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【印度多吉美药物名称】
        商品名称：印度多吉美
        通用名称：甲苯磺酸索拉非尼片
        英文名称：Sorafenib (sorafenat)
        汉语拼音：Jiabenhuangsuansuolafeini Pian

【印度多吉美成份】
        多吉美主要成份为甲苯磺酸索拉非尼。

【印度多吉美适应症】
        1、治疗不能手术的晚期肾细胞癌。
        2、治疗无法手术或远处转移的原发肝细胞癌。
        目前缺乏在晚期肝细胞癌患者中索拉非尼与介入治疗如肝动脉栓塞化疗（TACE）比较的随机对照临床研究数据，因此尚不能明确多吉美相对介入治疗的优劣，也不能明确对既往接受过介入治疗后患者使用索拉非尼是否有益（见[临床试验]项）。建议医生根据患者具体情况综合考虑，选择适宜治疗手段。

【印度多吉美用法用量】
        推荐剂量
        推荐服用索拉非尼的剂量为每次0.4g（2×0.2g）、每日两次，空腹或伴低脂、中脂饮食服用。
        服用方法
        口服，以一杯温开水吞服。
        治疗时间
        应持续治疗直至患者不能临床受益或出现不可耐受的毒性反应。
        剂量调整及特殊使用说明
        对疑似不良反应的处理包括暂停或减少索拉非尼用量，如必需，索拉非尼的用量减为每日一次，每次0.4g（2×0.2g）。
        根据皮肤毒性做相应的剂量调整：
       1级皮肤不良反应：麻痹，感觉迟钝，感觉异常，麻木感，无痛肿胀，手足红斑或不适但不影响平时活动等在任何时间出现，则建议剂量调整为继续使用多吉美，同时给予局部治疗以消除症状。
       2级皮肤不良反应：伴疼痛的手足红斑和肿胀，和/或影响平时生活的手足不适。
       首次出现时，则剂量调整为继续使用多吉美，同时给予局部治疗以消除症状。7天之内如果症状没有改善或第二、第三次出现时，中断多吉美治疗直到毒性缓解至0-1级。当重新开始多吉美治疗时，减少至单剂量（每日0.4g或隔日0.4g）。当第四次出现，则应终止多吉美治疗。
      3级皮肤不良反应：润性脱屑，溃疡，手足起疱、疼痛或导致患者不能工作和正常生活的严重的手足不适。
      当第一次或第二次出现时，应中断多吉美治疗直到毒性缓解至0-1级。当重新开始多吉美治疗时，减少至单剂量（每日0.4g或隔日0.4g）。当第三次出现时，则应终止多吉美治疗。
       特殊人群
       儿童患者
       尚无儿童患者应用索拉非尼的安全性及有效性资料。
       老年人（65岁以上）：性别和体重
       不需根据患者的年龄（65岁以上）、性别或体重调整剂量。
       肝损害患者
       轻度到中度肝损害患者（Child-Pugh A和B）无需调整剂量。尚未进行重度肝损害患者（Child-Pugh C）应用索拉非尼的研究。
       肾损害患者
       轻度、中度或不需要透析的重度肾功能损害的患者无需调整剂量。尚未进行透析患者应用索拉非尼的研究。

【印度多吉美不良反应】
        欧美关键性的支持多吉美上市的临床研究的安全性数据：
        来自于索拉非尼作为单一药物治疗的1286位患者（以白种人为主，包括少数非裔、亚裔、西班牙人及其他人种）。最常见的药物相关不良事件有腹泻，皮疹，脱发和手足综合征。
        实验室检查异常
        服 用索拉非尼后通常会出现脂肪酶和淀粉酶升高。研究中，索拉非尼组12%患者为CTCAE3或4级脂肪酶升高，安慰剂组患者为7%。索拉非尼组1%患者出现 CTCAE3或4级淀粉酶升高，安慰剂组患者为3%。451例服用索拉非尼的患者2例发生胰腺炎（CTCAE4级），而安慰剂组451例患者中为1例发生 （CTCAE2级）。
        亚洲人安全性数据结果：
        试验11515是在日本进行的一项非随机、非对照、开放索拉非尼治疗晚期肾癌的Ⅱ期临床研究，与欧美关键性的临床研究相比较，试验中报告的与药物相关的不良事件是相似的，最常见的有：脂肪酶升高，手足综合征，脱发，淀粉酶升高，皮疹/脱屑和腹泻。
        试 验11559是一项在亚洲进行的索拉非尼治疗晚期肾癌的多中心、非随机的Ⅲ期临床研究，包括中国大陆和台湾，该研究正在进行中。目前在所有的至少接受过一 次索拉非尼治疗的29名患者中，21名患者（72.4%）发生了与药物相关的不良事件，常见的为手足综合征（27.6%），皮疹（20.7%），高血压 （6.9%），腹泻（6.9%），疲劳（6.9%）等。在试验中索拉非尼体现了良好的安全性，发生的不良事件大多轻微，且可以耐受。

【印度多吉美注意事项】
        尚缺乏充分的中国人群临床研究数据，因此须在有多吉美使用经验的医生指导下使用。
        皮肤毒性：手足皮肤反应和皮疹是服用索拉非尼最常见的不良反应。皮疹和手足皮肤反应通常多为NCI CTC（国际肿瘤通用毒性标准）1到2级，且多于开始服用索拉非尼后的6周内出现。对皮肤毒性反应的处理包括局部用药以减轻症状，暂时性停药或/和对索拉非尼进行剂量调整。对于皮肤毒性严重且反应持久的患者可能需要永久停用索拉非尼。严重者应永久停药。
        高 血压：服用索拉非尼的患者高血压的发病率会增加。药物相关的高血压多为轻到中度，多在开始服药后的早期阶段就出现，用常规的降压药物即可控制。应常规监控 血压，如有需要则按照标准治疗方案进行治疗。对应用降压药物后仍严重或持续的高血压或出现高血压危象的患者需考虑永久停用索拉非尼。
        出血：服用索拉非尼治疗后可能增加出血的机会。严重出血病不常见。一旦出现需治疗，建议考虑永久停用索拉非尼。
华法林：部分同时服用索拉非尼和华法林治疗的患者偶发出血或凝血时间国际标准化比值（INR）升高。对合用华法林的患者应常规检测凝血酶原时间、INR值并注意临床出血迹象。
        伤口愈合并发症：服用索拉非尼对伤口愈合的影响未进行专门的研究。需要做大手术的患者建议暂停索拉非尼，手术后患者何时再应用索拉非尼的临床经验有限，因此决定患者再次服用前应先从临床考虑，确保伤口愈合。
        心 肌缺血和/或心肌梗死：在试验11213中，治疗相关的心肌缺血/心肌梗死在索拉非尼组的发生率（2.9%）高于安慰剂组（0.4%）。不稳定的冠心病患 者和近期的心肌梗死患者没有入组该试验。对于发生心肌缺血和/或心肌梗死的患者应该考虑暂时或长期终止索拉非尼的治疗。
        胃肠道穿孔：胃肠道穿孔较为少见。在使用索拉非尼的患者中报告出现胃肠道穿孔的不足1%。在一些病例中，胃肠道穿孔未伴随显在腹腔内肿瘤出现，应停止多吉美治疗（见[不良反应]）。
        肝损：没有肝损害Child Pugh C级的患者的研究资料。由于索拉非尼主要是经肝脏消除，其在肝功能严重受损的患者中暴露量会升高。
        药物-药物相互作用：
        UGT1A1途径：建议索拉非尼和通过UGT1A1途径代谢的药物（如伊立替康）联用时应予注意（见[药物相互作用]）。
多烯紫杉醇：多烯紫杉醇（75mg/m2或100mg/m2）与多吉美联用（0.2g或0.4g每日两次给药），多吉美和多烯紫杉醇之间有三天的用药间隔，多烯紫杉醇的AUC增加36～80%。多吉美与多烯紫杉醇联用时，建议保持谨慎（见[药物相互作用]）。
对驾驶和机器操作的影响：目前尚无索拉非尼对驾驶和机器操作的影响的研究。

【印度多吉美孕妇及哺乳期妇女用药】
        妊娠
        尚无怀孕期妇女服用索拉非尼的足够临床资料。动物实验表明药物存在生殖毒性包括致畸性。索拉非尼和其代谢产物可通过大鼠的胎盘屏障，推测索拉非尼可抑制胎儿的血管生成。
        育龄妇女在治疗期间应注意避孕。如在孕期应用索拉非尼，应告知患者药物对胎儿可能产生的危害，包括严重畸形，发育障碍和胎儿死亡（胚胎毒性）。
        孕期避免应用索拉非尼。只有在治疗收益超过对胎儿产生的可能危害时，才应用于妊娠妇女。
        基于已知的索拉非尼多激酶抑制机理和动物研究结果：当在动物中的暴露量显著低于临床剂量时发生多种不良反应，从而推测孕妇服用索拉非尼会危害胎儿。
        育龄妇女
        动物试验表明索拉非尼具有致畸性和胚胎毒性。治疗期间和治疗结束至少2周内应采用足够的避孕措施。
        哺乳
        目前尚未知索拉非尼是否可进入人类乳汁。动物试验表明索拉非尼和/或其代谢产物可进入到乳汁中。由于很多药物从乳汁中分泌，并且索拉非尼对婴儿的作用尚未研究，因此妇女在该药治疗期间应停止哺乳。
        生殖能力
        动物试验结果表明索拉非尼可损害男性和女性的生殖能力。

【印度多吉美儿童用药】
        尚无儿童患者应用索拉非尼的安全性有效性资料。

【印度多吉美老年用药】
        不需根据患者的年龄（65岁以上）调整剂量。

【印度多吉美药物相互作用】
        CYP3A4诱导剂：尚无CYP3A4诱导剂影响索拉非尼药物代谢的临床资料。CYP3A4诱导剂（如利福平、贯叶连翘（或贯叶金丝桃，俗称圣约翰草）、苯妥英、卡马西平、苯巴比妥和地塞米松）可能加快索拉非尼的代谢，因此降低索拉非尼的药物浓度。
        CYP3A4抑制剂：酮康唑是CYP3A4的强抑制剂，健康男性志愿者使用酮康唑每日一次连续7天，并合用索拉非尼单剂量50mg，索拉非尼的平均血药浓度并未改变。所以索拉非尼和CYP3A4抑制剂之间不太可能存在药物代谢的相互作用。
        CYP2C9底物：华法林是CYP2C9的底物，通过比较服用索拉非尼和安慰剂的患者来评估索拉非尼对华法林代谢的影响。与安慰剂组相比索拉非尼合用华法林的患者的平均PT-INR值并未改变。但患者合用华法林时应定期监测INR值。
        CYP异构体选择性底物：对于浙西哦细胞色素P450同工酶，索拉非尼既不是抑制剂也不是诱导物。
        和 其他抗肿瘤药物的相互作用：临床试验中，索拉非尼和其他常规剂量的抗肿瘤药物进行了联用，包括吉西他滨，奥沙利铂，阿霉素和伊立替康。索拉非尼不影响吉西 他滨和奥沙利铂的药物代谢。紫杉醇（225mg/m2）及卡铂（AUC=6）伴随多吉美（每日两次，每次0.1g，0.2g或0.4g）使用时，在使用紫 杉醇/卡铂前后，停用3天多吉美，对紫杉醇或卡铂的药代动力学不会造成显著影响。
        索拉非尼和阿霉素联用时可引起肝癌患者体内阿霉素的平均AUC值 增加21%。索拉非尼和伊立替康合用时，伊立替康活性代谢产物SN-38（通过UGTIAI酶代谢）的AUC升高67%-120%，伊立替康的AUC值升 高26%-42%。与此相关的临床意义尚未知（见[注意事项]）。
        多烯紫杉醇（75mg/m2或100mg/m2，每21天的治疗周期中，从第2 天到第19天，0.2g或0.4g每日两次给药），多吉美和多烯紫杉醇之间有三天的用药间隔，多烯紫杉醇的AUC增加36-80%，Cmax提高 16-32%。多吉美与多烯紫杉醇联用时，建议保持谨慎（见[注意事项]）。

【印度多吉美药物过量】
        尚无索拉非尼服用过量的特殊治疗措施。
        索拉非尼的最高剂量为0.8g每日两次，在此剂量下所观察到的主要不良反应为腹泻和皮肤毒副反应。
        如怀疑服用过量，则应停药并对患者进行密切观察和相应的支持治疗。

【印度多吉美药理毒理】
        药理作用
        索拉非尼是多种激酶抑制剂，在体外可以只肿瘤细胞增殖。
        索拉非尼抑制肿瘤细胞增殖，包括小鼠肾细胞癌、RENCA模型和无胸腺小鼠移植多种人肿瘤模型，并抑制肿瘤血管生成。
        毒理研究
        致癌性、致突变性，生育力损害
        通过小鼠、大鼠、犬和兔评价了索拉非尼的临床前安全性。重复剂量毒性试验显示不同器##官轻度至中度的改变（退化和再生）。
        幼 年和发育期犬多次给药后可观察到对骨和牙齿的影响，包括索拉非尼剂量达600mg/m2体表面积时（相当于临床推荐剂量500mg/m2/体表面积时的 1.2倍）股骨骺板不规则增厚，此生长板附近骨髓细胞减少（200mg/m2/天）和牙质成分的改变（600mg/m2/天）。在成年犬未发现类似情况。
        以 哺乳动物细胞（中国仓鼠卵巢）进行了体外染色体畸变试验，索拉非尼在代谢激活时具遗传毒性。生产过程中某一中间体的体外细胞遗传学试验（Ames试验）结 果为阳性，药物中其限度控制在0.15%以下。Ames试验和小鼠体内微核试验表明索拉非尼不具有遗传毒性（受试药物中此中间体含量为0.34%）。
        未进行索拉非尼的致癌性试验。
        未进行特异性动物生育力试验。重复用药毒性试验观察到动物的生殖器##官改变，因此可预见药物对雄性和雌性生育力的损害。
        大鼠、兔应用索拉非尼出现胚胎毒性、致畸性，包括母体和胎儿的体重减轻，流产机率增加，外表和内脏畸形增多。大鼠和兔口服剂量分别为6mg/m2/天、36mg/m2/天时观察到对胎儿的不良后果。

【印度多吉美药代动力学】
        尚缺乏中国人群的药代研究数据，以下均为来自外国人体药代动力学研究数据。
        与口服溶液相比，服用索拉非尼片剂平均相对生物利用度为38-49%。
        索拉非尼的清除半衰期约为25-48小时。与单剂量给药相比，重复给药7天可达到2.5-7倍的蓄积。
        给药7天后，索拉非尼血药浓度达到稳态，平均给药浓度峰谷比小于2。
        吸收分布
        索拉非尼口服后约3小时达到最高血药浓度。中度脂肪饮食与禁食状态下的生物利用度相似。高脂当口服剂量超过0.4g每日二次时，平均Cmax和AUC的升高不成线性关系。
        在体外，索拉非尼与人血浆蛋白结合率为99.5%。
        代谢和清除
        索拉非尼主要在肝脏内通过CYP3A4介导的氧化作用代谢，除此以外，还有UGT1A9介导的糖苷酸代谢。
        酶抑制性体外试验
        人肝微粒体试验表明索拉非尼竞争性地抑制CYP2C19，CYP2D6和CYP3A4。索拉非尼可升高某些药物（这些酶的底物）的血药浓度。
        索拉非尼通过UGT1A1和UGT1A9通路抑制糖苷酸代谢。当这些药物和索拉非尼合用时，可能会增加UGT1A1和UGT1A9的代谢底物的暴露浓度。
        体外试验显示索拉非尼一直CYP2B6和CYP2C8，Ki值分别是6和1-2?M。当和索拉非尼同时用药时，CYP2B6和CYP2C8的全身暴露量升高。
        CYP2C9底物
        人 肝微粒体试验表明索拉非尼竞争性地抑制CYP2C9，其Ki值为7-8?M。通过患者（索拉非尼组和安慰剂组）合用华法林来评价索拉非尼对CYP2C9底 物的潜在作用，索拉非尼组患者的PT-INR相对于基线的平均变化并不高于安慰剂组。该结果表明索拉非尼并非CYP2C9的体内抑制剂。

        特殊人群的药代动力学
        老年人（65岁以上）、性别
        人口数据资料显示不需根据患者的年龄或性别调整剂量。
        儿童患者
        尚无儿童患者的药代动力学数据。
        肝损害患者
        索拉非尼主要由肝脏清除。
        轻度（Child-Pugh A,N=14）到中度（Child-Pugh B,N=8）肝损害患者的药物暴露与无肝功能损害患者的暴露范围一致。暴露量位于无肝损害患者的变化范围内。重度肝损害患者（Child-Pugh C）应用索拉非尼的药代动力学研究尚未进行。
        肾损害患者
        对 于正常肾功能（N=71）、轻度肾功能损害（CrCl＞50-80ml/min,N=24）或中度肾功能能损害（CrCl30-50ml /min,N=4），未观察到索拉非尼（0.4g每日二次）稳态AUC和肾功能之间的关系。重度肾功能损害（CrCl＜30ml/min）或进行透析的患 者应用索拉非尼药代动力学研究尚未进行。
        人种
        一个在日本人中进行的小样本的药代动力学试验（N=6）中，受试者接受索拉非尼0.4g每日 二次给药，将该试验中有限的数据与高加索人Ⅰ期药代动力学试验综合结果相比（N=25），索拉非尼在日本人中的系统暴露量较低。鉴于索拉非尼的药代动力学 参数在日本患者间存在中度至高度个体差异，该发现的临床意义尚不明确。

【印度多吉美贮藏】
        低于25℃密封保存。请将药物放置在儿童触及不到的地方。

【印度多吉美规格】
        0.2g

【印度多吉美包装】
        120片/盒，铝铝包装。

【印度多吉美有效期】
        30个月

12

 

 

 

 

 

SORAfenib

Medically reviewed on Sep 10, 2018

 

 

 

Dosage Forms

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

Tablet, Oral:

NexAVAR: 200 mg

 

 

Brand Names: U.S.

· NexAVAR

 

 

Pharmacologic Category

· Antineoplastic Agent, Tyrosine Kinase Inhibitor

· Antineoplastic Agent, Vascular Endothelial Growth Factor (VEGF) Inhibitor

Pharmacology

Multikinase inhibitor; inhibits tumor growth and angiogenesis by inhibiting intracellular Raf kinases (CRAF, BRAF, and mutant BRAF), and cell surface kinase receptors (VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-beta, cKIT, FLT-3, RET, and RET/PTC)

 

 

 

Metabolism

Hepatic, via CYP3A4 (primarily oxidated to the pyridine N-oxide; active, minor) and UGT1A9 (glucuronidation)

Excretion

Feces (77%, 51% of dose as unchanged drug); urine (19%, as metabolites)

Time to Peak

~3 hours

Half-Life Elimination

25 to 48 hours

Protein Binding

99.5%

Special Populations: Race

Mean AUC in Asians is 30% lower than in white patients.

Use: Labeled Indications

Hepatocellular cancer: Treatment of unresectable hepatocellular cancer (HCC)

Renal cell cancer, advanced: Treatment of advanced renal cell cancer (RCC)

Thyroid cancer, differentiated: Treatment of locally recurrent or metastatic, progressive, differentiated thyroid cancer (refractory to radioactive iodine treatment)

Off Label UsesAngiosarcoma, recurrent or metastatic

Data from a phase II sarcoma study which included patients with angiosarcoma supports the use of sorafenib in the treatment of angiosarcoma [Maki 2009]. Additional trials may be necessary to further define the role of sorafenib in this condition.

Gastrointestinal stromal tumor, resistant

Data from a small phase II study in patients resistant to imatinib and sunitinib supports the use of sorafenib in the treatment of resistant gastrointestinal stromal tumor (GIST) [Wiebe 2008]. Additional trials may be necessary to further define the role of sorafenib in this condition.

Contraindications

Known severe hypersensitivity to sorafenib or any component of the formulation; use in combination with carboplatin and paclitaxel in patients with squamous cell lung cancer

Dosing: Adult

Note: Interrupt treatment (temporarily) in patients undergoing major surgical procedures.

Hepatocellular cancer (HCC): Oral: 400 mg twice daily; continue until no longer clinically benefiting or until unacceptable toxicity occurs (Llovet 2008)

Renal cell cancer (RCC), advanced: Oral: 400 mg twice daily; continue until no longer clinically benefiting or until unacceptable toxicity occurs (Escudier 2007; Escudier 2009)

Thyroid cancer, differentiated: Oral: 400 mg twice daily; continue until no longer clinically benefiting or until unacceptable toxicity occurs (Brose 2013)

Angiosarcoma (off-label use): Oral: 400 mg twice daily (Maki 2009)

Gastrointestinal stromal tumor (GIST) (off-label use): Oral: 400 mg twice daily (Wiebe 2008)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Manufacturer’s labeling: No dosage adjustment is necessary for mild, moderate, or severe impairment (not dependent on dialysis); has not been studied in dialysis patients.

A pharmacokinetic study evaluated sorafenib dosing to determine an initial tolerable dose in patients with varying degrees of renal dysfunction. The following empiric starting doses were identified based on patient tolerance (Miller 2009):

CrCl 40 to 59 mL/minute: 400 mg twice daily

CrCl 20 to 39 mL/minute: 200 mg twice daily

CrCl <20 mL/minute: Data inadequate to define dose

Hemodialysis (any CrCl): 200 mg once daily

Dosing: Hepatic Impairment

Hepatic impairment at baseline:

Manufacturer's labeling:

Mild to moderate (Child-Pugh class A and B) impairment: No dosage adjustment is necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

A pharmacokinetic study evaluated sorafenib dosing to determine an initial tolerable dose in patients with varying degrees of hepatic dysfunction. The following empiric starting doses were identified based on patient tolerance (Miller 2009):

Mild hepatic dysfunction (bilirubin >1 to ≤1.5 times ULN and/or AST >ULN): 400 mg twice daily

Moderate hepatic dysfunction (bilirubin >1.5 to ≤3 times ULN; any AST): 200 mg twice daily

Severe hepatic dysfunction:

Albumin <2.5 g/dL (any bilirubin and any AST): 200 mg once daily

Bilirubin >3 to 10 x ULN (any AST): A dose of 200 mg every 3 days was not tolerated, therefore no dosage was identified in this pharmacokinetic study for patients meeting these parameters.

Drug-induced liver injury during treatment: Unexplained (eg, not due to viral hepatitis or progressive underlying malignancy) significantly increased transaminases: Discontinue treatment.

Dosing: Adjustment for Toxicity

Temporary interruption and/or dosage reduction may be necessary for management of adverse drug reactions.

Cardiovascular toxicity:

Cardiac ischemia or infarction: Consider temporary interruption or permanent discontinuation.

Hypertension, severe or persistent (despite antihypertensive therapy): Consider temporary interruption or permanent discontinuation.

QT prolongation (QTc interval >500 msec or ≥60 msec increase from baseline): Interrupt treatment.

Gastrointestinal perforation: Permanently discontinue.

Hemorrhage requiring medical intervention: Consider permanent discontinuation.

Dermatologic toxicity: If Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, discontinue therapy.

US labeling:

RCC and HCC: If dosage reductions are necessary, decrease dose to 400 mg once daily. If further reductions are needed, decrease dose to 400 mg every other day.

Grade 1 (numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema, or discomfort of the hands or feet which do not disrupt normal activities): Continue sorafenib and consider symptomatic treatment with topical therapy.

Grade 2 (painful erythema and swelling of the hands or feet and/or discomfort affecting normal activities):

First occurrence: Continue sorafenib and consider symptomatic treatment with topical therapy. Note: If no improvement within 7 days, see dosing for second or third occurrence.

Second or third occurrence (or no improvement after 7 days of 1st occurrence): Hold treatment until resolves to grade 0-1; resume treatment with dose reduced by one dose level (400 mg daily or 400 mg every other day).

Fourth occurrence: Discontinue treatment.

Grade 3 (moist desquamation, ulceration, blistering, or severe pain of the hands or feet or severe discomfort that prevents working or performing daily activities):

First or second occurrence: Hold treatment until resolves to grade 0-1; resume treatment with dose reduced by one dose level (400 mg daily or 400 mg every other day).

Third occurrence: Discontinue treatment.

Thyroid cancer:

First dose level reduction: Reduce to 600 mg daily (in 2 divided doses, as 400 mg and 200 mg, separated by 12 hours).

Second dose level reduction: Reduce dose to 200 mg twice daily.

Third dose level reduction: Reduce dose to 200 mg once daily.

Grade 1 (numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema, or discomfort of the hands or feet which do not disrupt normal activities): Continue sorafenib treatment.

Grade 2 (painful erythema and swelling of the hands or feet and/or discomfort affecting normal activities):

First occurrence: Decrease dose to 600 mg daily (in divided doses). Note: If no improvement within 7 days, see dosing for second occurrence.

Second occurrence (or no improvement after 7 days of the reduced dose after 1st occurrence): Hold treatment until resolved or improved to grade 1; if resumed, decrease the dose by 1 dose level.

Third occurrence: Hold treatment until resolved or improved to grade 1; if resumed, decrease the dose by 1 dose level.

Fourth occurrence: Permanently discontinue.

Grade 3 (moist desquamation, ulceration, blistering, or severe pain of the hands or feet or severe discomfort that prevents working or performing daily activities):

First occurrence: Hold treatment until resolved or improved to grade 1; if resumed, decrease by 1 dose level.

Second occurrence: Hold treatment until resolved or improved to grade 1; if resumed, decrease by 2 dose levels.

Third occurrence: Permanently discontinue.

Following improvement of grade 2 or 3 dermatologic toxicity to grade 0 or 1 after at least 28 days of a reduced dose, the sorafenib dose may be increased 1 dose level from the reduced dose (~50% of patients requiring dose reduction for dermatologic toxicity may meet the criteria for increased dosing; and half of those patients may tolerate the increased dose without recurrent grade 2 or higher dermatologic toxicity).

Canadian labeling: RCC and HCC:

Grade 1 (any occurrence): Initiate supportive treatment immediately and continue sorafenib.

Grade 2:

First occurrence: Initiate supportive treatment immediately and consider a dose reduction to 400 mg daily for 28 days. If toxicity resolves to ≤grade 1 after 28 days with dose reduction, increase dose to 400 mg twice daily. If toxicity does not resolve to ≤ grade 1 despite dose reduction, withhold treatment for a minimum of 7 days until toxicity resolves to ≤ grade 1, then resume treatment at reduced dose of 400 mg daily for 28 days. If toxicity remains ≤ grade 1 at the reduced dose for 28 days, increase dose to 400 mg twice daily.

Second or third occurrence: Follow procedure for first occurrence; however, when resuming treatment, decrease dose to 400 mg daily (indefinitely).

Fourth occurrence: Treatment discontinuation should be considered based on clinical assessment and patient preference.

Grade 3:

First occurrence: Initiate supportive measures immediately and withhold treatment for a minimum of 7 days and until toxicity ≤ grade 1. Resume at reduced dose of 400 mg daily for 28 days. If toxicity remains ≤ grade 1 at the reduced dose for 28 days, increase dose to 400 mg twice daily.

Second occurrence: Follow procedure for first occurrence; however, when resuming treatment, decrease dose to 400 mg daily (indefinitely).

Third occurrence: Treatment discontinuation should be considered based on clinical assessment and patient preference.

Extemporaneously Prepared

An oral suspension may be prepared with tablets. Place two 200 mg tablets into a glass containing 60 mL (2 oz) water; let stand 5 minutes before stirring. Stir until tablets are completely disintegrated, forming a uniform suspension. Administer within 1 hour after preparation. Stir suspension again immediately before administration. To ensure the full dose is administered, rinse glass several times with a total of 180 mL (6 oz) water and administer residue. Note: Brown tablet coating may initially form a thin film but has no effect on the dosing accuracy.

Nexavar data on file, Bayer Healthcare Pharmaceuticals.

Administration

Administer on an empty stomach (1 hour before or 2 hours after eating).

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from moisture.

Drug Interactions

Acetaminophen: May enhance the hepatotoxic effect of SORAfenib. SORAfenib may increase the serum concentration of Acetaminophen. Consider therapy modification

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

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

Bevacizumab: May enhance the adverse/toxic effect of SORAfenib. Specifically, the risk for hand-foot skin reaction may be increased. Monitor therapy

Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

CARBOplatin: SORAfenib may enhance the adverse/toxic effect of CARBOplatin. Management: Concurrent sorafenib with carboplatin and paclitaxel in patients with squamous cell lung cancer is contraindicated. Use in other settings is not specifically contraindicated but should be approached with added caution.Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents.Monitor therapy

Cholic Acid: BSEP/ABCB11 Inhibitors may decrease the excretion of Cholic Acid. 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

CYP3A4 Inducers (Strong): May decrease the serum concentration of SORAfenib. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of SORAfenib. Monitor therapy

Dacarbazine: SORAfenib may decrease the serum concentration of Dacarbazine. Sorafenib may also increase the concentration of dacarbazine's active metabolite. 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

DOCEtaxel: SORAfenib may increase the serum concentration of DOCEtaxel. Monitor therapy

DOXOrubicin (Conventional): SORAfenib may increase the serum concentration of DOXOrubicin (Conventional). Monitor therapy

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

GlyBURIDE: SORAfenib may enhance the hypoglycemic effect of GlyBURIDE. Monitor therapy

Irinotecan Products: SORAfenib may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. SORAfenib may increase the serum concentration of Irinotecan Products. Monitor therapy

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

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

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

Neomycin: May decrease the serum concentration of SORAfenib. Monitor therapy

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

Obeticholic Acid: BSEP/ABCB11 Inhibitors may increase serum concentrations of the active metabolite(s) of Obeticholic Acid. Management: Avoid concomitant use of obeticholic acid and bile salt efflux pump (BSEP) inhibitors if possible. If concomitant therapy is necessary, monitor patients for elevated liver transaminases and elevated bilirubin. Consider therapy modification

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

PACLitaxel (Conventional): SORAfenib may enhance the adverse/toxic effect of PACLitaxel (Conventional). Management: Concurrent sorafenib with carboplatin and paclitaxel in patients with squamous cell lung cancer is contraindicated. Use in other settings is not specifically contraindicated but should be approached with added caution. Avoid combination

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

Propacetamol: SORAfenib may enhance the hepatotoxic effect of Propacetamol. SORAfenib may increase serum concentrations of the active metabolite(s) of Propacetamol. Specifically, acetaminophen exposure may be increased. Management: Consider less frequent and/or lower daily doses of propacetamol in patients who are also taking sorafenib. Monitor for liver toxicity, particularly with higher propacetamol doses. Consider therapy modification

QTc-Prolonging Agents (Highest Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

QTc-Prolonging Agents (Moderate Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). 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

St John's Wort: May decrease the serum concentration of SORAfenib. Avoid combination

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

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

Warfarin: SORAfenib may enhance the anticoagulant effect of Warfarin. SORAfenib may increase the serum concentration of Warfarin. Management: Warfarin dose adjustment will likely be necessary. Increase frequency of INR monitoring during sorafenib therapy (particularly when starting or stopping therapy), and increase monitoring for signs and symptoms of bleeding. Consider therapy modification

Adverse Reactions

>10%:

Cardiovascular: Hypertension (9% to 41%; grade 3: 3% to 4%; grade 4: <1%; grades 3/4: 10%, onset: ~3 weeks)

Central nervous system: Fatigue (37% to 46%), headache (≤10% to 17%), mouth pain (14%), voice disorder (13%), peripheral sensory neuropathy (≤13%), pain (11%)

Dermatologic: Palmar-plantar erythrodysesthesia (21% to 69%; grade 3: 6% to 8%; grades 3/4: 19%), alopecia (14% to 67%), skin rash (including desquamation; 19% to 40%; grade 3: ≤1%; grades 3/4: 5%), pruritus (14% to 20%), xeroderma (10% to 13%), erythema (≥10%)

Endocrine & metabolic: Hypoalbuminemia (≤59%), weight loss (10% to 49%), hypophosphatemia (35% to 45%; grade 3: 11% to 13%; grade 4: <1%), increased thyroid stimulating hormone level (>0.5 mU/L: 41%; due to impairment of exogenous thyroid suppression), hypocalcemia (12% to 36%), increased amylase (30% to 34% [usually transient])

Gastrointestinal: Diarrhea (43% to 68%; grade 3: 2% to 10%; grade 4: <1%), increased serum lipase (40% to 41% [usually transient]), abdominal pain (11% to 31%), decreased appetite (30%), anorexia (16% to 29%), stomatitis (24%), nausea (21% to 24%), constipation (14% to 16%), vomiting (11% to 16%)

Hematologic & oncologic: Lymphocytopenia (23% to 47%; grades 3/4: ≤13%), thrombocytopenia (12% to 46%; grades 3/4: 1% to 4%), increased INR (≤42%), neutropenia (≤18%; grades 3/4: ≤5%), hemorrhage (15% to 17%; grade 3: 2%), leukopenia

Hepatic: Increased serum ALT (59%; grades 3/4: 4%), increased serum AST (54%; grades 3/4: 2%), hepatic insufficiency (≤11%; grade 3: 2%; grade 4: 1%)

Infection: Infection

Neuromuscular & skeletal: Limb pain (15%), weakness (12%), myalgia

Respiratory: Dyspnea (≤14%), cough (≤13%)

Miscellaneous: Fever (11%)

1% to 10%:

Cardiovascular: Ischemic heart disease (including myocardial infarction; ≤3%), cardiac failure (2%, congestive), flushing

Central nervous system: Depression, glossalgia

Dermatologic: Hyperkeratosis (7%), acne vulgaris, exfoliative dermatitis, folliculitis

Endocrine & metabolic: Hypokalemia (5% to 10%), hyponatremia, hypothyroidism

Gastrointestinal: Dysgeusia (6%), dyspepsia, dysphagia, gastroesophageal reflux disease, mucositis, xerostomia

Genitourinary: Erectile dysfunction, proteinuria

Hematologic & oncologic: Squamous cell carcinoma of skin (3%; grades 3/4: 3%), anemia

Hepatic: Increased serum transaminases (transient)

Neuromuscular & skeletal: Muscle spasm (10%), arthralgia (≤10%), myalgia

Renal: Renal failure

Respiratory: Epistaxis (7%), flu-like symptoms, hoarseness, rhinorrhea

<1%, postmarketing, and/or case reports: Acute renal failure, anaphylaxis, angioedema, aortic dissection, amyotrophy, cardiac arrhythmia, cardiac failure, cerebral hemorrhage, cholangitis, cholecystitis, dehydration, eczema, erythema multiforme, gastritis, gastrointestinal hemorrhage, gastrointestinal perforation, gynecomastia, hepatic failure, hepatitis, hypersensitivity reaction (skin reaction, urticaria), hypertensive crisis, hyperthyroidism, increased serum alkaline phosphatase, increased serum bilirubin, interstitial pulmonary disease (acute respiratory distress, interstitial pneumonia, lung inflammation, pneumonitis, pulmonitis, radiation pneumonitis), jaundice, malignant neoplasm of skin (keratoacanthomas), nephrotic syndrome, ostealgia, osteonecrosis of the jaw, pancreatitis, pleural effusion, prolonged QT interval on ECG, respiratory tract hemorrhage, reversible posterior leukoencephalopathy syndrome, rhabdomyolysis, Stevens-Johnson syndrome, thromboembolism, tinnitus, toxic epidermal necrolysis, transient ischemic attacks, tumor lysis syndrome, tumor pain

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: Increased risk of bleeding may occur; consider permanently discontinuing with serious bleeding events (eg, requires medical intervention). Fatal bleeding events have been reported. Thyroid cancer patients with tracheal, bronchial, and esophageal infiltration should be treated with local therapy prior to administering sorafenib due to the potential bleeding risk.

• Cardiac ischemia/infarction: May cause cardiac ischemia or infarction; consider discontinuation (temporary or permanent) in patients who develop these conditions. Use in patients with unstable coronary artery disease or recent myocardial infarction has not been studied.

• Dermatologic toxicity: Hand-foot skin reaction and rash (generally grades 1 or 2) are the most common drug-related adverse events, and typically appear within the first 6 weeks of treatment; usually managed with topical treatment, treatment delays, and/or dose reductions. Consider permanently discontinuing with severe or persistent dermatological toxicities. The risk for hand-foot skin reaction increased with cumulative doses of sorafenib (Azad 2009). Severe dermatologic toxicities, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported; may be life-threatening. Discontinue sorafenib for suspected SJS or TEN.

The following treatments may be used to manage hand-foot skin reaction in addition to the recommended dosage modifications (Lacouture 2008): Prior to treatment initiation, a pedicure is recommended to remove hyperkeratotic areas/calluses, which may predispose to HFSR; avoid vigorous exercise/activities which may stress hands or feet. During therapy, patients should reduce exposure to hot water (may exacerbate hand-foot symptoms); avoid constrictive footwear and excessive skin friction. Patients may also wear thick cotton gloves or socks and should wear shoes with padded insoles. Grade 1 HFSR may be relieved with moisturizing creams, cotton gloves and socks (at night) and/or keratolytic creams such as urea (20% to 40%) or salicylic acid (6%). Apply topical steroid (eg, clobetasol ointment) twice daily to erythematous areas of grade 2 HFSR; topical anesthetics (eg, lidocaine 2%) and then systemic analgesics (if appropriate) may be used for pain control. Resolution of acute erythema may result in keratotic areas which may be softened with keratolytic agents.

• Gastrointestinal perforation: Gastrointestinal perforation has been reported (rare); monitor patients for signs/symptoms (abdominal pain, constipation, or vomiting); discontinue treatment if gastrointestinal perforation occurs.

• Hypertension: May cause hypertension (generally mild-to-moderate), especially in the first 6 weeks of treatment; monitor. Use caution in patients with underlying or poorly-controlled hypertension. Consider discontinuing (temporary or permanent) in patients who develop severe or persistent hypertension while on appropriate antihypertensive therapy.

• QT prolongation: QT prolongation has been observed; may increase the risk for ventricular arrhythmia. Avoid use in patients with congenital long QT syndrome. Monitor electrolytes and ECG in patients with heart failure, bradyarrhythmias, and concurrent medications know to prolong the QT interval. Correct electrolyte (calcium, magnesium, potassium) imbalances. Interrupt treatment for QTc interval >500 msec or for ≥60 msec increase from baseline.

• Thyroid impairment: Sorafenib impairs exogenous thyroid suppression. TSH level elevations were commonly observed in the thyroid cancer study; monitor TSH levels monthly and as clinically necessary, and adjust thyroid replacement as needed.

• Wound healing complications: May complicate wound healing; temporarily withhold treatment for patients undergoing major surgical procedures. The appropriate timing to resume sorafenib after major surgery has not been determined.

Disease-related concerns:

• Heart failure: In a scientific statement from the American Heart Association, sorafenib has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: minor) (AHA [Page 2016]).

• Hepatic impairment: Sorafenib levels in patients with mild-to-moderate hepatic impairment (Child-Pugh classes A and B) were similar to levels observed in patients without hepatic impairment. Not studied in patients with severe hepatic impairment (Child-Pugh class C). In a small study of Asian patients with advanced HCC, sorafenib demonstrated efficacy with adequate tolerability in a hepatitis B-endemic area (Yau 2009). There have been reports of sorafenib-induced hepatitis (including hepatic failure and death) which is characterized by hepatocellular liver damage and transaminase increases (significant); increased bilirubin and INR may also occur. Monitor hepatic function regularly; discontinue sorafenib for unexplained significant transaminase increases.

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. Avoid concurrent use with strong CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St John’s wort); may decrease sorafenib levels/effects. Use caution when administering sorafenib with compounds that are metabolized predominantly via UGT1A1 (eg, irinotecan). The incidence of hand-foot skin reaction is increased in patients treated with sorafenib plus bevacizumab in comparison to those treated with sorafenib monotherapy (Azad 2009). Use in combination with carboplatin and paclitaxel in patients with squamous cell lung cancer is contraindicated. Monitor PT/INR in patients on warfarin therapy due to potential for bleeding events to occur.

Monitoring Parameters

CBC with differential, electrolytes (magnesium, potassium, calcium), phosphorus, lipase and amylase levels; liver function tests; blood pressure (baseline, weekly for the first 6 weeks, then periodic); monitor for hand-foot skin reaction and other dermatologic toxicities; monitor ECG in patients at risk for prolonged QT interval; signs/symptoms of bleeding, GI perforation, and heart failure.

Thyroid function testing:

Patients with differentiated thyroid cancer: Monitor TSH monthly.

Patients with RCC and HCC (Hamnvik 2011):

Pre-existing levothyroxine therapy: Obtain baseline TSH levels, then monitor every 4 weeks until levels and levothyroxine dose are stable, then monitor every 2 months

Without pre-existing thyroid hormone replacement: TSH at baseline, then every 4 weeks for 4 months, then every 2 to 3 months

Pregnancy Risk Factor

D

Pregnancy Considerations

Animal reproduction studies have demonstrated teratogenicity and fetal loss. Based on its mechanism of action and because sorafenib inhibits angiogenesis, a critical component of fetal development, adverse effects on pregnancy would be expected. Women of childbearing potential should be advised to avoid pregnancy. Men and women of reproductive potential should use effective birth control during treatment and for at least 2 weeks after treatment is discontinued.

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 diarrhea, constipation, dry skin, hair loss, lack of appetite, itching, weight loss, muscle spasm, muscle pain, mouth irritation, change in taste, mouth sores, acne, flushing, rhinorrhea, or joint pain. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), depression, sexual dysfunction, shortness of breath, excessive weight gain, sweating a lot, vision changes, tachycardia, severe dizziness, passing out, angina, severe headache, severe abdominal pain, severe nausea, severe vomiting, abnormal heartbeat, swelling of arms or legs, painful extremities, severe loss of strength and energy, burning or numbness feeling, redness or irritation of palms of hands or soles of feet, or 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) (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.