[临床医学]20110708-吉西他滨药理、毒理及临床资料

[临床医学]20110708-吉西他滨药理、毒理及临床资料 Contents录目 1 / 45 1.Gemzar Drug Description 录录录录录健物明 Brand Name: Gemzar Generic Name: Gemcitabine Hcl Gemzar Drug Description GEMZAR (gemcitabine for injection) Powder, Lyophilized, For Solution For Intravenous Use Gemzar (gemcitabine for injection, USP) is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabine HC1 is 2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer). 健择(吉西他注射择择择择)是一核苷代抑制,具有抗瘤活性。择择择择择择择择择择择择择择择择择择 酸吉西他的化学名是:择择择择择择择2'-去氧-2',2'-二氟胞一酸择择择择 (β-异构体). The structural formula is as follows: The empirical formula for gemcitabine HC1 is CHFNO?HCl. It has a molecular weight 911234 of 299.66. 择择择择择择择酸吉西他的式是CHFNO?HCl,分子式是299.66。911234 Gemcitabine HC1 is a white to off-white solid. It is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents. 择择择择择择择择择择择择择择择择择择择择酸吉西他是一白色至灰白色的固体,溶于水,微 溶于甲醇,几乎不溶于乙醇和极性有机溶。择择 The clinical formulation is supplied in a sterile form for intravenous use only. Vials of Gemzar contain either 200 mg or 1 g of gemcitabine HC1 (expressed as free base) formulated with mannitol (200 mg or 1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized powder. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment. Last reviewed on RxList: 4/4/2011 择择择择择择择择择择择择床上以无菌的注射型。瓶健含每200mg或1g择择择择择择酸吉西他，以游离 碱,,择择择200mg或1g甘露醇,12.5 mg or 62.5 mg乙酸,用酸或氧化择择择择择择择择择择择择pH。 3 / 45 2. Gemzar Indication & Dosage 录录录录录录录健适症和用量 2.1 Indications 录录适症 2.1.1 Ovarian Cancer 卵癌巢 Gemzar (gemcitabine hcl) in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. 健，酸吉西他,与卡波合用于治，基治后至少择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择6个月,性择择择 择期卵癌。巢 2.1.2 Breast Cancer 乳腺癌 Gemzar (gemcitabine hcl) in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. 健，酸吉西他,与紫杉醇合用于一治，蒽择择择择择择择择择择择择择择择择择择择择择择择择择择 抗生素物助化失的,移性乳腺癌择择择择择择择择择择择择择择择择,除非蒽抗生素被床禁忌。择择择择择择择择择择择 2.1.3 Non-Small Cell Lung Cancer 非小胞肺癌录录录录 Gemzar (gemcitabine hcl) is indicated in combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer. 健，酸吉西他,与合用于一治手不能治愈的局部期，段择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择 IIIA 或 IIIB)或移性，段择择择择择择IV)非小胞肺癌。择择择择择 2.1.4 Pancreatic Cancer 胰腺癌 Gemzar (gemcitabine hcl) is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemzar (gemcitabine hcl) is indicated for patients previously treated with 5-FU. 健，酸吉西他,一治局部期，不能被切除的择择择择择择择择择择择择择择择择择择择择择择择择II期或 III期,或移择择 性，IV期,胰腺癌。健，酸吉西他,可用于择择择择择择择择择择择择择5-氟苷治的患者。择择择择择择择择 2.2 Dosage and Administration 用法用量 Gemzar (gemcitabine hcl) is for intravenous use only. Gemzar (gemcitabine hcl) may be administered on an outpatient basis. 健，酸吉西他,只用于静脉注射。健，酸吉西他,可用于患者。择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择 2.2.1 Ovarian Cancer 卵癌巢 2 Gemzar (gemcitabine hcl) should be administered intravenously at a dose of 1000 mg/mover 30 minutes on Days 1 and 8 of each 21-day cycle. Carboplatin AUC 4 should be administered intravenously on Day 1 after Gemzar (gemcitabine hcl) administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients 66should have an absolute granulocyte count ? 1500 x 10/L and a platelet count ? 100,000 x 10/L prior to each cycle. 2 健，酸吉西他,静脉注射择择择择择择择择择择择择择择1000 mg/m 30分，在第择择择择1天和第8天,,每21 天一个周期。在健，酸吉西他,注射后择择择择择择择择择择择择1天,静脉注射卡波，度曲择择择择择择择择4,。 用前患者完整的血球数,包括差异数。在择择择择择择择择择择择择择择择择择择择择择择择一个每 66周期前,患者完全粒胞数择择择择? 1500 x 10/L,血小板数? 100,000 x 10/L。 2.2.1.1 Dose Modifications 剂剂剂量整 Gemzar (gemcitabine hcl) dosage adjustment for hematological toxicity within a cycle of treatment is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, Gemzar (gemcitabine hcl) dosage should be modified according to guidelines in Table 1. 每次治周期后,要根据血液毒性，基于治的第择择择择择择择择择择择择择择择择择择择8天的粒胞数和血小板择择择择择择择 数,整健，酸吉西他,量。若到骨髓抑制,健择择择择择择择择择择择择择择择择择择择择择择择择择择 ，酸吉西他,用量根据表择择择择择择择择择择择择择1中的方法行整。择择择择择 Table 1: Day 8 Dosage Reduction Guidelines for Gemzar (gemcitabine hcl) in Combination with Carboplatin 表1:健，酸吉西他,与卡波合用第录录录录录录录录录录录录录录录录录录8天量减少指原录录录录录录录录 Absolute granulocyte count Platelet count% of full dose 完全粒胞数录录录血小板数录量百分比66(x 10/L)(x 10/L) And100? 1500? 100,000 1000-1499and/or75,000-99,99950 < 1000and/or< 75,000Hold In general, for severe (Grade 3 or 4) non-hematological toxicity, except nausea/vomiting, therapy with Gemzar (gemcitabine hcl) should be held or decreased by 50% depending on the 5 / 45 judgment of the treating physician. For carboplatin dosage adjustment, see manufacturer's prescribing information. 通常情况下,重的，择择择择3择或4择择择,非血液毒性，除心/择择择择择吐,都可以持使用健 择择择择择择择择择择择择择择择，酸吉西他,或根据医嘱减少50%的量。于卡波的量整,择择择择择择择择择择择择择择择制造商的录 方信息。 Dose adjustment for Gemzar (gemcitabine hcl) in combination with carboplatin for subsequent cycles is based upon observed toxicity. The dose of Gemzar (gemcitabine hcl) in 2subsequent cycles should be reduced to 800 mg/m on Days 1 and 8 in case of any of the following hematologic toxicities: 根据察到的毒性,整后期程中健，酸吉西他择择择择择择择择择择择择择择择择择择择择择择 择择择择择择择择择择择择择择择择择择择择择,与卡波合使用的量。根据如下血液毒性,在第1天和第8天量减少择择择择择800 2mg/m。 6•Absolute granulocyte count < 500 x 10/L for more than 5 days 6•择达5天以上,完全粒胞数择择择< 500 x 10/L 6•Absolute granulocyte count < 100 x 10/L for more than 3 days Febrile neutropenia 6•3天以上,中性粒胞减少伴,完全粒胞数择择择择择择择择择择择择择择< 100 x 10/L 6•Platelets < 25,000 x 10/L 6•血小板数< 25,000 x 10/L •Cycle delay of more than one week due to toxicity •由于毒性,推程择择择1周以上 If any of the above toxicities recur after the initial dose reduction, for the subsequent cycle, 2Gemzar (gemcitabine hcl) should be given on Day 1 only at 800 mg/m. 若在量降低后生以上毒性,健，酸吉西他,择择择择择择择择择择择择择择择择择择择择择择择 2在后程的第一天的使用量定择择择择择择择择择择择择择择800 mg/m。 2.2.2 Breast Cancer 乳腺癌 2 Gemzar (gemcitabine hcl) should be administered intravenously at a dose of 1250 mg/mover 30 minutes on Days 1 and 8 of each 21-day cycle. Paclitaxel should be administered at 175 2mg/m on Day 1 as a 3-hour intravenous infusion before Gemzar (gemcitabine hcl) administration. Patients should be monitored prior to each dose with a complete blood count, including 6differential counts. Patients should have an absolute granulocyte count ? 1500 x 10/L and a 6platelet count ? 100,000 x 10/L prior to each cycle. 2在程的第择择择择1天和第8天,静脉注射健，酸吉西他,择择择择择择择择择1250 mg/m30分,择择21天 2一个周期。在第1天健，酸吉西他,使用前,择择择择择择择择择择择择择3小静脉注射紫杉醇择择择择择择择择175 mg/m。用 择择择择择择择择择择择择择择择择择择择前患者完整的血球数,包括差异数。在一个周期前,每患者完全粒胞数择择择? 1500 x 66/L,血小板数? 100,000 x 10/L。10 Dose Modifications 剂剂剂量整 Gemzar (gemcitabine hcl) dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, Gemzar (gemcitabine hcl) dosage should be modified according to the guidelines in Table 2. 每次治周期后,要根据血液毒性，基于治的第择择择择择择择择择择择择择择择择择择择8天的粒胞数和血小板择择择择择择择 数,整健，酸吉西他,量。若到骨髓抑制,健择择择择择择择择择择择择择择择择择择择择择择择择择择 ，酸吉西他,用量根据表择择择择择择择择择择择择择2中的方法行整。择择择择择 Table 2: Day 8 Dosage Reduction Guidelines for Gemzar (gemcitabine hcl) in Combination with Paclitaxel 表2:健，酸吉西他,与紫杉醇合用第录录录录录录录录录录录录录录录录录录8天量减少指原录录录录录录录录 Absolute granulocyte count Platelet count% of full dose 66完全粒胞数录录录(x 10/L)血小板数(x 10/L)录量百分比 ? 1200And> 75,000100 1000-1199Or50,000-75,00075 700-999And? 50,00050 < 700Or< 50,000Hold In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with Gemzar (gemcitabine hcl) should be held or decreased by 50% depending on the judgment of the treating physician. For paclitaxel dosage adjustment, see manufacturer's prescribing information. 通常情况下,重的，择择择择3择或4择择,非血液毒性，除脱/择心/择择择择吐,都可以持使用 健，酸吉西他,或根据医嘱减少择择择择择择择择择择择择择择择择50%的量。于紫杉醇的量整,择择择择择择择择择择择择择择择制造商的录 方信息。 2.2.3 Non-Small Cell Lung Cancer 非小胞肺癌录录录录 Two schedules have been investigated and the optimum schedule has not been determined [see Clinical Studies]. With the 4-week schedule, Gemzar (gemcitabine hcl) should be 2administered intravenously at 1000 mg/m over 30 minutes on Days 1, 8, and 15 of each 28-day 2cycle. Cisplatin should be administered intravenously at 100 mg/m on Day 1 after the infusion of Gemzar (gemcitabine hcl) . With the 3-week schedule, Gemzar (gemcitabine hcl) should be 2administered intravenously at 1250 mg/m over 30 minutes on Days 1 and 8 of each 21-day cycle. 2Cisplatin at a dose of 100 mg/m should be administered intravenously after the infusion of 7 / 45 Gemzar (gemcitabine hcl) on Day 1. See prescribing information for cisplatin administration and hydration guidelines. 择择择择择择择择择择择择择择择择择两个安排,出最佳用，录床研究,。4周一程,在第择择择择择1天、第8天 2和第15天静脉注射健，酸吉西他,择择择择择择择择择1000 mg/m 30分,择择择每28天一个程。择择择择择择 2健，酸吉西他,静脉注射后第择择择择择择择择择择择择择择择1天,静脉注射择择100 mg/m。3周一程,在择择择一个每21 2天的周期中的第1天和第8天静脉注射健，酸吉西他,择择择择择择择择择1250 mg/m。健，酸择择择择 2吉西他,注射后的第择择择择择择择1天,静脉注射择择100 mg/m。，择录录录录录使用和水化指方法, Dose Modifications 剂剂剂量整 Dosage adjustments for hematologic toxicity may be required for Gemzar (gemcitabine hcl) and for cisplatin. Gemzar (gemcitabine hcl) dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on the day of therapy. Patients receiving Gemzar (gemcitabine hcl) should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet counts. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3. For cisplatin dosage adjustment, see manufacturer's prescribing information. 要根据血液毒性，基于治当天的粒胞数和血小板数,整健择择择择择择择择择择择择择择择择择择 ，酸吉西他,和的量。择择择择择择择择择择择择择择择择择择择择择择择择择次用前完全血胞数,每 包括差异数和血小板数。若到骨髓抑制,根据表择择择择择择择择择择择择3中的方法行量整或择择择择择择择择 停使用。择择择择择择择择择择于的量整,制造商的方信息。录录录录 In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with Gemzar (gemcitabine hcl) plus cisplatin should be held or decreased by 50% depending on the judgment of the treating physician. During combination therapy with cisplatin, serum creatinine, serum potassium, serum calcium, and serum magnesium should be carefully monitored (Grade 3/4 serum creatinine toxicity for Gemzar (gemcitabine hcl) plus cisplatin was 5% versus 2% for cisplatin alone). 通常情况下,即使生重的，择择择择择择3择或4择择,非血液毒性，除脱/择心/择择吐,都可以持 择择择择择择择择择择择择择择择择择择择择择合使用健，酸吉西他,和,或根据医嘱减少50%的量。在与合择择择择择择择择择 治期,密切血清肌,血,血,血择择择择择择择择择择择择择择择择择择择择择，健，酸吉西他,择择择择择择择择择择择择 合用:，择择择择择5%:2%,,3/4择择择择择血清肌毒性,。 2.2.4 Pancreatic Cancer 胰腺癌 Gemzar (gemcitabine hcl) should be administered by intravenous infusion at a dose of 1000 2mg/m over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks. 2 30分,周择择每1次,持择7周，或因毒性,静脉注射健，酸吉西他,择择择择择择择择择1000 mg/m 减少/择择择择择择择择择择择择择择择停用,,然后休息一周。随后的每4周的程中,择择择择择择择择择周注射一次,每3周。 Dose Modifications 剂剂剂量整 Dosage adjustment is based upon the degree of hematologic toxicity experienced by the patient [see WARNINGS AND PRECAUTIONS]. Clearance in women and the elderly is reduced and women were somewhat less able to progress to subsequent cycles [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. 根据到的患者血液毒性程度,整量择择择择择择择择择择择择择择择择择[择警告和防措施录录录录]。女和老人减少用择择择择择择择择择 择择择择择择择择择择择择择,女在随后的程中展不是那。强[择警告和防措施录录录录] Patients receiving Gemzar (gemcitabine hcl) should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3. 每次使用健，酸吉西他,前密切完全粒胞数，择择择择择择择择择择择择择择择择择择择择择CBC,,包括差异数和血 小板数。若到骨髓抑制,根据表择择择择择择择择择择择择3中的方法行量整或停使用。择择择择择择择择择择择择 Table 3: Dosage Reduction Guidelines 表3:量减少指录录录录录录 Absolute granulocyte count Platelet count% of full dose 66完全粒胞数录录录 (x 10/L)血小板数(x 10/L)录量百分比 ? 1000And? 100,000100 500-999Or50,000-99,99975 < 500Or< 50,000Hold 录停 Laboratory evaluation of renal and hepatic function, including transaminases and serum creatinine, should be performed prior to initiation of therapy and periodically thereafter. Gemzar (gemcitabine hcl) should be administered with caution in patients with evidence of significant renal or hepatic impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. 在治始前和治后行肝功能室价,包括氨择择择择择择择择择择择择择择择择择择择择择择择择择择择 择择择择择择择择择择择择择择择择择择择择择择择择择择择择、肌。于重或肝的患者,慎使用健，酸 吉西他,,因床研究上,尚没有明确的推荐量。择择择择择择择择择择择择择择择择择择择择择择 Patients treated with Gemzar (gemcitabine hcl) who complete an entire cycle of therapy may have the dose for subsequent cycles increased by 25%, provided that the absolute granulocyte 66count (AGC) and platelet nadirs exceed 1500 x 10/L and 100,000 x 10/L, respectively, and if non-hematologic toxicity has not been greater than WHO Grade 1. If patients tolerate the subsequent course of Gemzar (gemcitabine hcl) at the increased dose, the dose for the next cycle can be further increased by 20%, provided again that the AGC and platelet nadirs exceed 1500 x 9 / 45 6610/L and 100,000 x 10/L, respectively, and that non-hematologic toxicity has not been greater than WHO Grade 1. 健，酸吉西他,治的患者,整个治周期束后,若粒胞数择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择(AGC)和血小 66板数分不低于择择择择1500 x 10/L 和 100,000 x 10/L,并且非血液毒性未超择WHO1择择,随后的 程中量增加择择择择25%。若患者在随后的健，酸吉西他,治中,能耐择择择择择择择择择择择择择择择 66受增加的量,且粒胞数择择择择择择择择(AGC)和血小板数分不低于择择择择1500 x 10/L 和 100,000 x 10/L, 并且非血液毒性未超择WHO1择择择择择择择,下一程可再增加20%的量。择择择 2.2.5 Preparation and Administration Precautions 制和使用防措施录录录录录录录录 Caution should be exercised in handling and preparing Gemzar (gemcitabine hcl) solutions. The use of gloves is recommended. If Gemzar (gemcitabine hcl) solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water. Although acute dermal irritation has not been observed in animal studies, 2 of 3 rabbits exhibited drug-related systemic toxicities (death, hypoactivity, nasal discharge, shallow breathing) due to dermal absorption. 择择择择择择择择择择择择择择择择择择择择择择择择理和准健，酸吉西他,要慎。建使用手套。 若健，酸吉西他,接触到皮或粘膜,立即用肥皂择择择择择择择择择择择择择择择择择择择择择择择 和水底清皮,或用大量的水冲洗粘膜。然择择择择择择择择择择择择择择择择择择择择择择择择急性皮 刺激尚未在物中察到,择择择择择择择择择择但2/3的兔子由于皮择择择择择择择择择择择吸收,生物相性 全身性毒性，死亡,活性降低,流鼻涕,呼吸短择择择择,。 2.2.6 Preparation for Intravenous Infusion Administration 制静脉录录录 注射液 The recommended diluent for reconstitution of Gemzar (gemcitabine hcl) is 0.9% Sodium Chloride Injection without preservatives. Due to solubility considerations, the maximum concentration for Gemzar (gemcitabine hcl) upon reconstitution is 40 mg/mL. Reconstitution at concentrations greater than 40 mg/mL may result in incomplete dissolution, and should be avoided. 推荐健，酸吉西他,的择择择择择择择择择择择择择择择择择择择择择择择择择稀重方法是使用不含防腐的0.9%的生理水。择择择 由于溶解度的择择择择择择择择择择择择择择择择择择择择择择系,健，酸吉西他,重后的最大度是40 mg/mL。重度大于择择择择择 40 mg/mL会致择择择择择择择择择择择择择择溶解不完全,尽量避免。 To reconstitute, add 5 mL of 0.9% Sodium Chloride Injection to the 200-mg vial or 25 mL of 0.9% Sodium Chloride Injection to the 1-g vial. Shake to dissolve. These dilutions each yield a gemcitabine concentration of 38 mg/mL which includes accounting for the displacement volume of the lyophilized powder (0.26 mL for the 200-mg vial or 1.3 mL for the 1-g vial). The total volume upon reconstitution will be 5.26 mL or 26.3 mL, respectively. Complete withdrawal of the vial contents will provide 200 mg or 1 g of gemcitabine, respectively. Prior to administration the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL. 将5mL0.9%的生理水择择择择倒入200-mg容量的小玻璃瓶中,或者是25mL生理水择择择择装入1- g容量的玻璃瓶中,行重。择择择择择择择择择择择择择择择择择择择振溶解。根据干粉末百分含 量,推算此溶液吉西他度择择择择38 mg/mL，0.26mL/200mg或1.3mL/1g,。稀择择择择后的 体分择择择择5.26mL或26.3mL。吉西他完全择择择择择择择择择回收量分200mg或1g。用择择择择择择之前必将 适量的物用择择择0.9%生理水择择择择择择择择择择择择稀。最度要低至0.1 mg/mL。 Reconstituted Gemzar (gemcitabine hcl) is a clear, colorless to light straw-colored solution. After reconstitution with 0.9% Sodium Chloride Injection, the pH of the resulting solution lies in the range of 2.7 to 3.3. The solution should be inspected visually for paniculate matter and discoloration prior to administration, whenever solution or container permit. If particulate matter or discoloration is found, do not administer. 用生理水择择择择择择择择稀后的液pH择2.7~3.3,用前察溶液中或择择择择择择择择择择择择容器上 是否有和色。若有,不择择择择择择择择择择择择择择得使用。 When prepared as directed, Gemzar (gemcitabine hcl) solutions are stable for 24 hours at controlled room temperature 20? to 25?C (68? to 77?F) [see USP Controlled Room Temperature]. Discard unused portion. Solutions of reconstituted Gemzar (gemcitabine hcl) should not be refrigerated, as crystallization may occur. 按指方法准的健，酸吉西他,溶液在室择择择择择择择择择择择择择择择择择择择择择温20? to 25?C (68? to 77?F)下,择 定性持择择24小择 [择室温控制USP] 。择择择择择择择择择择择择择择择弃未使用的液。稀后的健 ，酸吉西他,不择择择择择择择择择择择择择择择择择择择得冷,防止出晶。 The compatibility of Gemzar (gemcitabine hcl) with other drugs has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets. 健，酸吉西他,和择择择择择择择择择择择择择择择择择择择择择择择其它物的兼容性尚未研究。 在注射瓶或聚择择择择择择择择择择择择择择择择择择择择择择乙液袋和器具上尚未不兼容象。 2.3 How Supplied 录录如何 2.3.1 Dosage Forms and Strengths 录录形式和度强 Gemzar (gemcitabine for injection, USP) is a white to off-white lyophilized powder available in sterile single-use vials containing 200 mg or 1 g gemcitabine. 11 / 45 健，注射用吉西他,择择择择择择择择择择USP,是白色或白色择择择择择择择择择择择择干粉末,独装于 无菌瓶中,吉西他含量择择择择择择择择择择择200mg或1g。 Gemzar (gemcitabine for injection, USP), is available in sterile single-use vials individually packaged in a carton containing: 200 mg white to off-white, lyophilized powder in a 10-mL size sterile single-use vial - NDC 0002-7501-01 (No. 7501) 1 g white to off-white, lyophilized powder in a 50-mL size sterile single-use vial - NDC 0002-7502-01 (No. 7502) 健，注射用吉西他,择择择择择择择择择择USP,,择择择择择择择择择择择择择择择择择独装于无菌瓶中,再用箱包装: 200mg白色至白色择择择择择择择择择择择择干粉末,独装于10mL无菌瓶中择择择- NDC 0002-7501-01 (No. 7501) 1g白色至白色择择择择择择择择择择择择干粉末,独装于50mL无菌瓶中择择择- NDC 0002-7502-01 (No. 7502) 2.3.2 Storage and Handling 录录录藏和理 Unopened vials of Gemzar (gemcitabine hcl) are stable until the expiration date indicated on the package when stored at controlled room temperature 20? to 25?C (68? to 77?F) and that allows for excursions between 15? and 30?C (59? and 86?F) [See USP Controlled Room Temperature] [see DOSAGE AND ADMINISTRATION]. 未择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择封的健，酸吉西他,在注的有效期内定,存条件:控制室温在20? ~25?C (68? ~ 77?F),允温择择择择择择择择度化范是15? ~30?C(59?~86?F) [择室温控制USP][择用法用 量]。 3.Gemzar Side Effects & Drug Interactions 健择的不良反录录和 录物的相互作用 3.1 Side Effects 录不良反 Clinical Trials Experience 择择择择择床 Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 由于床择择择择择择择择择择择择择择择择择择择择择择择择控制了广泛的化条件,察到的一物的 择择择择择择择择择择择择择择择择择择择择择择择择择床不良反率不能直接与另一物的床不良反率比, 也不能直接反择择择择择择择择择择察的反率。 Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced. 大多数的不良反择择择择择择择择择择择择择择择择择择择择择择择择择择择择都是可逆的,可能需要控制或减少量,但不需要中止治。 Gemzar (gemcitabine hcl) has been used in a wide variety of malignancies, both as a single-agent and in combination with other cytotoxic drugs. 健，酸吉西他,择择择择择择择择择择择择择择择择择择择择择择择择择已广泛用于多性瘤的治, 可作择择择择择择择择择择择择择择择择择择择择择择择治,也可与其他胞毒素物合治。 Single-Agent Use 择择使用 Myelosuppression is the principal dose-limiting toxicity with Gemzar (gemcitabine hcl) therapy. Dosage adjustments for hematologic toxicity are frequently needed [see DOSAGE AND ADMINISTRATION]. 健，酸吉西他,最重要的量择择择择择择择择择择择择择择择择择择择择择择择限制毒性是骨髓抑 制。血液毒性择择择择择择择择择择择择择需多次整量。[择用法用量] The data in Table 4 are based on 979 patients receiving Gemzar (gemcitabine hcl) as a single-agent administered weekly as a 30-minute infusion for treatment of a wide variety of malignancies. The Gemzar (gemcitabine hcl) starting doses ranged from 800 to 1250 mg/m2. Data are also shown for the subset of patients with pancreatic cancer treated in 5 clinical studies. The frequency of all grades and severe (WHO Grade 3 or 4) adverse reactions were generally similar in the single-agent safety database of 979 patients and the subset of patients with pancreatic cancer. Adverse reactions reported in the single-agent safety database resulted in discontinuation of Gemzar (gemcitabine hcl) therapy in about 10% of patients. In the comparative trial in 13 / 45 pancreatic cancer, the discontinuation rate for adverse reactions was 14.3% for the Gemzar (gemcitabine hcl) arm and 4.8% for the 5-FU arm. All WHO-graded laboratory adverse reactions are listed in Table 4, regardless of causality. Non-laboratory adverse reactions listed in Table 4 or discussed below were those reported, regardless of causality, for at least 10% of all patients, except the categories of Extravasation, Allergic, and Cardiovascular and certain specific adverse reactions under the Renal, Pulmonary, and Infection categories. 表4中的数据来源于择979例患者的研究,他接受健，酸吉西他,择择择择择择择择择择择择择择作 择择择择择择择择择择每周治,静脉注射30分,治择择择择择择择择择择择择择择择择择择择择择择择择择择多性瘤。健，酸吉西他,始量 2800 ~1250 mg/m。数据也展示了其择择择择择择择择择择中的胰腺癌患者的5择择择择择择择床治研究。从979例患者和 其中的胰腺癌患者的安全性数据中,择择择择择择择择择择择择择择择择择择择择择择择择择择择所有等和重程度的不良反，WHO3 择或4择择择择择,是似的。由于择择择择择择择择择择择择择择择择安全性不良反数据,致中止健，酸吉 西他,治的有择择择择择择择10%。在胰腺癌比治中,因健，酸吉西择择择择择择择择择择择择择择择择 他,不择择择择择择择择择择择择择择择择良反致中止治的概率是14.3%,因5-FU择致的概率是4.8%。所有的WHO 择择择择择择择择择择择的室不良反如表4所示,忽略因果系择择择择。表4择择择择择择择择择择择择择告示,忽略因果系, 除了外渗、择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择敏、和心血管症状和某些确定的、肺部不良反和感染症状,至少 10%的患者有非室不择择择择择择择择良反。 Table 4: Selected WHO-Graded Adverse Reactions in Patients Receiving Single-Agent Gemzar (gemcitabine hcl) WHO Grades (% incidence)a 表4:患者接受健，酸吉西他,后,择择择择择择择择择择择择择特定WHO不良反等及其择择择择择择择择择择生百分率a All PatientsbDiscontinuations Pancreatic Cancer Patientsc 胰 所有患者b(%)d未持百分择择择择率腺癌患者c All GradesGrade 3Grade 4All GradesGrade 3Grade 4All PatientsLaboratorye 择择室e Hematologic 血液学 Anemia 择血症68717382< 1 Leukopenia白胞减少症择择择择择629< I6481< 1 Neutropenia 中性粒胞减少症择择择择择6319661177- 2441367< 1< 1 Thrombocytopenia 血小板减少症 Hepatic 肝毒性择择择 < 1 688272101 ALT 676278125 AST Alkaline Phosohatase碱性磷酸择557277164 Bilirubin 胆择择素132< 12662 < 1Renal 择择毒性 45< 1032< 10 Proteinuria 蛋白尿症 Hematuria 血尿症35< 102300 16001500 BUN Creatinine 肌氨酸择8< 10600 Non-Iaboratoryf 非室择择择f 6913171102< 1Nausea and Vomiting 择择择心吐 Fever 择择41203820< 1 30< 1028< 10< 1 Rash 择疹 Dyspnea 呼吸困择233< 1100< 1< 1 Diarrhea 腹择191030300 17< 1< 142< 1< 1 Hemorrhage 大出血 Infection 感染161< 1102< 1< 1 15< 1016000 Alopecia 脱择 Stomatitis 口腔炎11< 1010< 10< 1 Somnolence 多梦11< 1< 1112< 1< 1 10< 1010< 100 Paresthesias 感择择择异常 a Grade based on criteria from the World Health Organization (WHO). 等择择择择择准依据WHO择定 b N=699-974; all patients with laboratory or non-laboratory data. 指所有室或非室数据择择择择择择择择择择 c N=161-241; all pancreatic cancer patients with laboratory or non-laboratory data. 指所有室或非室胰择择择择择择择择择 腺癌数据患者 d N=979. e Regardless of causality. 忽略因果系择择 f Table includes non-laboratory data with incidence for all patients ? 10%. For approximately 60% of the patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related.表格中包括非室数据择择择择择择择择择择择择所有患者生率? 10%。只可能与物择择择择择择择择择择择相的,60%的患者非室不择择择择择择择良反 择择择择行估。 Hematologic — In studies in pancreatic cancer myelosuppression is the dose-limiting toxicity with Gemzar (gemcitabine hcl) , but < 1% of patients discontinued therapy for either anemia, leukopenia, or thrombocytopenia. Red blood cell transfusions were required by 19% of patients. The incidence of sepsis was less than 1%. Petechiae or mild blood loss (hemorrhage), from any cause, was reported in 16% of patients; less than 1% of patients required platelet transfusions. Patients should be monitored for myelosuppression during Gemzar (gemcitabine hcl) therapy and dosage modified or suspended according to the degree of hematologic toxicity [see DOSAGE AND ADMINISTRATION]. 血液毒性——择择择择择择择择择择择胰腺癌研究中,骨髓抑制是健，酸吉西他,的 量限制毒性,<1%的患者因血、白胞减少症或血小板减少症中择择择择择择择择择择择择择择择择择择择择择止治。19%的患者需 要择择择择择择择择择择择择择择择择入胞。血症的生概率小于1%。告中有择择择择16%的患者由于各择择择择原因,有瘀点 或微失血，大出血择择择择择择择择,择择择择择择择择择择择择择择择择择择择择象。在健，酸吉西他,治期,密 切骨髓抑制择择择择择择择择择择择择择择择择择择择择择择择择择择象,根据血液毒性等整量或停止用 [择用法用量] 。 Gastrointestinal — Nausea and vomiting were commonly reported (69%) but were usually of mild to moderate severity. Severe nausea and vomiting (WHO Grade 3/4) occurred in < 15% of patients. Diarrhea was reported by 19% of patients, and stomatitis by 11% of patients. 胃道择——择择择择择择心、吐常，69%,,但通常只是度到中度。重的择择择择择择择择择 择择择择心吐，WHO3/4择择择择择择,生率小于15%。告择择择称19%的患者腹择择,11%的患者出择择择口腔 炎。 Hepatic — In clinical trials, Gemzar (gemcitabine hcl) was associated with transient elevations of one or both serum transaminases in approximately 70% of patients, but there was no 15 / 45 evidence of increasing hepatic toxicity with either longer duration of exposure to Gemzar (gemcitabine hcl) or with greater total cumulative dose. Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving Gemzar (gemcitabine hcl) alone or in combination with other potentially hepatotoxic drugs [see ADVERSE REACTIONS]. 肝床中,健，酸吉西他,与一或两血清氨的择——择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择片刻升高， 70%的患者,相择择择择择择择择择择择择择择择择择择择择择择,但尚没有据明肝毒性的增加与健， 酸吉西他,持或接触或择择择择择择择择择择择择择择择择择择择择择择择择择择累量的增加相。在健， 酸吉西他,治或与择择择择择择择择择择择择择择择择择择择择择择择择择其他潜在肝毒性物合治中, 重的肝中毒,包括肝功能失效或坏死很少。择择 Renal—In clinical trials, mild proteinuria and hematuria were commonly reported. Clinical findings consistent with the Hemolytic Uremic Syndrome (HUS) were reported in 6 of 2429 patients (0.25%) receiving Gemzar (gemcitabine hcl) in clinical trials. Four patients developed HUS on Gemzar (gemcitabine hcl) therapy, 2 immediately posttherapy. The diagnosis of HUS should be considered if the patient develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, reticulocytosis, severe thrombocytopenia, and/or evidence of renal failure (elevation of serum creatinine or BUN). Gemzar (gemcitabine hcl) therapy should be discontinued immediately. Renal failure may not be reversible even with discontinuation of therapy and dialysis may be required [see ADVERSE REACTIONS]. 择择——择择择择择择择择择择择择择择择择择择择择择择择在床告中,常蛋白尿症和血尿症。床6/2429，0.25%,接受健择 ，酸吉西他,的患者,患有溶血性择择择择择择择择择择择择择择择择择择择择尿毒症，HUS,。择择择择择择择择于因健，酸吉西他 择择择择择择择择择择择择择择择择,引溶血性尿毒症的患者,立即治。HUS的择择择择择择择择择择择择断,兼患者是否展 成择择择择择择择择择择择择择血和微血管溶血、胆素或LDH升高、网状择择择择择择择择择择择择胞多症、重的血小板 减少症、择择择择择衰症状，血清肌或择择择择择择择择尿素氮升高,。若出,立即中择择择择择择择择择择择止健，酸 吉西他,治。即使中择择择择择择择择择择择择择择择择择择择择择择择择择择择择止治,衰竭也可能不可逆,需要透析治[择择不良反]。 Fever — The overall incidence of fever was 41%. This is in contrast to the incidence of infection (16%) and indicates that Gemzar (gemcitabine hcl) may cause fever in the absence of clinical infection. Fever was frequently associated with other flu-like symptoms and was usually mild and clinically manageable. 择择——择择择择择择择的整体生概率是41%。相比感染的生，择择择16%,,健，酸吉西择择择择择择 他,治,可能在无床择择择择择择择择择择择择择择择择择择择择择择择择择择择感染的情况下。与其他 似感冒症状都很繁择择择择择择择择择择择择择择择择择,通常是度的,床上易理。 Rash — Rash was reported in 30% of patients. The rash was typically a macular or finely granular maculopapular pruritic eruption of mild to moderate severity involving the trunk and extremities. Pruritus was reported for 13% of patients. 皮疹——30%的患者患有皮疹。皮疹是在躯干和四肢突典择择择择择择择择型的度至中 度的黄斑或粒择择择择择择择择择择择择择择择择择择择择状的，瘙痒的,斑丘疹。皮瘙痒者占13%。 Pulmonary — In clinical trials, dyspnea, unrelated to underlying disease, has been reported in association with Gemzar (gemcitabine hcl) therapy. Dyspnea was occasionally accompanied by bronchospasm. Pulmonary toxicity has been reported with the use of Gemzar (gemcitabine hcl) [see ADVERSE REACTIONS]. The etiology of these effects is unknown. If such effects develop, Gemzar (gemcitabine hcl) should be discontinued. Early use of supportive care measures may help ameliorate these conditions. 肺部症状——择择择择择择择择择择择择择择择择择择择择床中,告示呼吸困，与潜在疾病无 择择择择择择择择择择择择择择择择择择择择择择择择择,与健，酸吉西他,的治相。呼吸困偶伴有支 气管择择择择择择择择择择择择择择择择择择择择择择择 。使用健，酸吉西他,后有肺部毒性告[择不 良反择] 。择择择择择择择择择择择择择择择择择择择择择择择些反的病源尚不明确。若不良反展,中 止使用健，酸吉西他,。择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择早期使用支持性理措施有助于改善状况。 Edema — Edema (13%), peripheral edema (20%), and generalized edema ( < l%) were reported. Less than 1% of patients discontinued due to edema. 水告择——择择择择择择示水，13%,,血管神择择择择择性水，20%,,全身性水，择择< l%)。少于 1%的患者因水中择择择择择择止治。 Flu-like Symptoms — "Flu syndrome" was reported for 19% of patients. Individual symptoms of fever, asthenia, anorexia, headache, cough, chills, and myalgia were commonly reported. Fever and asthenia were also reported frequently as isolated symptoms. Insomnia, rhinitis, sweating, and malaise were reported infrequently. Less than 1% of patients discontinued due to flu-like symptoms. 择——择择择感冒症状告示19%的患者有“择”择流感。合症个择常择症状有,择择择择择乏力, 择择择择择择择择择择择择择择择择择择择择食,痛,咳嗽,寒和肌肉痛。和衰弱也屡择择告。失眠,鼻炎,出汗,全身乏力 的很少。不到1择择择择择择择择择,的患者因似流感的症状停止用。择 Infection — Infections were reported for 16% of patients. Sepsis was rarely reported ( < 1%). 感染 - 感染的择择择道16,。血症有择择择择择择择择道，<1,,。 Alopecia — Hair loss, usually minimal, was reported by 15% of patients. 脱脱,通常少,择——择择择择择择择择15%的患者。 Neurotoxicity — There was a 10% incidence of mild paresthesias and a < 1% rate of severe paresthesias. 神择择择——毒性10%的患者度择择择择择择择感异常,<1,的重度感择择择择异常。 17 / 45 Extravasation — Injection-site related events were reported for 4% of patients. There were no reports of injection site necrosis. Gemzar (gemcitabine hcl) is not a vesicant. 外渗——4%的患者有注射部位相反择择择择择择择择择择择择择择。没有出注射部位坏死。 健，酸吉西他,不是择择择择择择择择择择择择择择择泡。 Allergic — Bronchospasm was reported for less than 2% of patients. Anaphylactoid reaction has been reported rarely. Gemzar (gemcitabine hcl) should not be administered to patients with a known hypersensitivity to this drug [see CONTRAINDICATIONS]. 择——择择择择择择择敏支气管的告少于2%。择择择择择择择择择择择择择择择敏性反少有告。已知物 有择择择择择择择择择择择择择择择择择择择择敏反,不得再使用健，酸吉西他,[择禁忌征候] 。 Cardiovascular — During clinical trials, 2% of patients discontinued therapy with Gemzar (gemcitabine hcl) due to cardiovascular events such as myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension. Many of these patients had a prior history of cardiovascular disease [see ADVERSE REACTIONS]. 心血管——择择择择择择床期,2%的患者因心血管症状择择择择择择择择择如心肌梗塞、血 管意外、心律失常和高血择择择择择择择择择择择择择择择择择择择择择而中止治。其中很多患者都有心血管疾病史[择择不良反]。 Combination Use in Non-Small Cell Lung Cancer 在非小胞肺癌中合使用择择择择择择择择择 In the Gemzar (gemcitabine hcl) plus cisplatin versus cisplatin study, dose adjustments occurred with 35% of Gemzar (gemcitabine hcl) injections and 17% of cisplatin injections on the combination arm, versus 6% on the cisplatin-only arm. Dose adjustments were required in greater than 90% of patients on the combination, versus 16% on cisplatin. Study discontinuations for possibly drug-related adverse reactions occurred in 15% of patients on the combination arm and 8% of patients on the cisplatin arm. With a median of 4 cycles of Gemzar (gemcitabine hcl) plus cisplatin treatment, 94 of 262 patients (36%) experienced a total of 149 hospitalizations due to possibly treatment-related adverse reactions. With a median of 2 cycles of cisplatin treatment, 61 of 260 patients (23%) experienced 78 hospitalizations due to possibly treatment-related adverse reactions. 健，酸吉西他,合治与治比研究。健择择择择择择择择择择择择择择择择择择择择择择择择择择择择 择择择择择择择择择择择择择择择择择择择合治中,整健，酸吉西他,35%的量、择择择择择17%,相之择择择择择下整6%的择择 择择择择择择治。多于90%的合治患者择择择择择择择择择择择择需整量,16%的治患者择择择择择择择择择择择需整量。 因可能的物择择择择择择择择择择择择择择择择择择择择相不良反而中止治的占合治的15%,治的择择择择择择择8%。择4个 健，酸吉西他,合治周期后,择择择择择择择择择择择择择择择择择择择262例患者中94例，36%,择择149次由于可 能的治择择择择择择择择择择择择相不良反住院治。2个治周期后,择择择择择择择择260例中61例，23%,78次由于 可能的治择择择择择择择择择择择择相不良反住院治。 In the Gemzar (gemcitabine hcl) plus cisplatin versus etoposide plus cisplatin study, dose adjustments occurred with 20% of Gemzar (gemcitabine hcl) injections and 16% of cisplatin injections in the Gemzar (gemcitabine hcl) plus cisplatin arm compared with 20% of etoposide injections and 15% of cisplatin injections in the etoposide plus cisplatin arm. With a median of 5 cycles of Gemzar (gemcitabine hcl) plus cisplatin treatment, 15 of 69 patients (22%) experienced 15 hospitalizations due to possibly treatment-related adverse reactions. With a median of 4 cycles of etoposide plus cisplatin treatment, 18 of 66 patients (27%) experienced 22 hospitalizations due to possibly treatment-related adverse reactions. In patients who completed more than one cycle, dose adjustments were reported in 81% of the Gemzar (gemcitabine hcl) plus cisplatin patients, compared with 68% on the etoposide plus cisplatin arm. Study discontinuations for possibly drug- related adverse reactions occurred in 14% of patients on the Gemzar (gemcitabine hcl) plus cisplatin arm and in 8% of patients on the etoposide plus cisplatin arm. The incidence of myelosuppression was increased in frequency with Gemzar (gemcitabine hcl) plus cisplatin treatment (~90%) compared to that with the Gemzar (gemcitabine hcl) monotherapy (~60%). With combination therapy Gemzar (gemcitabine hcl) dosage adjustments for hematologic toxicity were required more often while cisplatin dose adjustments were less frequently required. 健，酸吉西他,合治与择择择择择择择择择择择择择择择择择择择择择择择择择择择依托泊苷合治 比研究。健合治中,整择择择择择择择择择择择20%健，酸吉西他,注射,择择择择择择择择择择择择16%择择择注射。相 之下,依托泊苷合治中,整择择择择择择择择择择20%依托泊苷和15%择择择注射。5个健，酸择择择择 吉西他,合治周期中,择择择择择择择择择择择择69例患者中15例，22%,择择15次由于可能的治择择择相 不良反住院择择择择择择治。4个依托泊苷治周期后,择择择择择择择择66例中18例，27%,22次由于可能的 治择择择择择择择择择择择择择择相不良反住院治。完成1个周期以上治的患者,健，酸吉择择择择择择择择择择择 西他,合治患者有择择择择择择择择择择择81%择择择择择择择择择择择择择择择择择整量,相之下,依托泊苷的有68%。健择择择 择择择合治中14%的患者,依托泊苷合治中择择择择择择择8%的患者由于可能的治择择择择择相不良 反而择择择择择择择择择择择择择择择择择择择择择择择择择中止治。相于健，酸吉西他,治，~60%,,健合治择择择择择择择择 生骨髓抑制的概率，~90%,有所增加。合治中,因血液毒性择择择择择择择择择择择择择择需整 择择择择择择择择择择择量的,健比生得更多。 Table 5 presents the safety data from the Gemzar (gemcitabine hcl) plus cisplatin versus cisplatin study in non-small cell lung cancer. The NCI Common Toxicity Criteria (CTC) were used. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm. Nine cases of febrile neutropenia were reported on the combination therapy arm compared to 2 on the cisplatin arm. More patients required RBC and platelet transfusions on the Gemzar (gemcitabine hcl) plus cisplatin arm. 表5展示了择择择择择择择择择择择择择择择择择择择择择择择非小胞肺癌,健，酸吉西他,合治 择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择和治的比研究。使用美国国家癌症研究常毒性准，CTC,定。择择择 19 / 45 两物合治生择择择择择择择择择择择择择择择择择择择择择择择择疑似治相骨髓抑制性死亡的有4例，1.5%,,包括3例由于骨 髓抑制感染和1例由于全血胞减少症和择择择择择择择择择择择择择择择择择择择感染致的衰竭。 治中没有治择择择择择择择择择择择择择择择择择择相性死亡。合治生9例中性粒胞减少伴症,择择择择择择择择择择择择 择择择择择治中生2例。健，酸吉西他,合治中,择择择择择择择择择择择择择择择择择择择择择更多的患 者需要择择择择择择择择择择入胞和血小板。 Myelosuppression occurred more frequently on the combination arm, and in 4 possibly treatment-related deaths myelosuppression was observed. Sepsis was reported in 4% of patients on the Gemzar (gemcitabine hcl) plus cisplatin arm compared to 1% on the cisplatin arm. Platelet transfusions were required in 21% of patients on the combination arm and < ]% of patients on the cisplatin arm. Hemorrhagic events occurred in 14% of patients on the combination arm and 4% on the cisplatin arm. However, severe hemorrhagic events were rare. Red blood cell transfusions were required in 39% of the patients on the Gemzar (gemcitabine hcl) plus cisplatin arm, versus 13% on the cisplatin arm. The data suggest cumulative anemia with continued Gemzar (gemcitabine hcl) plus cisplatin use. 择择择择择择择择择择择择择择择择合用生骨髓抑制的概率更大,在4例疑似治择择择择择择择择择择相死亡中了骨 髓抑制。4%的健，酸吉西他,合治患者出血症,治有择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择 1%。合治择择择择择21%需要血小板择择择择择择择择择择择择择择择入,相比之下治1%。出血症状择择择择择合治14%,择择 择择择择治4%。重的出血症择择择择择择择择择择择择择择择择择择择择择择择择择状少。需要入胞的占合用的39%,治择择择择择 择择的13%。数据择择择择择择择择择择择择择择择择择择择择择择示随着健，酸吉西他,和累量的增 加,出择择择择择择择 累性血。 Nausea and vomiting despite the use of antiemetics occurred more often with Gemzar (gemcitabine hcl) plus cisplatin therapy (78%) than with cisplatin alone (71%). In studies with single-agent Gemzar (gemcitabine hcl) , a lower incidence of nausea and vomiting (58% to 69%) was reported. Renal function abnormalities, hypomagnesemia, neuromotor, neurocortical, and neurocerebellar toxicity occurred more often with Gemzar (gemcitabine hcl) plus cisplatin than with cisplatin monotherapy. Neurohearing toxicity was similar on both arms. 尽管使用止择择择择择择择择择择择择择择择择择择择吐,合治生心和吐的概率，78%,是比治择择择择择择择择 生概率，71%,更高。健，酸吉西他,治研究告中,择择择择择择择择择择择择择择择择择择择择 心吐的生择择择择择择择择率更低(58%~ 69%)。健，酸吉西他,合治比择择择择择择择择择择择择择择择择择择择 择择择择择择择择择择择择择择择择择择择择择择择择择择治生功能异常、低血症、运神毒性、皮毒性、 小择择择择择择择择择择择神毒性的概率更高。听神择择择择择择择择择择择择毒性在两中相似。 Cardiac dysrrhythmias of Grade 3 or greater were reported in 7 (3%) patients treated with Gemzar (gemcitabine hcl) plus cisplatin compared to one ( < 1%) Grade 3 dysrrhythmia reported with cisplatin therapy. Hypomagnesemia and hypokalemia were associated with one Grade 4 arrhythmia on the Gemzar (gemcitabine hcl) plus cisplatin combination arm. 健，酸吉西他,合治中择择择择择择择择择择择择择择择择7例患3择择择择择择或以上的心dysrrhythmias,择择 择择择择择治中有1例，< 1%)。健，酸吉西他,合治中,择择择择择择择择择择择择择择择择择1例低血症和择择择择 低血症与择择择择4择择心律失常相。 Table 6 presents data from the randomized study of Gemzar (gemcitabine hcl) plus cisplatin versus etoposide plus cisplatin in 135 patients with NSCLC. One death (1.5%) was reported on the Gemzar (gemcitabine hcl) plus cisplatin arm due to febrile neutropenia associated with renal failure which was possibly treatment-related. No deaths related to treatment occurred on the etoposide plus cisplatin arm. The overall incidence of Grade 4 neutropenia on the Gemzar (gemcitabine hcl) plus cisplatin arm was less than on the etoposide plus cisplatin arm (28% versus 56%). Sepsis was experienced by 2% of patients on both treatment arms. Grade 3 anemia and Grade 3/4 thrombocytopenia were more common on the Gemzar (gemcitabine hcl) plus cisplatin arm. RBC transfusions were given to 29% of the patients who received Gemzar (gemcitabine hcl) plus cisplatin versus 21% of patients who received etoposide plus cisplatin. Platelet transfusions were given to 3% of the patients who received Gemzar (gemcitabine hcl) plus cisplatin versus 8% of patients who received etoposide plus cisplatin. Grade 3/4 nausea and vomiting were also more common on the Gemzar (gemcitabine hcl) plus cisplatin arm. On the Gemzar (gemcitabine hcl) plus cisplatin arm, 7% of participants were hospitalized due to febrile neutropenia compared to 12% on the etoposide plus cisplatin arm. More than twice as many patients had dose reductions or omissions of a scheduled dose of Gemzar (gemcitabine hcl) as compared to etoposide, which may explain the differences in the incidence of neutropenia and febrile neutropenia between treatment arms. Flu syndrome was reported by 3% of patients on the Gemzar (gemcitabine hcl) plus cisplatin arm with none reported on the comparator arm. Eight patients (12%) on the Gemzar (gemcitabine hcl) plus cisplatin arm reported edema compared to one patient (2%) on the etoposide plus cisplatin arm. 表6中数据来源于择135例非小胞肺癌患者,行的健，酸吉择择择择择择择择择择择择择择择择 西他,合治与择择择择择择择择择择择择择择择择择择择择择择择择择择择依托泊苷合治随机比研究。健 择择择择择择择择择择择择择择择择择择择择择择择择择择择，酸吉西他,治中由于，与治相的,，与 衰相择择择择择择择择择择择择择择择择的,中性粒胞减少伴致了1例死亡(1.5%)。依托泊苷合治中择择择择择择择择 无治择择择择择择择相性死亡。4择择择择择择择择择择择择择择择择择择择中性粒胞减少症在健，酸吉西他, 择择择择择择择择择择择择择择择择择择择择择合治中的生率低于依托泊苷合治(28% 比 56%)。2个治中血症择择择择择择 的生择择择择择率都是2%。健，酸吉西他,合治中,择择择择择择择择择择择择择择择择择择3择择血和3/4择血小板减少 症生择择择择择择择择择择择择择择择择择择择择择择择择更繁。健，酸吉西他,合治中29%的患者择择择择择择择入胞,依 托泊苷合治中择择择择择择择择21%。健治中接受血小板择择择择择择择择择择择择择择择择入的有3%,依托泊苷择择择 8%。3/4择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择择心吐在健中更常。健，酸吉西他,治中,7%的 患者由于中性粒胞减少伴择择择择择择择择择择择择择择择择择择择择择择择择择留院察,依托泊苷合治中有12%。，由于中 性粒胞减少症或中性粒胞减少伴症在两中生择择择择择择择择择择择择择择择择择择择择择择择择概 率的差异,与依托泊苷比,择择择择2倍的健治患者减少量或停择择择择择择择择择择择择择择择止用。 21 / 45 Table 5: Selected CTC-Graded Adverse Reactions From Comparative Trial of Gemzar (gemcitabine hcl) Plus Cisplatin Versus Single-Agent Cisplatin in NSCLC 表5:于非小胞肺癌比治，健择择择择择择择择择择择择择择择[择择酸吉西他]择择择择择择择择择择择择择择合治比治,的 不良反择CTC择择 CTC Grades (% incidence)a CTC择数，%择生百分率, Gemzar plus Cisplatinb 健择择择Cisplatinc 择择 All GradesGrade 3Grade 4All GradesGrade 3Grade 4 Laboratory d 择择择 择 室反所有等3择 4择 择 所有等3择 4择Hematologic 血液学的 Anemia 择血892236761 RBC Transfusione 择择择择胞入39 13 Leukopenia 白胞减少症择择择择择8235112521 Neutropenia 嗜中性白血球减少症7922352031 Thrombocytopenia 血小板减少症8525251331 Platelet Transfusionse 血小板择择入21 < 1 Lymphocytes 淋巴球75251851125Hepatic 肝择 Transaminase 择择氨22211010 Alkaline Phosphatase 碱性磷酸择19101300Renal 择择 Proteinuria 蛋白尿症23001800 Hematuria 血尿症15001300 Creatinine 肌氨酸择384< 1312< 1Other Laboratory 其它择择择择择室反 Hyperglycemia 高血糖症30402330 Hypomagnesemia 低症择择30431720 Hypocalcemia 低血症择择182070< 1Non-laboratoryf 非室择择择择择反 932528720< 1 Nausea 择心 78111271109 Vomiting 择 吐 53103300 Alopecia 脱择 351201530 Neuro Motor 运神择择择 25602160 Neuro Hearing 听神择择择 24221300 Diarrhea 腹择 23101810 Neuro Sensory 感神择择择 18321210 Infection 感染 1600500 Fever 择择 1631910 Neuro Cortical 神择择择皮 16101010 Neuro Mood 神择择择择性情 1500600 Local 局部 1400700 Neuro Headache 神择择择择性痛 1410500 Stomatitis 口腔炎 1410400 Hemorrhage 大出血 12431132 Dyspnea 呼吸困择 1210710 Hypotension 血低择择择 1100300 Rash 择疹 a Grade based on Common Toxicity Criteria (CTC). Table includes data for adverse reactions with incidence ? 10% in either arm. b N=217-253; all Gemzar (gemcitabine hcl) plus cisplatin patients with laboratory or non-laboratory data. Gemzar (gemcitabine hcl) at 1000 mg/m2 on Days 1, 8, and 15 and cisplatin at 100 mg/m2 on Day 1 every 28 days. c N=213-248; all cisplatin patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 every 28 days. d Regardless of causality. e Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events. f Non-laboratory events were graded only if assessed to be possibly drug-related. Table 6: Selected WHO-Graded Adverse Reactions From Comparative Trial of Gemzar (gemcitabine hcl) Plus Cisplatin Versus Etoposide Plus Cisplatin in NSCLC 表6:于非小胞肺癌比治，健择择择择择择择择择择择择择择择[择择酸吉西他]择择择择择择择择择择择择择择合治比治,的 不良反择WHO择择 WHO Grades (% incidence)a 世界择择择择择择择生等，%择生百分率, Gemzar plus Cisplatinb健择择择Cisplatinc 择择 All GradesGrade 3Grade 4All GradesGrade 3Grade 4 Laboratoryd 择择择室反 Hematologic 血液学 Anemia 择血8822077132 RBC Transfusionse 择择择择胞入29 21 Leukopenia 白胞减少症择择择择择8626387367 Neutropenia 嗜中性白血球减少症883628872056 Thrombocytopenia血小板减少症8139164585 Platelet Transfusionse 血小板择择入3 8 Hepatic 肝择 ALT6001200 AST3001100 Alkaline Phosphatase 碱性磷酸择16001100 Bilirubin 胆择择素000000 Renal 择择 Proteinuria 蛋白尿症1200500 Hematuria 血尿症22001000 BUN600400 Creatinine 肌氨酸择200200 Non-laboratoryf,g 非室择择择择择反 Nausea and Vomiting 择择择心、吐9635486197 Fever 择择600300 Rash 择疹1000300 Dyspnea 呼吸困择101300 Diarrhea 腹择14111302 Hemorrhage 大出血903303 Infection 感染28312180 Alopecia 脱择7713092510 Stomatitis 口腔炎20401820 Somnolence 嗜睡300320 Paresthesias 感择择择异常38001620 23 / 45 a Grade based on criteria from the World Health Organization (WHO). b N=67-69; all Gemzar (gemcitabine hcl) plus cisplatin patients with laboratory or non-laboratory data. Gemzar (gemcitabine hcl) at 1250 mg/m2 on Days 1 and 8 and cisplatin at 100 mg/m2 on Day 1 every 21 days. c N=57-63; all cisplatin plus etoposide patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 and intravenous etoposide at 100 mg/m2 on Days 1, 2, and 3 every 21 days. d Regardless of causality. e Percent of patients receiving transfusions. Percent transfusions are not WHO-graded events. f Non-laboratory events were graded only if assessed to be possibly drug-related. g Pain data were not collected. Combination Use in Breast Cancer 择合适用于乳腺癌 In the Gemzar (gemcitabine hcl) plus paclitaxel versus paclitaxel study, dose reductions occurred with 8% of Gemzar (gemcitabine hcl) injections and 5% of paclitaxel injections on the combination arm, versus 2% on the paclitaxel arm. On the combination arm, 7% of Gemzar (gemcitabine hcl) doses were omitted and < 1% of paclitaxel doses were omitted, compared to < 1% of paclitaxel doses on the paclitaxel arm. A total of 18 patients (7%) on the Gemzar (gemcitabine hcl) plus paclitaxel arm and 12 (5%) on the paclitaxel arm discontinued the study because of adverse reactions. There were two deaths on study or within 30 days after study drug discontinuation that were possibly drug-related, one on each arm. Table 7 presents the safety data occurrences of ? 10% (all grades) from the Gemzar (gemcitabine hcl) plus paclitaxel versus paclitaxel study in breast cancer. Table 7: Adverse Reactions From Comparative Trial of Gemzar (gemcitabine hcl) Plus Paclitaxel Versus Single-Agent Paclitaxel in Breast Cancera CTC Grades (% incidence) Gemzar plus PaclitaxelPaclitaxel (N=262)(N=259) All GradesGrade 3Grade 4All GradesGrade 3Grade 4 Laboratoryb Hematologic 69 61513< 1 Anemia 6931173147 Neutropenia 265< 17< 1< 1 Thrombocytopenia 211011220 Leukopenia Hepatobiliary ALT185< 16< 10 AST16205< 10 Non-laboratoryc 9014492193 Alopecia 645< 15830 Neuropathy-sensory 50103120 Nausea 406< 1281< 1 Fatigue 3340333< 1 Myalgia 29201520 Vomiting 2430222< 1 Arthralgia 20301320 Diarrhea 170012< 10 Anorexia 152< 110< 10 Neuropathy-motor 131< 18< 10 Stomatitis/pharyngitis 13< 10300 Fever 11< 1< 1500 Rash/desquamation a Grade based on Common Toxicity Criteria (CTC) Version 2.0 (all grades ? 10%). b Regardless of causality. c Non-laboratory events were graded only if assessed to be possibly drug-related. The following are the clinically relevant adverse reactions that occurred in > 1% and < 10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse reactions (Gemzar (gemcitabine hcl) plus paclitaxel versus paclitaxel): febrile neutropenia (5.0% versus 1.2%), infection (0.8% versus 0.8%), dyspnea (1.9% versus 0), and allergic reaction/hypersensitivity (0 versus 0.8%). No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65. Combination Use in Ovarian Cancer In the Gemzar (gemcitabine hcl) plus carboplatin versus carboplatin study, dose reductions occurred with 10.4% of Gemzar (gemcitabine hcl) injections and 1.8% of carboplatin injections on the combination arm, versus 3.8% on the carboplatin alone arm. On the combination arm, 13.7% of Gemzar (gemcitabine hcl) doses were omitted and 0.2% of carboplatin doses were omitted, compared to 0% of carboplatin doses on the carboplatin alone arm. There were no differences in discontinuations due to adverse reactions between arms (10.9% versus 9.8%, respectively). Table 8 presents the adverse reactions (all grades) occurring in ? 10% of patients in the ovarian cancer study. Table 8: Adverse Reactions From Comparative Trial of Gemzar (gemcitabine hcl) Plus Carboplatin Versus Single-Agent Carboplatin in Ovarian Cancera CTC Grades (% incidence) Gemzar plus CarboplatinCarboplatin (N=175)(N=174) All GradesGrade 3Grade 4All GradesGrade 3Grade 4 Laboratoryb Hematologic 90422958111 Neutropenia 862267592 Anemia 86485706< 1 Leukopenia 7830557101 Thrombocytopenia 3815 RBC Transfusionsc 93 Platelet Transfusionsc Non-laboratoryb 25 / 45 69606130 Nausea 49001700 Alopecia 4660362< 1 Vomiting 42613730 Constipation 403< 13250 Fatigue 29102720 Neuropathy-sensory 253014< 10 Diarrhea 22< 101300 Stomatitis/pharyngitis 16101300 Anorexia a Grade based on Common Toxicity Criteria (CTC) Version 2.0 (all grades ? 10%). b Regardless of causality. c Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood. In addition to blood product transfusions as listed in Table 8, myelosuppression was also managed with hematopoietic agents. These agents were administered more frequently with combination therapy than with monotherapy (granulocyte growth factors: 23.6% and 10.1%, respectively; erythropoietic agents: 7.3% and 3.9%, respectively). The following are the clinically relevant adverse reactions, regardless of causality, that occurred in > 1% and < 10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse reactions (Gemzar (gemcitabine hcl) plus carboplatin versus carboplatin): AST or ALT elevation (0 versus 1.2%), dyspnea (3.4% versus 2.9%), febrile neutropenia(l.l% versus 0), hemorrhagic event (2.3% versus 1.1%), hypersensitivity reaction (2.3% versus 2.9%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0). No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65. Post-Marketing Experience The following adverse reactions have been identified during post-approval use of Gemzar (gemcitabine hcl) . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions have occurred after Gemzar (gemcitabine hcl) single-agent use and Gemzar (gemcitabine hcl) in combination with other cytotoxic agents. Decisions to include these events are based on the seriousness of the event, frequency of reporting, or potential causal connection to Gemzar (gemcitabine hcl) . Cardiovascular — Congestive heart failure and myocardial infarction have been reported very rarely with the use of Gemzar (gemcitabine hcl) . Arrhythmias, predominantly supraventricular in nature, have been reported very rarely. Vascular Disorders — Clinical signs of peripheral vasculitis and gangrene have been reported very rarely. Skin — Cellulitis and non-serious injection site reactions in the absence of extravasation have been rarely reported. Severe skin reactions, including desquamation and bullous skin eruptions, have been reported very rarely. Hepatic — Increased liver function tests including elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GOT), alkaline phosphatase, and bilirubin levels have been reported rarely. Serious hepatotoxicity including liver failure and death has been reported very rarely in patients receiving Gemzar (gemcitabine hcl) alone or in combination t with other potentially hepatotoxic drugs. Hepatic veno-occlusive disease has been reported. Pulmonary — Parenchyma! toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported rarely following one or more doses of Gemzar (gemcitabine hcl) administered to patients with various malignancies. Some patients experienced the onset of pulmonary symptoms up to 2 weeks after the last Gemzar (gemcitabine hcl) dose. Respiratory failure and death occurred very rarely in some patients despite discontinuation of therapy. Renal— Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar (gemcitabine hcl) . Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS. Injury, Poisoning, and Procedural Complications — Radiation recall reactions have been reported [see WARNINGS AND PRECAUTIONS]. 3.2 Drug Interactions 录物相互作用 No specific drug interaction studies have been conducted. Information is available on the pharmacodynamics and pharmacokinetics of Gemzar (gemcitabine hcl) in combination with cisplatin, paclitaxel, or carboplatin [see CLINICAL PHARMACOLOGY]. 27 / 45 4 Gemzar Warnings & Precautions 健择警告和防措施录录录录 4.1 Warnings 警告 Included as part of the PRECAUTIONS section. 4.2 Precautions 录防措施 Patients receiving therapy with Gemzar (gemcitabine hcl) should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents. 4.2.1 Infusion Time Caution — Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity [see Clinical Studies]. 4.2.2 Hematology Gemzar (gemcitabine hcl) can suppress bone marrow function as manifested by leukopenia, thrombocytopenia, and anemia [see ADVERSE REACTIONS], and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy [see DOSAGE AND ADMINISTRATION]. 4.2.3 Pulmonary Pulmonary toxicity has been reported with the use of Gemzar (gemcitabine hcl) . In cases of severe lung toxicity, Gemzar (gemcitabine hcl) therapy should be discontinued immediately and appropriate supportive care measures instituted [see ADVERSE REACTIONS]. 4.2.4 Renal Hemolytic Uretnic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar (gemcitabine hcl) . Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been reported. The majority of the cases of renal failure leading to death were due to HUS [see ADVERSE REACTIONS]. Gemzar (gemcitabine hcl) should be used with caution in patients with preexisting renal impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations [see Use In Specific Populations]. 4.2.5 Hepatic Serious hepatotoxicity, including liver failure and death, has been reported in patients receiving Gemzar (gemcitabine hcl) alone or in combination with other potentially hepatotoxic drugs [see ADVERSE REACTIONS]. Gemzar (gemcitabine hcl) should be used with caution in patients with preexisting hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of Gemzar (gemcitabine hcl) in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency [see Use In Specific Populations]. 4.2.6 Pregnancy Gemzar (gemcitabine hcl) can cause fetal harm when administered to a pregnant woman. In pre-clinical studies in mice and rabbits, gemcitabine was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of Gemzar (gemcitabine hcl) in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use In Specific Populations]. 4.2.7 Laboratory Tests Patients receiving Gemzar (gemcitabine hcl) should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. Suspension or modification of therapy should be considered when marrow suppression is detected [see DOSAGE AND ADMINISTRATION]. Laboratory evaluation of renal and hepatic function should be performed prior to initiation of therapy and periodically thereafter [see DOSAGE AND ADMINISTRATION]. 4.2.8 Radiation Therapy A pattern of tissue injury typically associated with radiation toxicity has been reported in association with concurrent and non-concurrent use of Gemzar (gemcitabine hcl) . 29 / 45 Non-concurrent (given > 7 days apart) — Analysis of the data does not indicate enhanced toxicity when Gemzar (gemcitabine hcl) is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that Gemzar (gemcitabine hcl) can be started after the acute effects of radiation have resolved or at least one week after radiation. Concurrent (given together or ? 7 days apart) — Preclinical and clinical studies have shown that Gemzar (gemcitabine hcl) has radiosensitizing activity. Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of Gemzar (gemcitabine hcl) , frequency of Gemzar (gemcitabine hcl) administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. In a single trial, where 2Gemzar (gemcitabine hcl) at a dose of 1000 mg/m was administered concurrently for up to 6 consecutive weeks with therapeutic thoracic radiation to patients with non-small cell lung cancer, significant toxicity in the form of severe, and potentially life-threatening mucositis, especially esophagitis and pneumonitis was observed, particularly in patients receiving large volumes of 3radiotherapy [median treatment volumes 4795 cm]. Subsequent studies have been reported and suggest that Gemzar (gemcitabine hcl) administered at lower doses with concurrent radiotherapy has predictable and less severe toxicity. However, the optimum regimen for safe administration of Gemzar (gemcitabine hcl) with therapeutic doses of radiation has not yet been determined in all tumor types. 4.2.9 Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies to evaluate the carcinogenic potential of Gemzar (gemcitabine hcl) have not been conducted. Gemcitabine induced forward mutations in vitro in a mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine was negative when tested using the Ames, in vivo sister chromatid exchange, and in vitro chromosomal aberration assays, and did not cause unscheduled DNA synthesis in vitro. Gemcitabine IP doses of 20.5 mg/kg/day (about 1/700 the human dose on a mg/m basis) in male mice had an effect on fertility with moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 21.5 mg/kg/day administered intravenously (about 1/200 the human dose on a mg/m basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 21/1300 the human dose on a mg/m basis). 4.2.10 Use In Specific Populations 4.2.10.1 Pregnancy Pregnancy Category D. See 'WARNINGS and PRECAUTIONS' section. Gemzar (gemcitabine hcl) can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, Gemzar (gemcitabine hcl) is expected to result in adverse reproductive effects. There are no adequate and well-controlled studies of Gemzar (gemcitabine hcl) in pregnant women. - Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 the recommended human 2dose on a mg/m basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 1/600 the 2recommended human dose on a mg/m basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. If this 1 drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see WARNINGS AND PRECAUTIONS]. 4.2.10.2 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Gemzar (gemcitabine hcl) , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 4.2.10.3 Pediatric Use The safety and effectiveness of Gemzar (gemcitabine hcl) in pediatric patients has not been established. Gemzar (gemcitabine hcl) was evaluated in a Phase 1 trial in pediatric patients with 2 refractory leukemia and determined that the maximum tolerated dose was 10 mg/m/min for 360 minutes three times weekly followed by a one-week rest period. Gemzar (gemcitabine hcl) was also evaluated in a Phase 2 trial in patients with relapsed acute lymphoblastic leukemia (22 2patients) and acute myelogenous leukemia (10 patients) using 10 mg/m/min for 360 minutes three times weekly followed by a one-week rest period. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation, which were similar to those reported in adults. No meaningful clinical activity was observed in this Phase 2 trial. 4.2.10.4 Geriatric Use Gemzar clearance is affected by age [see CLINICAL PHARMACOLOGY]. There is no evidence, however, that unusual dose adjustments [see DOSAGE AND ADMINISTRATION] are necessary in patients over 65, and in general, adverse reaction rates in the single-agent safety database of 979 patients were similar in patients above and below 65. Grade 3/4 thrombocytopenia was more common in the elderly. In the randomized clinical trial of Gemzar (gemcitabine hcl) in 31 / 45 combination with carboplatin for recurrent ovarian cancer [see Clinical Studies], 125 women treated with Gemzar (gemcitabine hcl) plus carboplatin were < 65 years and 50 were ? 65 years. Similar effectiveness was observed between older and younger women. There was significantly higher Grade 3/4 neutropenia in women 65 years of age or older. Overall, there were no other substantial differences in toxicity profile of Gemzar (gemcitabine hcl) plus carboplatin based on age. 4.2.10.5 Renal Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar (gemcitabine hcl) . Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been reported. The majority of the cases of renal failure leading to death were due to HUS [see ADVERSE REACTIONS]. Gemzar (gemcitabine hcl) should be used with caution in patients with preexisting renal impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations [see WARNINGS AND PRECAUTIONS]. 4.2.10.6 Hepatic Serious hepatotoxicity, including liver failure and death, has been reported in patients receiving Gemzar (gemcitabine hcl) alone or in combination with other potentially hepatotoxic drugs [see ADVERSE REACTIONS]. Gemzar (gemcitabine hcl) should be used with caution in patients with preexisting hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of Gemzar (gemcitabine hcl) in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency [see WARNINGS AND PRECAUTIONS]. 4.2.10.7 Gender Gemzar clearance is affected by gender [see CLINICAL PHARMACOLOGY]. In the single-agent safety database (N=979 patients), however, there is no evidence that unusual dose adjustments [see DOSAGE AND ADMINISTRATION] are necessary in women. In general, in single-agent studies of Gemzar (gemcitabine hcl) , adverse reaction rates were similar in men and women, but women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia. There was a greater tendency in women, especially older women, not to proceed to the next cycle. 33 / 45 5.Gemzar Overdosage & Contraindications 健择录量和禁忌征 候 5.1 Overdosage 录量 There is no known antidote for overdoses of Gemzar (gemcitabine hcl) . Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5700 2mg/m was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a Phase 1 study. In the event of suspected overdose, the patient should be monitored with appropriate blood counts and should receive supportive therapy, as necessary.5.2 Contraindications 禁忌征候 Gemzar (gemcitabine hcl) is contraindicated in those patients with a known hypersensitivity to the drug. 6. Gemzar Clinical Pharmacology 健择录录录录床理学 Mechanism of Action Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and also blocking the progression of cells through the Gl/S-phase boundary. Gemcitabine is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is attributed to a combination of two actions of the diphosphate and the triphosphate nucleosides, which leads to inhibition of DNA synthesis. First, gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. Inhibition of this enzyme by the diphosphate nucleoside causes a reduction in the concentrations of deoxynucleotides, including dCTP. Second, gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP (by the action of the diphosphate) enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands. After this addition, there is inhibition of further DNA synthesis. DNA polymerase epsilon is unable to remove the gemcitabine nucleotide and repair the growing DNA strands (masked chain termination). In CEM T lymphoblastoid cells, gemcitabine induces internucleosomal DNA fragmentation, one of the characteristics of programmed cell death. Pharmacodynamics Gemcitabine demonstrated dose-dependent synergistic activity with cisplatin in vitro. No effect of cisplatin on gemcitabine triphosphate accumulation or DNA double-strand breaks was observed. In vivo, gemcitabine showed activity in combination with cisplatin against the LX-1 and CALU-6 human lung xenografts, but minimal activity was seen with the NCI-H460 orNCI-H520 xenografts. Gemcitabine was synergistic with cisplatin in the Lewis lung murine xenograft. Sequential exposure to gemcitabine 4 hours before cisplatin produced the greatest interaction. Pharmacokinetics Absorption and Distribution The pharmacokinetics of gemcitabine were examined in 353 patients, with various solid tumors. Pharmacokirietic parameters were derived using data from patients treated for varying durations of therapy given weekly with periodic rest weeks and using both short infusions ( < 70 minutes) and long infusions (70 to 285 minutes). The total Gemzar (gemcitabine hcl) dose varied 2from 500 to 3600 mg/m. 35 / 45 The volume of distribution was increased with infusion length. Volume of distribution of 2gemcitabine was 50 L/m following infusions lasting < 70 minutes. For long infusions, the volume 2of distribution rose to 370 L/m. Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and gender. Gemcitabine plasma protein binding is negligible. Metabolism 2Gemcitabine disposition was studied in 5 patients who received a single 1000 mg/m/30 minute infusion of radiolabeled drug. Within one (1) week, 92% to 98% of the dose was recovered, almost entirely in the urine. Gemcitabine ( < 10%) and the inactive uracil metabolite, 2'-deoxy-2',2'-difluorouridine (dFdU), accounted for 99% of the excreted dose. The metabolite dFdU is also found in plasma. The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells. The half-life of the terminal phase for gemcitabine triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours. Excretion Clearance of gemcitabine was affected by age and gender. The lower clearance in women and the elderly results in higher concentrations of gemcitabine for any given dose. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. Table 9 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender. Table 9: Gemcitabine Clearance and Half-Life for the "Typical" Patient a a AgClearance Clearance Half-LifeHalf-Life e Men Women Men (min)Women (min) 22(L/hr/m)(L/hr/m) 2992.269.44249 4575.757.04857 6555.141.56173 7940.730.77994 a Half-life for patients receiving a short infusion ( < 70 min). Gemcitabine half-life for short infusions ranged from 42 to 94 minutes, and the value for long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions. Drug Interactions 22When Gemzar (gemcitabine hcl) (1250 mg/m on Days 1 and 8) and cisplatin (75 mg/m on Day 1) were administered in NSCLC patients, the clearance of gemcitabine on Day 1 was 128 22L/hr/m and on Day 8 was 107 L/hr/m. The clearance of cisplatin in the same study was reported 2to be 3.94 mL/min/m with a corresponding half-life of 134 hours [see DRUG INTERACTIONS]. Analysis of data from metastatic breast cancer patients shows that, on average, Gemzar (gemcitabine hcl) has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of Gemzar (gemcitabine hcl) . Data from NSCLC patients demonstrate that Gemzar (gemcitabine hcl) and carboplatin given in combination does not alter the pharmacokinetics of Gemzar (gemcitabine hcl) or carboplatin compared to administration of either single-agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed. Clinical Studies Ovarian Cancer Gemzar (gemcitabine hcl) was studied in a randomized Phase 3 study of 356 patients with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. 2Patients were randomized to receive either Gemzar (gemcitabine hcl) 1000 mg/m on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after Gemzar (gemcitabine hcl) on Day 1 of each cycle or single-agent carboplatin AUC 5 administered on Day 1 of each 21-day cycle as the control arm. The primary endpoint of this study was progression free survival (PFS). Patient characteristics are shown in Table 10. The addition of Gemzar (gemcitabine hcl) to carboplatin resulted in statistically significant improvement in PFS and overall response rate as shown in Table 11 and Figure 1. Approximately 75% of patients in each arm received poststudy chemotherapy. Only 13 of 120 patients with documented poststudy chemotherapy regimen in the carboplatin arm received Gemzar (gemcitabine hcl) after progression. There was not a significant difference in overall survival between arms. Table 10: Gemzar (gemcitabine hcl) Plus Carboplatin Versus Carboplatin in Ovarian Cancer - Baseline Demographics and Clinical Characteristics Gemzar/CarboCarboplatin platin Number of randomized patients178178 Median age, years Range59 36 to 7858 21 to 81 Baseline ECOG performance 94%95% astatus 0-l Disease Status Evaluable7.9%2.8% 91.6%95.5% Bidimensionally measurable bPlatinum-free interval 6-12 months39.9%39.9% 59.0%59.6% > 12 months First-line therapy Platinum-taxane combination70.2%71.3% 28.7%27.5% Platinum-non-taxane combination 1.1%1.1% Platinum monotherapy 37 / 45 a Nine patients (5 on the Oemzar plus carboplatm arm and 4 on the carboplatin arm) did not have baseline bastern Cooperative Oncology Group (ECOG) performance status recorded. b Three patients (2 on the Gemzar (gemcitabine hcl) plus carboplatin arm and 1 on the carboplatin arm) had a platinum-free interval of less than 6 months. Table 11: Gemzar (gemcitabine hcl) Plus Carboplatin Versus Carboplatin in Ovarian Cancer- Results of Efficacy Analysis Gemzar/CarboCarbo platin platin (N=178)(N=178) PFS 8.6 (8.0, 9.7)5.8(5.2p=0.0 Median (95%, C.I.) dmonths ,7.1)038 0.72 (0.57, 0.90) Hazard Ratio (95%, C.I.) Overall Survival 18.0 (16.2,20.3)17.3(1p=0.8 Median (95%, C.I.) dmonths 5.2, 19.3)977 0.98 (0.78, 1.24) Hazard Ratio (95%, C.l.) Ratio a0.86 (0.67, 1.10) Adjusted Hazard Ratio (95%, C.I.) Investigator Reviewed 47.2%30.9%p=0.0 Overall Response Rate e016 CR14.6%6.2% b32.6%24.7% PR+PRNM Independently Reviewed c,f Overall Response Rate46.3%35.6%p=0.1 e1 9.1%4.0% CR PR+PRNM37.2%31.7% a Treatment adjusted for performance status, tumor area, and platinum-free interval. b Partial response non-measurable disease c Independent reviewers could not evaluate disease demonstrated by sonography or physical exam. d Log Rank, unadjusted e Chi Square f Independently reviewed cohort - Gemzar (gemcitabine hcl) /Carboplatin N= 121, Carboplatin N= 101 Figure 1: Kaplan-Meier Curve of Progression Free Survival in Gemzar (gemcitabine hcl) Plus Carboplatin Versus Carboplatin in Ovarian Cancer (N=356) Breast Cancer Data from a multi-national, randomized Phase 3 study (529 patients) support the use of Gemzar (gemcitabine hcl) in combination with paclitaxel for treatment of breast cancer patients who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically 2contraindicated. Gemzar (gemcitabine hcl) 1250 mg/m was administered on Days 1 and 8 of a 21- 2day cycle with paclitaxel 175 mg/m administered prior to Gemzar (gemcitabine hcl) on Day 1 of 2each cycle. Single-agent paclitaxel 175 mg/m was administered on Day 1 of each 21-day cycle as the control arm. The addition of Gemzar (gemcitabine hcl) to paclitaxel resulted in statistically significant improvement in time to documented disease progression and overall response rate compared to monotherapy with paclitaxel as shown in Table 12 and Figure 2. Final survival analysis results at 440 events were Hazard Ratio of 0.86 (95%, CI: 0.71 - 1.04) for the ITT population, as shown in Table 12. Table 12: Gemzar (gemcitabine hcl) Plus Paclitaxel Versus Paclitaxel in Breast Cancer Gemzar/PaclPaclit itaxelaxel Number of patients267262 Median age, years Range53 26 to 8352 26 to 75 Metastatic disease97.0%96.9 % aBaseline KPS ? 9070.4%74.4 % Number of tumor sites 39 / 45 56.6% 58.8 1-2 % ? 343.4%41.2 % Visceral disease73.4%72.9 % Prior anthracycline96.6%95.8 % bOverall Survival 18.6 15.8 Median (95%, CI) (16.5,20.7)(14.1, 17.3) 0.86 (0.71,1.04) Hazard Ratio (95%, CI) cTime to Documented Disease Progression Median (95%, C.I.), months 5.2 (4.2, 5.6)2.9 p < (2.6, 3.7)0.000l 0.650 (0.524, 0.805)p < Hazard Ratio (95%, C.I.) 0.000l Overall Response Rate0 40.8% (34.9, 22.1p < 46.7)% (17.1, 0.000l(95%, C.I.) 27.2) a Karnofsky Performance Status. b Based on the ITT population c These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm. Figure 2: Kaplan-Meier Curve of Time to Documented Disease Progression in Gemzar (gemcitabine hcl) Plus Paclitaxel Versus Paclitaxel Breast Cancer Study (N=529) Non-Small Cell Lung Cancer (NSCLC) Data from 2 randomized clinical studies (657 patients) support the use of Gemzar (gemcitabine hcl) in combination with cisplatin for the first-line treatment of patients with locally advanced or metastatic NSCLC. Gemzar (gemcitabine hcl) plus cisplatin versus cisplatin: This study was conducted in Europe, the US, and Canada in 522 patients with inoperable Stage III A, IIIB, or IV NSCLC who 2 was administered on had not received prior chemotherapy. Gemzar (gemcitabine hcl) 1000 mg/m 2Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m administered on Day 1 of each 2cycle. Single-agent cisplatin 100 mg/m was administered on Day 1 of each 28-day cycle. The primary endpoint was survival. Patient demographics are shown in Table 13. An imbalance with regard to histology was observed with 48% of patients on the cisplatin arm and 37% of patients on the Gemzar (gemcitabine hcl) plus cisplatin arm having adenocarcinoma. The Kaplan-Meier survival curve is shown in Figure 3. Median survival time on the Gemzar (gemcitabine hcl) plus cisplatin arm was 9.0 months compared to 7.6 months on the single-agent cisplatin arm (Log rank p=0.008, two-sided). Median time to disease progression was 5.2 months on the Gemzar (gemcitabine hcl) plus cisplatin arm compared to 3.7 months on the cisplatin arm (Log rank p=0.009, two-sided). The objective response rate on the Gemzar (gemcitabine hcl) plus cisplatin arm was 26% compared to 10% with cisplatin (Fisher's Exact p < 0.0001, two-sided). No difference between treatment arms with regard to duration of response was observed. Gemzar (gemcitabine hcl) plus cisplatin versus etoposide plus cisplatin: A second, multicenter, study in Stage IIIB or IV NSCLC randomized 135 patients to Gemzar (gemcitabine 22hcl) 1250 mg/m on Days 1 and 8, and cisplatin 100 mg/m on Day 1 of a 21-day cycle or to 22intravenous etoposide 100 mg/m on Days 1, 2, and 3 and cisplatin 100 mg/m on Day 1 of a 21- day cycle (Table 13). There was no significant difference in survival between the two treatment arms (Log rank p=0.18, two-sided). The median survival was 8.7 months for the Gemzar (gemcitabine hcl) plus cisplatin arm versus 7.0 months for the etoposide plus cisplatin arm. Median time to disease progression for the Gemzar (gemcitabine hcl) plus cisplatin arm was 5.0 months compared to 4.1 months on the etoposide plus cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the Gemzar (gemcitabine hcl) plus cisplatin arm was 33% compared to 14% on the etoposide plus cisplatin arm (Fisher's Exact p=0.01, two-sided). Figure 3: Kaplan-Meier Survival Curve in Gemzar (gemcitabine hcl) Plus Cisplatin Versus Cisplatin NSCLC Study (N=522) 41 / 45 Table 13: Randomized Trials of Combination Therapy With Gemzar (gemcitabine hcl) Plus Cisplatin in NSCLC Pancreatic Cancer Data from 2 clinical trials evaluated the use of Gemzar (gemcitabine hcl) in patients with locally advanced or metastatic pancreatic cancer. The first trial compared Gemzar (gemcitabine hcl) to 5-Fluorouracil (5-FU) in patients who had received no prior chemotherapy. A second trial studied the use of Gemzar (gemcitabine hcl) injjapcreatic cancer patients previously treated with 5-FU or a 5-FU-containing regimen. In both studies, the first cycle of Gemzar (gemcitabine hcl) 2was administered intravenously at a dose of 1000 mg/m over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitated holding a dose) followed by a week of rest from treatment with Gemzar (gemcitabine hcl) . Subsequent cycles consisted of injections once weekly for 3 consecutive weeks out of every 4 weeks. The primary efficacy parameter in these studies was "clinical benefit response," which is a measure of clinical improvement based on analgesic consumption, pain intensity, performance status, and weight change. Definitions for improvement in these variables were formulated prospectively during the design of the 2 trials. A patient was considered a clinical benefit responder if either: i) the patient showed a ? 50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption, or a 20-point or greater improvement in performance status (Karnofsky Performance Status) for a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other parameters. Sustained worsening was defined as 4 consecutive weeks with either any increase in pain intensity or analgesic consumption or a 20-point decrease in performance status occurring during the first 12 weeks of therapy. OR: ii) the patient was stable on all of the aforementioned parameters, and showed a marked, sustained weight gain ( ? 7% increase maintained for ? 4 weeks) not due to fluid accumulation. The first study was a multicenter (17 sites in US and Canada), prospective, single-blinded, two-arm, randomized, comparison of Gemzar (gemcitabine hcl) and 5-FU in patients with locally advanced or metastatic pancreatic cancer who had received no prior treatment with chemotherapy. 25-FU was administered intravenously at a weekly dose of 600 mg/m for 30 minutes. The results from this randomized trial are shown in Table 14. Patients treated with Gemzar (gemcitabine hcl) had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to 5-FU. The Kaplan-Meier curve for survival is shown in Figure 4. No confirmed objective tumor responses were observed with either treatment. Table 14: Gemzar (gemcitabine hcl) Versus 5-FU in Pancreatic Cancer Gemzar5-FU Number of patients6363 3434 Male Female2929 Median age62 years61 years 37 to 7936 to 77 Range Stage IV disease71.4%76.2% aBaseline KPS ? 7069.8%68.3% eClinical benefit 22.2% 4.8% p=0.004 ccresponse(N=14)(N=3) Survivalp=0.0009 5.7 months4.2 months Median 6-month (N=30) (N=19)29 b46%%probability 9-month (N=14)24(N=4) 5% b%probability b 1-year probability(N=9) 1 (N=2) 2% 8% 0.2 to 18.6 0.4 to 1 5. Range dmonthsl+ months 95% C.I. of the 4.7 to 6.9 3.1 to 5.1 monthsmonthsmedian Time to Disease p=0.0013 Progression 2.1 months0.9 months Median d Range0.1 + to 0.1 to 43 / 45 d9.4 months12.0+ months 1.9 to 3. 4 0.9 to 1.1 95% C.I. of the medianmonthsmonths a Karnofsky Performance Status. b Kaplan-Meier estimates. c N=number of patients. d No progression at last visit; remains alive. e The p-value for clinical benefit response was calculated using the two-sided test for difference in binomial proportions. All other p-values were calculated using the Log rank test for difference in overall time to an event. Clinical benefit response was achieved by 14 patients treated with Gemzar (gemcitabine hcl) and 3 patients treated with 5-FU. One patient on the Gemzar (gemcitabine hcl) arm showed improvement in all 3 primary parameters (pain intensity, analgesic consumption, and performance status). Eleven patients on the Gemzar (gemcitabine hcl) arm and 2 patients on the 5-FU arm showed improvement in analgesic consumption and/or pain intensity with stable performance status. Two patients on the Gemzar (gemcitabine hcl) arm showed improvement in analgesic consumption or pain intensity with improvement in performance status. One patient on the 5-FU arm was stable with regard to pain intensity and analgesic consumption with improvement in performance status. No patient on either arm achieved a clinical benefit response based on weight gain. Figure 4: Kaplan-Meier Survival Curve The second trial was a multicenter (17 US and Canadian centers), open-label study of Gemzar (gemcitabine hcl) in 63 patients with advanced pancreatic cancer previously treated with 5-FU or a 5-FU-containing regimen. The study showed a clinical benefit response rate of 27% and median survival of 3.9 months. Other Clinical Studies When Gemzar (gemcitabine hcl) was administered more frequently than once weekly or with infusions longer than 60 minutes, increased toxicity was observed. Results of a Phase 1 study of Gemzar (gemcitabine hcl) to assess the maximum tolerated dose (MTD) on a daily x 5 schedule showed that patients developed significant hypotension and severe flu-like symptoms that were 2intolerable at doses above 10 mg/m. The incidence and severity of these events were dose-related. 2Other Phase 1 studies using a twice-weekly schedule reached MTDs of only 65 mg/m (30-minute 2infusion) and 150 mg/m (5-minute bolus). The dose-limiting toxicities were thrombocytopenia and flu-like symptoms, particularly asthenia. In a Phase 1 study to assess the maximum tolerated infusion time, clinically significant toxicity, defined as myelosuppression, was seen with weekly 2doses of 300 mg/m at or above a 270-minute infusion time. The half-life of gemcitabine is influenced by the length of the infusion and the toxicity appears to be increased if Gemzar (gemcitabine hcl) is administered more frequently than once weekly or with infusions longer than 60 minutes [see WARNINGS AND PRECAUTIONS]. REFERENCES 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. 2. OSHA Technical Manual, TED 1-0.ISA, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. 3. American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous Drugs: Am J Health-Syst Pharm. 2006;63:1172-1193. 4. Polovich, M., White, J. M, & Kelleher, L. O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society. 45 / 45