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培美曲塞使用说明书

力比泰 pemetrexed for Injection

【主要成份】培美曲塞

【性状】印度力比泰为白色至淡黄色或绿黄色冷冻干燥固体。

【适应症】印度力比泰联合顺铂用于治疗无法手术的恶性胸膜间皮瘤。

【用法用量】

力比泰应该在有抗肿瘤化疗应用经验的合格医师的指导下使用。力比泰只能用于静脉滴注，其溶液的配制必须按照“静脉滴注准备”的说明进行。

恶性胸膜间皮瘤：

力比泰联合顺铂用于治疗恶性胸膜间皮瘤的推荐剂量为每21天500mg／m2滴注力比泰超过10分钟，顺铂的推荐剂量为75mg／m2滴注超过2小时，应在力比泰给药结束30分钟后再给予顺铂滴注。接受顺铂治疗要有水化方案。具体可参见顺铂说明书。

预服药物：

皮质类固醇—未预服皮质类固醇药物的患者，应用力比泰皮疹发生率较高。预服地塞米松(或相似药物)可以降低皮肤反应的发生率及其严重程度。给药方法：地塞米松4mg口服每日2次，

力比泰给药前1天、给药当天和给药后1天连服3天。维生素补充一为了减少毒性反应，力比泰治疗必须同时服用低剂量叶酸或其他含有叶酸的复合维生素制剂。服用

时间：第一次给予力比泰治疗开始前7天至少服用5次日剂量的叶酸，一直服用整个治疗周期，在后1次力比泰给药后21天可停服。患者还需在第一次力比泰给药前7天内肌肉注射维生素B12一次，以后每3个周期肌注一次，以后的维生素B12给药可与力比泰用药在同一天进行。叶酸给药剂量：350-1000μg，常用剂量是400μg：维生素B12剂量1000μg。(参见[注意事项]项下的“警告”部分)。

实验室检查监测扣推荐的剂量调整方法：

监测—所有准备接受力比泰治疗的患者，用药前需完成包括血小板计数在内的血细胞检查，给药后需监测血细胞低点及恢复情况，临床研究时每周期的开始、第8天和第15天需检查上述项目。患者必须在中性粒细胞≥1500／mm3，血小板≥100,000cells／mm3、肌酐清除率≥45mL/min时，才能开始力比泰治疗。每周期治疗需进行肝功能和肾功能的生化检查。

推荐剂量调整方法一根据既往周期血细胞低计数和严重的非血液学毒性进行剂量调整。患者如果21天周期仍未从不良反应中恢复，治疗应延迟进行。等待患者恢复后，按照表1、表2、表3的要求进行治疗。

静脉滴注准备：

1、配置过程应无菌操作。

2、计算力比泰用药剂量及用药支数。每支药含有500mg力比泰。每支瓶中实际所含力比泰大于500mg以保证静脉滴注时能达到标示量。

3、每支500mg药品用20mL 0.9%的氯化钠注射液（不含防腐剂）溶解成浓度为25mg/mL的力比泰溶液，慢慢旋转直至粉未完全溶解。完全溶解后的溶液澄清，颜色为无色至黄色或黄绿色都是正常的。力比泰溶液的pH值为6.6—7.8。且溶液需要进一步稀释。

4、静脉滴注前观察药液有无沉淀及颜色变化：如果有异样，不能滴注。

5、力比泰滴液配好后应用0.9%氯化钠注射液（不含防腐剂）稀释至100mL，静脉滴注超过10分钟。

6、配好的力比泰溶液，置于冰箱冷藏或置于室温（15—30℃），无需避光，其物理及化学特性24小时内保持稳定。按照上述方法配制的力比泰溶液，不含抗菌防腐剂。不用部分丢弃。力比泰只建议用0.9%的氯化钠注射液（不含防腐剂）溶解稀释。力比泰不能溶于含有钙的稀释剂，包括美国药典林格氏乳酸盐注射液和美国药典林格氏注射液。其他稀释液和其他药物与力比泰能否混合尚未确定，因此不推荐使用。

【药理毒理】

药理作用

培美曲塞是一种结构上含有核心为吡咯嘧啶基团的抗叶酸制剂，通过破坏细胞内叶酸依赖性的正常代谢过程，抑制细胞复制，从而抑制肿瘤的生长。体外研究显示，培美曲塞能够抑制胸苷酸合成酶、二氢叶酸还原酶和甘氨酰胺核苷酸甲酰转移酶的活性，这些酶都是合成叶酸所必需的酶，参与胸腺嘧啶核苷酸和嘌吟核苷酸的生物再合成过程，培美曲塞通过运载叶酸的载体和细胞膜上的叶酸结合蛋白运输系统进入细胞内。

一旦培美曲塞进入细胞内，它就在叶酰多谷氨酸合成酶的作用下转化为多谷氨酸的形式。多谷氨酸存留于细胞内成为胸苷酸合成酶和甘氨酰胺核苷酸甲酰转移酶的抑制剂．，多谷氨酸化在肿瘤细胞内呈现时间-浓度依赖性过程，而在正常组织内浓度很低。多谷氨酸化代谢物在肿瘤细胞内的半衰期延长，从而也就延长了药物在肿瘤细胞内的作用时间。

临床前研究显示培美曲塞体外可抑制间皮瘤细胞系(MSTO-211H，NCI-H2052)的生长。间皮瘤细胞系MSTO-211H的研究显示出培美曲塞与顺铂联合有协同作用。

人群药效学分析采用的指标是绝对中性粒细胞计数；此时人群接受的为单药培美曲塞，未接受叶酸和维生素B12的补充治疗。通过观察粒细胞低值来判断血液学毒性发生的严重程度，结果发现其与力比泰全身给药剂量且呈负相关关系。

研究中也发现如果患者基线检查时胱硫醚或高半胱氨酸浓度高，那么其绝对粒细胞计数下降的会更为严重。叶酸和维生素B12；可以降低胱硫醚或高半胱氨酸这两种底物的浓度。经过培美曲塞多周期治疗，未见对中性粒细胞的累积毒性。

培美曲塞全身给药后(AUC38．3－316．8μg·hr／mL)，中性粒细胞下降至低点的时间约为8-9．6天，经过低点后，中性粒细胞计数恢复至基线水平的时间为4．2-7．5天。

【毒理研究】

遗传毒性：小鼠骨髓体内微核测定显示培美曲塞是断裂剂，但体外的多个实验研究(Ames测定，CHO细胞测定)．均未显示致突变作用。

生殖毒性：培美曲塞按照0．1mg／kg／日或更大剂量(相当于人类推荐用量的1／1666)给予雄性小鼠，可导致生育能力下降、，精液过少和睾丸萎缩。

致癌作用：未进行培美曲寨致癌作用的研究。

【药代动力学】

培美曲塞药代动力学评价在426例多种肿瘤类型的患者中进行，采用单药治疗，剂量为0．2-838mg／m2，10分钟静脉内给药。培美曲塞主要以原药形式从尿路排泄，在给药后的24小时内，70％-90％的培美曲塞还原成原药的形式从尿中排出。

培美曲塞总体清除率为91．8mL／min(肌酐消除率是90mL/min)，对于肾功能正常的患者，体内半衰期为3．5小时；随着肾功能降低，清除率会降低，但体内剂量会增加。随着培美曲塞剂量的增加，曲线下面积AUC和高血浆浓度(Cmax)会成比例增加。

多周期治疗并未改变培美曲塞的药代动力学参数，培美曲塞呈现一稳态分布容积为16．1升。体外研究显示，培美曲塞的血浆蛋白结合率约为81％，且不受肾功能影响。

特殊人群

培美曲塞特殊人群中的药代动力学研究为在总计400例患者中的单组研究。

老年人一—对于年龄为26－80岁的人群，培美曲塞药代动力学无明显变化。

儿童——临床研究中未纳入儿童患者。

性别—男性患者与女性患者相比，培美曲塞药代动力学无差别。

种族一高加索裔和非洲裔患者，培美曲塞的药代动力学相似。曾有试验对日本患者的药代动力学进行研究，虽然没有日本患者和西方患者之间药代动力学参数规范的统计学对照报告，  但仍可说明两者的绝对剂量参数值是基本相似的，而且没有显著的临床差异。

肝脏功能不全—谷草转氨酶(AST、SGOT)、谷丙转氨酶(ALT、SGpT)和总胆红素升高，不影响培美曲塞的药代动力学。但是，未进行肝损害患者的药代动力学研究。(参见[注意事项]项下“肝功能不全的患者”部分)。   肾功能不全—总计127例肾功能不全患者进行了培美曲塞药代动力学研究。如果同时合并有顺铂治疗，随着肾功能降低，培美曲塞的血浆清除率降低，而全身暴露剂量增加。将培美曲塞全身总暴露量(AUC)与100mL／min的肌酐清除率比较，当肌酐清除率分别为45、50和80mL／min时，全身总暴露量(AUC)增加65％、54％和13％。(参见[用法用量]和[注意事项]项下“警告”部分)

【禁忌】

力比泰禁用于对培美曲塞或药品其他成份有严重过敏史的患者。

【注意事项】   警告 肾功能减低的患者

力比泰主要通过尿路以原药形式排除体外。如果患者肌酐清除率≥45mL/min，力比泰无需剂量调整。对于肌酐清除率<45mL/min的患者，无足够患者的研究资料来给予推荐剂量。因此，对于肌酐清除率<45mL/min的患者，不应给予力比泰治疗。（参见[用法用量]中的“推荐剂量调整方法”）。

临床研究中，曾有一位严重肾功能不全（肌酐清除率19ml/min）的患者，未接受叶酸和维和素B12补充治疗，接受单药力比泰的治疗后，死于药物相关毒性。

骨髓抑制

力比泰可以引起骨髓抑制，包括中性粒细胞、血小板减少和贫血（参见 [不良反应] ）。骨髓抑制是常见的剂量限制性毒性，应根据既往治疗周期中出现的低中性粒细胞、血小板值和严重非血液学毒性来进行剂量调整。（参见 [用法用量] 中的“推荐剂量调整方法” ）。

叶酸及维生素B12的补充治疗

接受力比泰治疗同时应接受叶酸和维生素B1的补充治疗，可以预防或减少治疗相关的血液学或胃肠道不良反应。（参加 [用法用量] 部分）。临床研究显示，给予叶酸和维生素B1补充治疗的患者，接受力比泰治疗时总的不良反应发生率降低，包括3/4度的血液学毒性以及非血液学毒性，例如中性粒细胞减少、粒细胞减少性发热和3/4度粒细胞减少性感染。

一般注意事项

力比泰应在有抗肿瘤药物应用经验的合格医师指导下使用。应在有足够诊断与治疗技术的医疗机构进行力比泰治疗，这也可以保证并发症的及时处理。临床研究中看到的治疗相关不良反应均是可以恢复的。给药前未给予类皮质激素预处理的患者易出现皮疹。地塞米松（或相似药物）预处理可以降低皮肤反应的发生率及严重程度。（参见 [用法用量] 部分）

力比泰是否导致体液储留例如胸水或腹水还不清楚。对于临床有明显症状的体液储留患者，可以考虑力比泰用药前进行体腔积液引流。

实验室检查

所有准备接受力比泰治疗的患者，用药说需完成包括血小板计数在内的血细胞检查和血生化检查，给药后需监测血细胞低点及恢复情况，临床研究时每周期的开始，第8天和第15天需检查上述项目。患者需在中性粒细胞≥1500/mm3，血小板≥100,000cells/ mm3、肌酐清除率≥45ml/min时，才能开始力比泰治疗。

肝功能不全的患者

胆红素>1.5倍正常上限的患者不纳入力比泰临床研究：无肝转移的患者，如果转氨酶>3.0倍正常上限，不纳入力比泰临床研究；有肝转移的患者，如果转氨酶在3.0和5.0倍正常上限之间，纳入力比泰临床研究。肝功能不全患者的剂量调整见表2。（参见 [药代动力学] 项下的“特殊人群”部分）。

肾功能不全的患者

力比泰主要通过肾脏排泄。与肾功能正常患者相比。肾功能不全患者的总体清除率下降，AUC增加。有中度肾功能不全患者，顺铂与力比泰联合用药的安全性尚未确定（参见 [药代动力学] 项下的“特殊人群”部分）。

药物与实验室检查的相互作用尚未确定。

尚没有研究证明服用力比泰是否对患者驾驶和操作机器造成影响，然而研究证明力比泰可能导致疲劳，如果有这种情况发生，患者应被告知小心驾驶和操作机器。

【孕妇及哺乳期妇女用药】

妊娠：妊娠妇女接受力比泰治疗可能对胎儿有害。妊娠6天—15天的小鼠，静脉予以0.2mg/kg(0.6mg/m2)或5mg/kg(15 mg/m2)培美曲塞，有胎儿毒性并能致畸。给予小鼠0.2mg/kg剂量（大约为人类推荐剂量的1/833）培美曲塞即可引起胎儿畸形（距骨和头颅骨的不完全骨化），5mg/kg时可导致腭裂（相当于人类推荐剂量的1/33）。

胚胎毒性主要表现于胚胎死亡率增加，同时胚胎发育迟缓。没有有关妊娠妇女接受力比泰治疗的研究，因为建议患者避孕。如果在妊娠期间使用了力比泰的患者在使用力比泰期间怀孕，应告知可能对胎儿的潜在危险。

哺乳：力比泰或其代谢产物是否能从乳汁中分泌尚确定。但是力比泰可能对吃奶的婴儿有潜在严重危害，接受力比泰治疗的母亲应停止哺乳。

【儿童用药】

儿童用药的安全性和有效性尚未确定。

【老年患者用药】

按照所有患者的剂量调整方法进行，无需特殊方案（参见 [药代动力学] 中特殊人群部分）。

【药物相互作用】

化疗药物——顺铂不改变培美曲塞的药代动力学，培美曲塞也对所有铂类药物的药代动力学无影响。

维生素——同时给予口服叶酸和肌注维生素B12不改变培美曲塞的药代动力学。

细胞色素p450酶对药物代谢——体外肝脏微球蛋白预测研究结果显示，培美曲塞未导致通过CYp3A酶，CYp2D6酶，CYp2C9酶和CYp1A2酶代谢的药物清除率降低。没有进行研究观察培美曲塞对细胞色素p450同工酶的影响。因为，如果按照推荐的给药日程（每21天1次），力比泰对任何酶均无明显诱导作用。

阿司匹林——给予低到中等剂量（每6小时325mg）的阿司匹林，未影响培美曲塞的药代动力学，高剂量的阿司匹林对培美曲塞药代动力学影响目前还不清楚。

布洛芬——肾功能正常患者，布洛芬每日剂量为400mg，4次/日时，可使培美曲塞的清除率降低20%（AUC增加20%）。更高剂量的布洛芬对培美曲塞药代动力学影响目前还不清楚。

力比泰主要通过肾小球的过滤和肾小管的排泄作用，以原药形式从尿路排出体外。同时给予对肾脏有危害的药物会延迟力比泰的清除，同时给予增加肾小管负担的其他药物（例如丙磺舒）也可能延迟力比泰的清除。

对于肾脏功能正常（肌酐清除率的患者≥80ml/min）的患者，力比泰可以和布洛芬同时用药（400mg，4次/日），但是对于有轻到中度肾功能不全（肌酐清除率在45到79ml/min之间）的患者，力比泰与布洛芬同时使用要小心。有轻到中度肾功能不全的患者，在应用力比泰治疗前2天、用药当天和用药后2天，不要使用半衰期短的非甾体类抗炎药。

长半衰期的非甾体类抗炎药与力比泰潜在相互作用，目前还不确定。但在应用力比泰治疗前5天、用药当天和用药后2天，也要中断非甾体类抗炎药的治疗。如果一定要应用非甾体类抗炎药，一定要密切监测毒性反应，特别是骨髓抑制、肾脏及胃肠道的毒性。

【药物过量】

仅有几例力比泰药物过量的报告。报告的主要不良反应为中性粒细胞减少、贫血、血小板减少、粘膜炎和皮疹。

可预料到的药物过量并发症主要有骨髓抑制，表现为中性粒细胞减少、血小板减少和贫血。

另外，也可能出现伴随或不伴随发热的的感染、腹泻和粘膜炎。一旦发生药物过量，应立即在医生指导下采取合适医疗措施。

临床研究中，如果出现3天以上4度白细胞减少或3天以上4度中性粒细胞减少，可以使用甲酰四氢叶酸，如果出现4度血小板减少或3度血小板减少相关的出血或3/4度粘膜炎，应立即使用甲酰四氢叶酸。

甲酰四氢叶酸的推荐使用剂量和方法是：静脉给药，第1次剂量100mg/m2，以后50mg/m2，每6小时1次，连用8天。通过透析解除力比泰过量的作用尚未确定。

【规格】100mg/瓶

【贮藏】

力比泰应室温保存。

按照上述方法配制的力比泰溶液，不含抗菌防腐剂，从微生物的角度应该立即使用，不用部分丢弃。

如果没有一次用完，配好的力比泰溶液可置于冰箱冷藏（2-8℃）或室温保存（15-30℃），无需避光，其物理、化学特性在24小时内保持稳定。

力比泰没有光敏性。

【包装】玻璃瓶装，1瓶1盒 

 pemetrexed

Generic Name: pemetrexed (pem e TREX ed)
      Brand Name: Alimta

 

Pronunciation

(pem e TREKS ed)

Index Terms

LY231514

Pemetrexed Disodium

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Alimta: 100 mg (1 ea); 500 mg (1 ea)

Brand Names: U.S.

Alimta

Pharmacologic Category

Antineoplastic Agent, Antimetabolite

Antineoplastic Agent, Antimetabolite (Antifolate)

Pharmacology

Pemetrexed is an antifolate; it disrupts folate-dependent metabolic processes essential for cell replication. Pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT), and aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), the enzymes involved in folate metabolism and DNA synthesis, resulting in inhibition of purine and thymidine nucleotide and protein synthesis.

Distribution

Vdss: 16.1 L

Metabolism

Minimal

Excretion

Urine (70% to 90% as unchanged drug)

Half-Life Elimination

Normal renal function: 3.5 hours

Protein Binding

81%

Special Populations: Renal Function Impairment

Pemetrexed clearance decreases and AUC increases as renal function decreases; in patients with creatinine clearance (CrCl) of 45, 50, and 80 mL/minute, AUC was increased 65%, 54%, and 13%, respectively, compared to patients with CrCl of 100 mL/minute

Use: Labeled Indications

Mesothelioma: Initial treatment of unresectable malignant pleural mesothelioma (in combination with cisplatin) or in patients who are not otherwise candidates for curative surgery

Non-small cell lung cancer (NSCLC), nonsquamous: Initial treatment of locally advanced or metastatic nonsquamous NSCLC (in combination with cisplatin); maintenance treatment of locally advanced or metastatic nonsquamous NSCLC if no progression after 4 cycles of initial platinum-based first-line therapy; single-agent treatment (after prior chemotherapy) of recurrent/metastatic nonsquamous NSCLC

Limitation of use: Not indicated for the treatment of squamous cell NSCLC

Off Label UsesBladder cancer, metastatic

Data from a phase II study supports the use of pemetrexed as second-line treatment of locally advanced, metastatic, or relapsed transitional cell urothelium cancer [Sweeny 2006]. Additional trials may be necessary to further define the role of pemetrexed in this condition.

Cervical cancer, persistent or recurrent

Data from two phase II studies support the use of pemetrexed for persistent or recurrent cervical cancer [Lorusso 2010], [Miller 2008]. Additional trials may be necessary to further define the role of pemetrexed in this condition.

Malignant pleural mesothelioma (single agent and off-label combination)

Data from two phase II studies support the use of pemetrexed in combination with carboplatin in the treatment of malignant pleural mesothelioma [Castagneto 2008], [Ceresoli 2006]. Data from an expanded access study supports the use of pemetrexed as a single agent in the management of unresectable malignant pleural mesothelioma [Taylor 2008]. Additional trials may be necessary to further define the role of pemetrexed as a single agent or plus carboplatin in the management of malignant pleural mesothelioma.

Ovarian cancer, platinum-resistant

Data from a phase II study support the use of pemetrexed in platinum-resistant epithelial ovarian or primary peritoneal cancer [Vergote 2009]. Additional trials may be necessary to further define the role of pemetrexed in this condition.

Thymic malignancies, metastatic

Data from a phase II study support the use of pemetrexed in previously treated unresectable advanced thymoma or thymic carcinoma [Loehrer 2006]. Additional trials may be necessary to further define the role of pemetrexed in this condition.

Contraindications

Severe hypersensitivity to pemetrexed or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Concomitant yellow fever vaccine

Dosing: Adult

Note: Start vitamin supplements 1 week before initial pemetrexed dose: Folic acid 400 to 1,000 mcg orally once daily (begin 7 days prior to treatment initiation; continue daily during treatment and for 21 days after last pemetrexed dose) and vitamin B12 1,000 mcg IM 7 days prior to treatment initiation and then every 3 cycles. Give dexamethasone 4 mg orally twice daily for 3 days, beginning the day before treatment to minimize cutaneous reactions. New treatment cycles should not begin unless ANC ≥1,500/mm3, platelets ≥100,000/mm3, CrCl ≥45 mL/minute, and recovery of nonhematologic toxicity to ≤ grade 2.

Malignant pleural mesothelioma: IV: 500 mg/m2 on day 1 of each 21-day cycle (in combination with cisplatin); continue until disease progression or unacceptable toxicity or (off-label) in combination with carboplatin (Castagneto 2008; Ceresoli 2006) or (off-label) as single-agent therapy (Taylor 2008)

Non-small cell lung cancer, nonsquamous: IV:

Initial treatment of locally advanced or metastatic NSCLC: 500 mg/m2 on day 1 of each 21-day cycle (in combination with cisplatin) for up to 6 cycles or until disease progression or unacceptable toxicity

Maintenance treatment of locally advanced or metastatic NSCLC (after 4 cycles of initial platinum-based therapy): 500 mg/m2 on day 1 of each 21-day cycle (as a single-agent); continue until disease progression or unacceptable toxicity

Second-line treatment of recurrent/metastatic disease (after prior chemotherapy): 500 mg/m2 on day 1 of each 21-day cycle (as a single-agent); continue until disease progression or unacceptable toxicity

Bladder cancer, metastatic (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle until disease progression or unacceptable toxicity (Sweeney 2006)

Cervical cancer, persistent or recurrent (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle until disease progression or unacceptable toxicity occurs (Lorusso 2010) or 900 mg/m2 on day 1 of each 21-day cycle (Miller 2008)

Ovarian cancer, platinum-resistant (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle (Vergote 2009)

Thymic malignancies, metastatic (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle for 6 cycles or until disease progression or unacceptable toxicity occurs (Loehrer 2006)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Renal function may be estimated using the Cockcroft-Gault formula.

CrCl ≥45 mL/minute: No dosage adjustment necessary.

CrCl <45 mL/minute: Use is not recommended by the manufacturer (an insufficient number of patients have been studied for dosage recommendations).

Renal toxicity during treatment: Withhold pemetrexed until CrCl is 45 mL/minute or higher.

According to a phase I study in advanced cancer patients with renal impairment, pemetrexed doses up to 500 mg/m2 (with vitamin supplementation) were well tolerated in patients with glomerular filtration rate (GFR) 40 to 79 mL/minute; however, accrual was halted in patients with GFR <29 mL/minute (due to toxicity) and accrual did not occur in patients with GFR 30 to 39 mL/minute. Patients with GFR ≥80 mL/minute tolerated doses of 600 mg/m2 (Mita 2006).

Concomitant ibuprofen use with renal dysfunction:

CrCl ≥80 mL/minute: No dosage adjustment necessary.

CrCl 45 to 79 mL/minute: Avoid ibuprofen for 2 days before, the day of, and for 2 days following a dose of pemetrexed. Monitor more frequently for myelosuppression, renal, and GI toxicities if concomitant ibuprofen administration cannot be avoided.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; however, pemetrexed pharmacokinetics do not appear to be affected based on elevated ALT, AST, or total bilirubin.

Dosing: Adjustment for Toxicity

Note: Concomitant combination chemotherapy agents (eg cisplatin) may also require dosage modification.

Hematologic toxicity: Upon recovery, reinitiate therapy as follows:

ANC <500/mm3 and platelets ≥50,000/mm3: Reduce pemetrexed dose to 75% of previous dose

Platelets <50,000/mm3 without bleeding: Reduce pemetrexed dose to 75% of previous dose

Platelets <50,000/mm3 with bleeding: Reduce pemetrexed dose to 50% of previous dose

Recurrent grade 3 or 4 myelosuppression after 2 dose reductions: Discontinue

Nonhematologic toxicity: Withhold treatment until recovery to ≤ grade 2; upon recovery, reinitiate or discontinue therapy as follows:

Grade 3 or 4 toxicity (excluding mucositis and neurotoxicity): Reduce pemetrexed dose to 75% of previous dose

Grade 3 or 4 diarrhea or any diarrhea requiring hospitalization: Reduce pemetrexed dose to 75% of previous dose

Grade 3 or 4 mucositis: Reduce pemetrexed dose to 50% of previous dose

Grade 3 or 4 neurotoxicity: Permanently discontinue

Interstitial pneumonitis: Permanently discontinue

Radiation recall signs/symptoms: Permanently discontinue

Severe or life-threatening dermatologic toxicity: Permanently discontinue

Recurrent grade 3 or 4 nonhematologic toxicity after 2 dose reductions: Permanently discontinue

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

Reconstitute with NS (preservative free); add 4.2 mL to the 100 mg vial and 20 mL to the 500 mg vial, resulting in a 25 mg/mL concentration. Gently swirl until powder is completely dissolved. Solution may be colorless to green-yellow. Further dilute in 100 mL NS prior to infusion (the manufacturer recommends a total volume of 100 mL).

Administration

IV: Infuse over 10 minutes. When used in combination with cisplatin, administer prior to cisplatin.

Dietary Considerations

Initiate folic acid supplementation 1 week before first dose of pemetrexed, continue for full course of therapy, and for 21 days after last pemetrexed dose. Institute vitamin B12 1 week before the first dose; administer every 9 weeks thereafter.

Storage

Store intact vials at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Reconstituted solution and solution diluted for infusion are stable for 24 hours when refrigerated at 2°C to 8°C (36°F to 46°F).

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Ibuprofen: May increase the serum concentration of PEMEtrexed. Management: In patients with an estimated creatinine clearance of 45 to 79 mL/min, avoid ibuprofen for 2 days before, the day of, and 2 days following the administration of pemetrexed. Monitor for increased pemetrexed toxicities if combined. Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy.Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Teriflunomide: May increase the serum concentration of OAT3 Substrates. Monitor therapy

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

>10%:

Central nervous system: Fatigue (18% to 34%; dose-limiting)

Dermatologic: Desquamation (≤14%), skin rash (≤14%)

Gastrointestinal: Nausea (12% to 31%), anorexia (19% to 22%), vomiting (6% to 16%), stomatitis (5% to 15%), diarrhea (5% to 13%)

Hematologic & oncologic: Anemia (15% to 19%; grades 3/4: 3% to 5%), leukopenia (6% to 12%; grades 3/4: 2% to 4%), neutropenia (6% to 11%; grades 3/4: 3% to 5%; dose-limiting; nadir: 8 to 10 days; recovery: 4 to 8 days after nadir)

Respiratory: Pharyngitis (15%)

1% to 10%:

Cardiovascular: Edema (1% to 5%)

Central nervous system: Neuropathy (sensory: ≤9%; motor: ≤5%)

Dermatologic: Pruritus (1% to 7%), alopecia (1% to 6%), erythema multiforme (≤5%)

Endocrine & metabolic: Weight loss (1%)

Gastrointestinal: Constipation (1% to 6%), abdominal pain (≤5%)

Hematologic & oncologic: Thrombocytopenia (1% to 8%; grades 3/4: 2%; dose-limiting), febrile neutropenia (grades 3/4: 2%)

Hepatic: Increased serum ALT (8% to 10%; grades 3/4: ≤2%), increased serum AST (7% to 8%; grades 3/4: ≤1%)

Hypersensitivity: Hypersensitivity reaction (≤5%)

Infection: Infection (≤5%), sepsis (1%)

Ophthalmic: Conjunctivitis (≤5%), increased lacrimation (≤5%)

Renal: Decreased creatinine clearance (≤5%), increased serum creatinine (≤5%)

Miscellaneous: Fever (1% to 8%)

<1% (Limited to important or life-threatening): Cardiac arrhythmia, chest pain, colitis, dehydration, depression, esophagitis, gastrointestinal obstruction, hemolytic anemia, hepatobiliary disease (failure), hypertension, increased gamma-glutamyl transferase, interstitial pneumonitis, pain, pancreatitis, pancytopenia, peripheral ischemia, pulmonary embolism, radiation recall phenomenon (median onset: 6 days; range: 1 to 35 days), renal failure, Stevens-Johnson syndrome, supraventricular cardiac arrhythmia, syncope, thromboembolism, toxic epidermal necrolysis, ventricular tachycardia

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Pemetrexed may cause severe myelosuppression, including anemia, neutropenia, thrombocytopenia and/or pancytopenia; frequent laboratory monitoring is necessary (myelosuppression is often dose-limiting). Severe myelosuppression may require blood transfusion. Prophylactic folic acid and vitamin B12 supplements are necessary to reduce hematologic toxicity, febrile neutropenia and infection; initiate supplementation 1 week before the first dose of pemetrexed and continue for 21 days after the last pemetrexed dose (the risk for myelosuppression is higher in patients who did not receive vitamin supplementation). Monitor blood counts at the beginning of each cycle, and as clinically indicated. Dose reductions in subsequent cycles may be required due to myelosuppression.

• Cutaneous reactions: Serious and occasionally fatal dermatologic toxicity may occur; pretreatment with dexamethasone is necessary to reduce the incidence and severity of cutaneous reactions. Rarely, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Permanently discontinue pemetrexed for severe and life-threatening bullous, blistering, or exfoliating dermatologic toxicity.

• Gastrointestinal toxicity: Gastrointestinal toxicity may occur; prophylactic folic acid and vitamin B12supplements are necessary to reduce gastrointestinal toxicity. Initiate supplementation 1 week before the first dose of pemetrexed and continue for 21 days after the last pemetrexed dose.

• Hypersensitivity: Hypersensitivity (including allergic reaction) has been reported with pemetrexed.

• Nephrotoxicity: Pemetrexed may cause severe (and potentially fatal) renal toxicity (renal toxicity may occur with single-agent pemetrexed or when used in combination with other chemotherapy agents). Measure creatinine clearance prior to each dose and monitor renal function throughout treatment. May require therapy discontinuation. Withhold pemetrexed treatment for creatinine clearance <45 mL/minute.

• Pulmonary toxicity: Interstitial pneumonitis has been observed with use; may be serious and/or fatal. Interrupt therapy and evaluate promptly for acute onset new or progressive pulmonary symptoms (eg, dyspnea, cough, or fever). If interstitial pneumonitis is confirmed, permanently discontinue pemetrexed.

• Radiation recall: Radiation recall may occur in patients administered pemetrexed who received radiation previously (weeks to years). Monitor for inflammation or blistering in areas of prior radiation treatment; permanently discontinue pemetrexed if radiation recall is confirmed.

Disease-related concerns:

• Renal impairment: Pemetrexed is primarily cleared by the kidneys; decreased renal function results in increased toxicity. The manufacturer does not recommend use if CrCl <45 mL/minute. Use caution in patients receiving concurrent nephrotoxins; may result in delayed pemetrexed clearance.

• Third space fluid: Although the effect of third space fluid on pemetrexed pharmacokinetics has not been fully defined, studies have determined pemetrexed concentrations in patients with mild-to-moderate ascites/pleural effusions were similar to concentrations in trials of patients without third space fluid accumulation.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Ibuprofen: Ibuprofen may reduce the clearance of pemetrexed. In patients with CrCl 45 to 79 mL/minute, interrupt ibuprofen therapy 2 days prior to, during, and 2 days after pemetrexed therapy. If concomitant use cannot be avoided, monitor for myelosuppression, renal, and gastrointestinal toxicity.

Monitoring Parameters

CBC with differential and platelets (before each cycle, on days 8 and 15 of each cycle, and as needed; monitor for nadir and recovery); renal function tests (serum creatinine, creatinine clearance, BUN; prior to each cycle and as needed) total bilirubin, ALT, AST (periodic); signs/symptoms of mucositis and diarrhea, pulmonary toxicity, dermatologic toxicity, and radiation recall.

Pregnancy Considerations

Adverse effects were observed in animal reproduction studies. Based on the mechanism of action, pemetrexed may cause fetal harm if administered to a pregnant woman. Women of reproductive potential should use effective contraception during treatment and for at least 6 months after the last pemetrexed dose. Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last pemetrexed dose. Pemetrexed may impair fertility in males.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience constipation, change in taste, lack of appetite, or hair loss. Have patient report immediately to prescriber signs of infection, signs of dehydration (dry skin, dry mouth, dry eyes, increased thirst, tachycardia, dizziness, fast breathing, or confusion), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), shortness of breath, severe nausea, severe vomiting, severe diarrhea, edema, bruising, bleeding, severe loss of strength and energy, difficulty swallowing, severe mouth pain or irritation, burning or numbness feeling, or pale skin (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.