肺癌的分子靶向药物，通过竞争性结合到酪氨酸激酶的ATP结合区，抑制EGFR 酪氨酸激酶的活化，并能抑制EGFR的磷酸化作用和下游区的信号转导通路。
规格：250mg x 10 片/盒用法用量：推荐剂量为250mg(1片)每日1次，空腹或与食物同服。
不推荐用于儿童或青少年，对于这一患者群的安全性和疗效尚未进行研究。
不良反应：最常见的药物不良反应( ADRs )为腹泻、皮疹、瘙痒、皮肤干燥和痤疮，发生率20%以上，一般见于服药后一个月内，通常是可逆性的。
更多阅读分子靶向药物易瑞沙Iressa 吉非替尼治疗晚期或转移性非小细胞肺癌吉非替尼治疗晚期NSCLC2012-03-12 回复阳光明媚3楼厄洛替尼商品名：特罗凯英文名：Erlotinib Hydrochloride Tablets, Tarceva结构式：适应症及作用机制：可试用于两个或两个以上化疗方案失败的局部晚期或转移的非小细胞肺癌的三线治疗。
厄洛替尼(erlotinib) 可与ATP 结合区可逆性结合，并且完全抑制EGFR 酪氨酸激酶的自主磷酸化作用，从而阻断下游区EGFR 信号通路，引起细胞周期停滞，以及抑制血管生成。
爱必妥ERBITUX_西妥昔单抗cetuximab_使用说明书
重心脏毒性。2/21 例患者死亡，一例是肺炎的结果和一例原因不明。四例患者 由于不良事件终止治疗。这些终止中 2 例是由于心脏事件。
5.6 低镁血症和电解质异常
临床试验期间被评价患者中，接受 Erbitux 患者的 55%(199/365)中发生低镁血 症和 6–17%是严重(NCI CTC 3 和 4 级)。开始用 Erbitux 后数天至数月发生低镁 血症的开始和伴电解质异常。Erbitux 治疗期间和完成后至少 8 周定期监测患者 低镁血症，低钙血症，和低钾血症。需要时补充电解质。
2.2 结肠直肠癌
（1）推荐的初始剂量，或单独治疗或与依立替康联用，是 400 mg/平方米，120分钟静脉输注给药(最大输注速率 10 mg/min)。 （2）推荐的随后每周剂量，或单独治疗或与依立替康联用，是 250 mg/平方米， 60 分钟输注(最大输注速率 10 mg/min)直至疾病进展或不能接受的毒性。
头颈部癌
n （1）局部或区域晚期头颈部鳞状上皮癌与放疗联用。(1.1, 14.1) U （2）复发或转移头颈部鳞状上皮癌基于铂治疗后正在进展。(1.1, 14.1)
结肠直肠癌
（1）在基于依立替康[irinotecan]-和奥沙利铂基于[oxaliplatin]-方案后或对 基于依立替康方案不能耐受患者都失败的 EGFR-表达转移结肠直肠癌中作为单 药治疗。(1.2, 14.2) （2）在 EGFR-表达转移结肠直肠癌对基于依立替康化疗难治患者中与依立替康 联用。批准是根据客观缓解率；得到的资料没有证实增加生存的改善。(1.2, 14.2) （3）转移或晚期结肠直肠癌试验的回顾性子组分析未显示在密码子 12 或 13 有 KRAS 突变肿瘤患者中 Erbitux 治疗效益。对有这些突变结肠直肠癌的治疗不建 议用 Erbitux。(1.2, 12.1, 14.2)
西妥昔单抗
英文商品名：ERBITUX原产地英文药品名：Cetuximab份子结构名：西妥昔单抗包装规格及销售价：100毫克/50毫升/瓶( 附加过滤器)中文剂型：注射剂100毫克/20毫升/瓶( 免过滤器)计价单位：瓶生产厂家：德国默克里昂制药公司适应症：结肠直肠癌扩大适应症：鼻咽癌, 肺癌西妥昔单抗本品单剂治疗或与化疗、放疗联合治疗时的药动学呈非线性特的增加程度超过剂量的增长倍数。
当剂量从20mg/m2增加到200mg/m2时，清除率（Cl）从0.08L/(m2.h)下降至0.02L/(m2.h)，接近2～3L/m2。
本品400mg/m2滴注2小时后，平均最大血药浓度（Cmax）为184μg/ml（92～327μg/ml），平均消除半衰期（t1/2）为97小时（41～213小时）。
按250mg/m2滴注1小时后，平均Cmax为140μg/ml （120～170μg/ml）。
在推荐剂量下（初始400mg/m2，以后一周范围分别为168～235和41～85μg/ml。
平均t1/2为114小时（75～188小时）。
一项多中心随机Ⅱ期临床对照研究评价了本品治疗转移性结直肠癌的疗效，329例EGF受体过度表达的受试者中，206例为男性，平均59岁（26～84岁），58%为结肠癌患者，40%为直肠癌患者，其中63%的患者用奥沙利铂（oxaliplatin）治疗无效。
研究中患者随机分成2组，本品和伊立替康联用组218例，本品单用组111例。
本品的初始剂量为一周400mg，随后一周250mg，治疗终点为疾病进展或出现不能耐受的不良反应。
伊立替康的使用剂量为每3周350mg/m2，每2周180mg/m2，或第6周4次125mg/m2。
结果显示，联合治疗组和本品单用组有效率分别为22.9%和10.8%。
疗效平均持续时间，联合治疗组和本品单用组分别为5.7和4.2个月；与本品单用组相比，联合治疗组患者明显延缓了疾病的进展。
另一项多中心单组开放性临床研究，评价了138例EGF受体过度表达的转移性结直肠癌患者接受本品与伊立替康联用的疗效。
注射用西妥昔单抗爱必妥治疗RAS基因野生型的转移性结直肠癌操作指引
注射用西妥昔单抗（爱必妥）治疗RAS基因野生型的转移性结直肠癌操作指引
一、基本信息
产品名称：西妥昔单抗(Cetuximab Solution for Infusion) 商品名：爱必妥
包装规格：100mg(20ml)/瓶
生产厂商：德国默克公司(Merck KGaA)
进口药品注册证号：S
贮藏：本品应贮藏在冰箱中（2-8℃）。
开启后应立即使用，禁止冰冻。
请置于儿童不可触及处。
二、医保基金支付适应症
西妥昔单抗注射液（爱必妥）：用于治疗RAS基因野生型的转移性结直肠癌。
三、医学标准
患者必须是经病理组织学或细胞学检查证实为结直肠癌且结合影像学检查等确诊转移的，基因检测为RAS野生
型。
RAS基因检查必须在三级甲等医院进行或复核。
四、特药待遇
自治疗之日起一个医疗年度内，医保基金和参保患者共同承担12个月西妥昔单抗（爱必妥）费用。
五、患者申请特药待遇提供材料
1．参保人员患RAS野生型转移性结直肠癌的相关病历、RAS检测结果及诊治记录。
其中病理报告、CT影像诊断报告、组织标本的相关基因检测报告是必需的医学诊断检查报告。
2．参保患者填写，经指定责任医师签字确认，指定医院医保办审核盖章的《南通市医疗保险特药使用申请表》；
3．参保患者社会保障卡；
4．参保患者近期1寸免冠照片1张；
5．其他有关材料。
六、复查评估
使用西妥昔单抗（爱必妥）的参保患者应每2个月到指定责任医师处复查评估，并将由责任医师签字确认的《南通市医疗保险特药使用评估表》交特定药店留存，以确保合理
用药和治疗，并继续享受特药待遇。
西妥昔单抗ppt课件
已知对西 妥昔单抗有严 重超敏反应(3 级或4级)的患 者禁用本`品。 伊立替康的有 关禁忌．请参 阅其使用说明 书。
尚无药物 过量的报道。 无西妥昔单 抗单次给药 剂量超过 500mg/m2体 表面积的经 验。
伊立替康不会 影响西妥昔单抗的 安全性，反之亦 然。。同样，本品 也不会影响伊立替 康的药代动力学性 质。尚未进行本品 与其它药物相互作 用的人体研究。
适应症
本品为注射用溶液，无色，可能含 有与产品相关的白色可见的无定形颗粒 。 本品与伊立替康(irinotecan)联合用 药治疗表达表皮生长因子受体（EGFR ）、经伊立替康细胞毒治疗失败后的转 移性直肠癌的治疗。
性
状
适应症
西妥昔单抗注射液
用法用量
建议在经验丰富的试验室按照验证后 的方法检测EGFR。在用药过程中及用药 结束后1小时内，需密切监测患者的状况 ，并必须配备复苏设备。 滴注本品之前，患者必须接受抗组胺 药物和皮质醇药物的治疗。本品每周给药 一次。初始剂量400mg/m2体表面积，其 后每周的给药剂量为250mg/m2体表面积 。与本品联合使用的伊立替康的给药剂量 ，请参照伊立替康的使用说明书。 通常情况下，伊立替康的给药剂量与 患者上次用药时最后一个周期的使用剂量 相同，伊立替康的使用必须在本品滴注结 束1小时之后开始。
药理毒理
毒理 在使用人类治疗剂量的等效剂量作 为起始剂量进行的恒河猴毒理试验中主 要观察到剂量依赖性的皮肤毒性。当猴 体浓度达到人临床标准治疗时体内血液 浓度的17倍时，本品能引起猴的严重皮 肤毒性及致命的综合症。 到目前为止，尚无抗EGFR抗体 对伤口愈合的非临床数据。然而，非临 床伤口愈合模型显示EGFR选择性酪氨酸 激酶抑制剂能延迟伤口愈合。
西妥昔单抗说明书
西妥昔单抗说明书【药品名称】通用名称：西妥昔单抗商品名称：＿____【成份】本品主要成份为西妥昔单抗。
【性状】本品为无色或淡黄色澄明液体。
【适应症】本品用于治疗转移性结直肠癌，以及头颈部鳞状细胞癌。
【规格】＿____【用法用量】1、转移性结直肠癌在开始治疗前，应进行 KRAS 基因状态检测。
KRAS 野生型的患者适用西妥昔单抗治疗。
推荐初始剂量为 400mg/m²，静脉输注，输注时间约120 分钟。
此后每周250mg/m²，静脉输注，输注时间约60 分钟。
2、头颈部鳞状细胞癌初始剂量为 400mg/m²，静脉输注，输注时间约 120 分钟。
此后每周 250mg/m²，静脉输注，输注时间约 60 分钟。
【不良反应】使用西妥昔单抗可能会出现一系列不良反应。
常见的不良反应包括皮肤反应，如痤疮样皮疹、皮肤干燥、瘙痒、甲沟炎等；还可能出现输液反应，如发热、寒战、呼吸困难等。
此外，可能会有胃肠道反应，如恶心、呕吐、腹泻等；以及血液学毒性，如白细胞减少、贫血等。
皮肤反应通常在治疗开始后的第 1-2 周出现，多数为轻至中度。
对于皮肤反应，应注意保持皮肤清洁，避免阳光直射，并根据症状的严重程度使用相应的药物治疗。
输液反应可能在首次输注时发生，也可能在后续输注时出现。
在输注过程中应密切监测患者的生命体征，一旦出现输液反应，应立即停止输注，并给予相应的治疗。
如果出现严重的不良反应，如严重的输液反应、呼吸困难、心脏功能异常等，应立即停止使用西妥昔单抗，并进行积极的治疗。
【禁忌】对本品活性成份或其它任何成份过敏者禁用。
【注意事项】1、在使用西妥昔单抗之前，应告知医生患者的过敏史、疾病史和正在使用的其他药物。
2、治疗期间应定期进行血液学检查，包括血常规、肝肾功能等，以监测药物的不良反应。
3、患者在接受西妥昔单抗治疗期间应避免接种活疫苗。
4、对于有眼部疾病史的患者，应密切监测眼部症状。
化疗药物配置及注意事项
B
23
顺铂
2、避免采用与本品肾毒性或耳毒性叠加的药物，如氨 基糖苷类抗生素、两性霉素B、头孢噻吩、戊炔喃苯胺酸、利尿 酸纳等。
3、静滴时需避光。
B
24
2. 卡 铂
250-500ml5%葡萄糖注射液溶解，缓慢静脉滴
注意事项注：。 （1）对顺铂或其他含铂化合物过敏者及对甘露醇过敏者禁用。 （2）本品溶解后应在8小时内用完，滴注或存放时应避免直接日晒。 （3）尽量避免与可能损害肾功能的药物如氨基糖甙类抗菌素同时使用。
B
6
2. 吉西他滨
250ml生理盐水溶解，静脉滴注30分钟
注意事项： 1、仅0.9%氯化钠注射用水允许使用溶解本品的无菌粉末，配制时，至少将5
mL 0.9%氯化钠注射液注入该药的200 mg瓶中或将至少25 mL 0.9%氯化钠注射 液注入该药的1 g瓶中，振摇使其溶解，给药时所需药量可用0.9%氯化钠注射液 作进一步稀释，配制好的吉西他滨溶液应贮存在室温(15-30℃)并在24 hr内使用， 未用完部份要丢弃。
B
11
3. 吡柔比 星
10ml-50ml注射用水或5%葡萄糖注射液溶解，静脉注射。
注意事项： 1、本品难溶于生理盐水，故不宜用生理盐水做溶剂。 2、溶解后药液，即时用完，室温下放置不得超过6小 时。
B
12
4. 博莱霉 素
20ml生理盐水或5%葡萄糖注射液溶解，缓慢静脉注射。 2-5ml生理盐水或5%葡萄糖注射液溶解，肌肉注射。
2、提前给予H1受体阻断剂，对预防输液反应有一定作用。使用前勿振荡、稀释。 3、2～8℃下可保存12小时以上，20～25℃下可保存8小时以上。
B
29
2、贝伐珠单抗（安维汀）
爱必妥作用机制及不良反应处理
角质层变薄 炎症细胞渗出 角蛋白过多阻塞毛囊
精品课件
皮肤反应-痤疮样皮疹
• 出现时间：中位出现时间 为爱必妥应用的第1-2周， 常在第3-4周时达到顶峰
• 常见部位：主要位于皮脂 腺分布的部位，即头面颈 部及和躯干上部
精品课件
皮肤反应-痤疮样皮疹
• 临床表现：
感觉障碍伴皮肤红斑和水肿（第0-1周） 丘疹脓疱性皮疹（第1-3周） 结痂（第3-5周）
• 爱必妥输注结束时需用生理盐水冲洗输液管线，以将剩 余的药品注射完全
• 联合应用的化疗药物应该在爱必妥输注结束一小时后开 始输注
精品课件
爱必妥主要不良反应
• 输注相关不良反应 • 皮肤反应
精品课件
输注相关不良反应
• 在接受爱必妥治疗的患者中，约5%出现输注相 关不良反应，其中约一半为重度超敏反应
阻断受体形成二聚体， 酪氨酸激酶磷酸化以及 信号转导 阻止放化疗后肿瘤细胞 自身修复及存活 促进凋亡 细胞周期停滞 下调血管生长因子 抑制侵袭/转移 激发ADCC效应
爱必妥® 的化疗増敏作用 —临床前研究的数据
适应症 mCRC SCCHN NSCLC
化疗药物
伊利替康 拓扑替康 奥沙利铂 卡铂 阿霉素 吉西他滨 伊利替康 拓扑替康 卡铂 顺铂 阿霉素 吉西他滨 伊利替康 拓扑替康 卡铂 奥沙利铂 阿霉素 吉西他滨 紫杉醇
59
24
erbB-3 HER3
79 酪氨酸激酶区
ห้องสมุดไป่ตู้
28
羧基端
erbB-4 HER4
EGFR 信号转导通路
生长因子(如表皮生长因子 [EGF]或转化生长因子- [TGF-])可以激活EGFR EGFR激活后形成同源或异 源二聚体 受体二聚作用可激发细胞 内信号级联反应, 基因激 活,并促进细胞周期进展
爱必妥使用方法及不良反应管理
皮肤损害和症状 EGFRI剂量调整 局部治疗 全身治疗 干预
丘疹、脓疱或无症状性红斑 无 无 无 一般性宣教*
意大利专家共识-2级皮疹的处理方法
皮肤损害和症状
EGFRI剂量调整
局部治疗
全身治疗
丘疹（2A级）或脓疱（2B级）覆盖<50%体表面积，症状中等，不影 响日常生活
无
抗感染：1％克林霉素凝胶、3％红霉素凝胶/霜或0.75％ ～ 1％甲硝 唑霜/凝胶，每天2次，直到病情消退至1级（避免使用过氧化苯甲 酰）。头皮病变：2％红霉素洗剂。
EGFR拮抗剂毒性发生率
帕尼单抗
16%
90%
厄洛替尼 150 mg QD[1]
10%
85%
西妥昔单抗
9%
75%
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 3级及以上 所有级别
1. Shepherd FA, et al. N Engl J Med. 2005; 353:123-132. 2. Rosell R, et al. Ann Oncol. 2008;19:362-369. 3. Van Cutsem E, et al. J Clin Oncol. 2007;25:1658-1664. 4. Geyer CE, et al. N Engl J Med. 2006;355:2733-2743. 5. Thomas J. Lynch ,et al.The Oncologist.2007,12::610-621.
输注注意事项（１）
• 原液输注，可与0.9%无菌氯化钠溶液相容 • 不能与其它静脉输注药品混合 • 可使用输液泵、注射泵或重力滴注 • 输注时必须使用输液管 • 爱必妥注射液内可能含有一些可见粒子，不会影响产品的品质；若输液 速率明显降低时应考虑是否发生管
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爱必妥（西妥昔单抗注射液）说明书
【爱必妥药品名称】
商品名称：爱必妥
通用名称：西妥昔单抗注射液
英文名称：CetuximabSolutionforInfusion
【爱必妥成份】
爱必妥主要成份为西妥昔单抗。
【爱必妥性状】
爱必妥为注射用溶液，无色，可能含有与产品相关的白色可见的无定形颗粒。
【爱必妥药理作用】
爱必妥可与表达于正常细胞和多种癌细胞表面的EGF受体特异性结合，并竞争性阻断EGF 和其他配体，如α转化生长因子（TGF-α）的结合。
爱必妥是针对EGF受体的IgG1单克隆抗体，两者特异性结合后，通过对与EGF受体结合的酪氨酸激酶（TK）的抑制作用，阻断细胞内信号转导途径，从而抑制癌细胞的增殖，诱导癌细胞的凋亡，减少基质金属蛋白酶和血管内皮生长因子的产生。
爱必妥单剂治疗或与化疗、放疗联合治疗时的药动学呈非线性特征。
当剂量从20mg/m2增加到400mg/m2时，药时曲线下面积（AUC）的增加程度超过剂量的增长倍数。
当剂量从20mg/m2增加到200mg/m2时，清除率（Cl）从0.08L/(m2.h)下降至0.02L/(m2.h)，当剂量＞200mg/m2时，Cl不变。
表观分布容积（Vd）与剂量无关，接近2～3L/m2。
爱必妥400mg/m2滴注2小时后，平均血药浓度（Cmax）为184μg/ml（92～327μg/ml），平均消除半衰期（t1/2）为97小时（41～213小时）。
按250mg/m2滴注1小时后，平均Cmax 为140μg/ml（120～170μg/ml）。
在推荐剂量下（初始400mg/m2，以后一周250mg/m2）到第3周时，爱必妥达到稳态血药浓度，峰值、谷值波动范围分别为168～235和41～85μg/ml。
平均t1/2为114小时（75～188小时）。
【爱必妥临床评价】
一项多中心随机Ⅱ期临床对照研究评价了爱必妥治疗转移性结直肠癌的疗效。
329例EGF受体过度表达的受试者中，206例为男性，平均59岁（26～84岁），58为结肠癌患者，40为直肠癌患者，其中63％的患者用奥沙利铂（oxaliplatin）治疗无效。
研究中患者随机分成2组，爱必妥和伊立替康联用组218例，爱必妥单用组111例。
爱必妥的初始剂量为一周400mg，随后一周250mg，治疗终点为疾病进展或出现不能耐受的不良反应。
伊立替康的使用剂量为每3周350mg/m2，每2周180mg/m2，或第6周4次125mg/m2。
结果显示，联合治疗组和爱必妥单用组分别为22.9和10.8％。
疗效平均持续时间，联合治疗组和爱必妥单用组分别为5.7和4.2个月；与爱必妥单用组相比，联合治疗组患者明显延缓了疾病的进展。
另一项多中心单组开放性临床研究，评价了138例EGF受体过度表达的转移性结直肠癌患者接受爱必妥与伊立替康联用的疗效。
患者先前均接受过伊立替康治疗，其中74例在治疗后EGF受体仍呈过度表达。
本?返某跏技亮课恢?400mg，随后一周250mg直至疾病发展哐出现不能耐受的不良反应。
伊立替康的使用剂量为每3周350mg/m2，每2周180mg/m2，
或每6周4次125mg/m2。
总为15，平均疗效持续时间为6.5个月，而伊立替康治疗无效组为12，平均疗效持续时间6.7个月。
另一项多中心单组开放性临床研究，评价了57例EGF受体过度表达的转移性结直肠癌患者单用爱必妥治疗的疗效，患者先前均接受过伊立替康治疗，其中28例在接受伊立替康治疗后EGF受体仍呈过度表达。
经爱必妥治疗后，总为9，其中伊立替康治疗无效组的为14％，疾病进展的平均时间分别为1.4和1.3个月。
两组的疗效持续时间平均为4.2个月。
【爱必妥适应症】
爱必妥单用或与伊立替康(irinotecan)联用于表皮生长因子（EGF）受体过度表达的，对以伊立替康为基础的化疗方案耐药的转移性直肠癌的治疗。
【爱必妥用法用量】
推荐起始剂量为400mg/m2，滴注时间120分钟，滴速应控制在5ml/min以内。
维持剂量为一周250mg/m2，滴注时间不少于60分钟。
提前给予H1受体阻断剂，对预防输液反应有一定作用。
使用前勿振荡、稀释。
【爱必妥不良反应】
爱必妥耐受性好，不良反应大多可耐受，常见的是痤疮样皮疹、疲劳、腹泻、恶心、呕吐、腹痛、发热和便秘等。
其他不良反应还有白细胞计数下降、呼吸困难等。
皮肤毒性反应（痤疮样皮疹、皮肤干燥、裂伤和感染等）多数可自然消失。
少数患者可能发生严重过敏反应、输液反应、败血症、肺间质疾病、肾衰、肺栓塞和脱水等。
在接受爱必妥单药治疗和爱必妥与伊立替康联合治疗的患者中，分别为5和10的患者因不良反应退出。
【爱必妥注意事项】
使用爱必妥前应进行过敏试验，静脉注射爱必妥20mg，并观察10分钟以上，结果呈阳性的患者慎用，但阴性结果并不能完全排除严重过敏反应的发生。
爱必妥常可引起不同程度的皮肤毒笥反应，此类患者用药期间应注意避光。
轻至中度皮肤毒笥反应无需调整剂量，发生重度皮肤毒性反应者，应酌情减量。
研究发现妇性患者的药物清除率较男性低25％，但疗效和安全性相近，无需根据性别调整剂量。
因爱必妥能透过胎盘屏障，可能会损害胎儿或影响妇性的生育能力，故孕妇及未采取避孕措施的育龄妇女慎用。
因爱必妥可通过乳汁分泌，故哺乳期妇女慎用。
在爱必妥对儿童患者的安全性尚未得到确认前，儿童禁用。
严重的输液反应发生率为3，致死率低于0.1％。
其中90发生于第1次使用时，以突发性气道梗阻、荨麻疹和低血压为特征。
因部分输液反应发生于后续用药阶段，故应在医生监护下用药。
发生轻至中度输液反应时，可减慢输液速度或服用抗组胺药物，若发生严重的输液反应需立即停止输液，静脉注射肾上腺素、糖皮质激素、抗组胺药物并给予支气管扩张剂及输氧等治疗。
部分患者应禁止再次使用爱必妥。
此外，在使用爱必妥期间如发生急性发作的肺部症状，应立即停用，查明原因，若确系肺间质疾病，则禁用并进行相应的治疗。
【爱必妥规格】
每20ml含有爱必妥100mg
【爱必妥贮藏】
爱必妥需在冰箱内保存(2～8℃)，禁止冰冻。
【爱必妥有效期】
36个月
【爱必妥批准文号】
注册证号S2*******
【爱必妥生产企业】
德国默克里昂制药公司
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