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英文药名: Nexavar(Sorafenib Tablets)

中文药名: 多吉美（索拉非尼片）

生产厂家: Bayer Corp.

多吉美的部分中文处方资料（仅供参考）

[药品名称] 
商品名：多吉美 
通用名：甲苯磺酸索拉非尼片 
英文商品名：Nexavar
英文通用名：Sorafenib tosylate
汉语拼音：Jiabenhuangsuan Suolafeini Pian
                  
[成分 ]

化学名：4-{4-[3-（4-氯-3-三氟甲基-苯基）-酰脲]-苯氧基}-吡啶-2-羧酸甲胺-4-甲苯磺酸盐。 
实验式：C21H16ClF3N4O3 * C7H8O3S。 
分子量：637.0克/摩尔。

 
[性状] 
本品为红色圆形片 

[适应症] 
治疗不能手术的晚期肾细胞癌。 

[规格] 
0.2g

[用法用量] 
推荐剂量：推荐服用索拉非尼为每次0.4 g（2x0.2g），每日两次，空腹或伴低脂、中脂饮食服用。 
服用方法：口服，以一杯温水吞服。 
治疗时间：应持续治疗直至患者不能临床受益或不能耐受的毒性反应 

[禁忌] 
对索拉非尼或药物的非活性成分有严重过敏症状的患者禁用。

 
[注意事项]
尚缺乏充分的中国人群临床研究数据，因此须在有本品使用经验的医生指导下使用。 

[药物相互作用] 
 索 拉非尼与阿霉素或依立替康合用时，后两者的药时曲线下面积(AUC)将分别增加21%和26%～42%，目前尚不清楚上述现象是否具有临床意义，但一般建 议索拉非尼与上述两种药物合用时应注意密切观察。索拉非尼与酮康唑合用时较安全。从理论上说，任何能够诱导CYP3A4的药物均能加快索拉非尼的代谢，降 低其血药浓度和临床疗效。索拉非尼是CYP2C9的竞争性抑制剂，因此，它有可能会升高其他经CYP2C9代谢的药物的血药浓度。当索拉非尼与其他治疗范 围较窄的CYP2C9底物(如塞来昔布、双氯芬酸、屈大麻酚、THC、苯妥英或磷苯妥英、吡罗昔康、舍曲林、甲苯磺丁脲、托吡酯和华法林等)合用时应注意 观察，以防出现严重不良反应。 

[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0.8 g每日两次，在此剂量下所观察导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疗法。 

[药理及药代动力学] 
 索拉非尼是一种多激酶抑制剂。临床前研究显示，索拉非尼能同时抑制多种存在于细胞内和细胞表面的激酶，包括RAF激酶、血管内皮生长因子受体 -2（VEGFR-2）、血管内皮生长因子受体-3（VEGFR-3）、血小板衍生生长因子受体－β（PDGFR－β）、KIT和FLT-3。由此可见， 索拉非尼具有双重抗肿瘤效应，一方面，它可以通过抑制RAF/MEK/ERK信号传导通路，直接抑制肿瘤生长；另一方面，它又可通过抑制VEGFR和 PDGFR而阻断肿瘤新生血管的形成，间接抑制肿瘤细胞的生长.

与口服溶液相比，索拉非尼片的相对生物利用度为38%~49%；高脂饮食可使索拉 非尼生物利用度降低29%。索拉非尼达峰时间约为3小时，平均消除半衰期约为25~48小时，血浆蛋白结合率为99.5%。索拉非尼主要通过肝脏代谢酶 CYP3A4进行氧化代谢，以及通过UGT1A9进行葡萄糖苷酸化代谢。目前已知索拉非尼有8种代谢产物，其中5种可在索拉非尼达到稳态后的患者血浆中检 测到。索拉非尼主要以原形物（占总剂量51%）和代谢物方式随粪便排泄，有部分葡萄糖苷酸化代谢产物（占总剂量19%）随尿液排泄。 

[不良反应 ]
索 拉非尼引起的常见不良事件包括皮疹、腹泻、血压升高，以及手掌或足底部发红、疼痛、肿胀或出现水疱。在临床试验中，最常见的与治疗有关的不良事件有腹泻、 皮疹／脱屑、疲劳、手足部皮肤反应、脱发、恶心、呕吐、瘙痒、高血压和食欲减退。在索拉非尼治疗的患者中，3级和4级不良事件的数目分别占不良事件总数的 31%和7%，而安慰剂对照组患者则分别为22%和6%。

 
[用药提示 ]
患者在服药之前应仔细阅读产品说明书及患者须知。应告知患者在服药期间必须采取有效避孕措施，以及在停药至少２周之后方可尝试怀孕。告知患者最好空腹服药。若患者忘记服药，下一次服药时也无需加大剂量。当患者在服药期间出现手足部皮疹，应及时联络医生进行相应处理。 

[贮藏] 
低于25℃密封保存，请将药物放到儿童触及不到的地方。 

---------------------------------------------------------
肿瘤专家点评晚期肾癌新药Sorafenib

由拜耳药业开发的多靶点新药Sorafenib(索拉非尼，商品名Nexavar)2005年12月经美国食品药品局（FDA）批准作为治疗晚期肾癌的一线药物上市。 
肾癌如果超越了手术切除的范围，多年来主要以生物治疗或生物化学治疗为主，但疗效不理想，中位生存期只有10个月左右。当一线方案失败后，更无有效的二线方案。 

拜耳和Onyx药业公司从肿瘤的发生机理和肿瘤生长需要新生血管提供营养入手，联合研制了Sorafenib。Sorafenib是一种口服的新颖 靶向治疗药物，能抑制RAF-1、B-RAF的丝氨酸/苏氨酸激酶活性，以及VGFR-2、VEGF-3、PDGF-β、KIT、FLT-3多种受体的酪 氨酸激酶活性。Sorafenib具有双重的抗肿瘤作用：既可通过阻断由RAF/MEK/ERK介导的细胞信号传导通路而直接抑制肿瘤细胞的增殖，还可通 过作用于VEGFR，抑制新生血管的形成和切断肿瘤细胞的营养供应而达到遏制肿瘤生长的目的。 
Sorafenib在临床前动物试验中显示了广泛 的抗肿瘤活性。

在美国和欧洲进行的治疗晚期肾癌的III期随机临床研究中，903例接受过一次系统治疗(生物免疫或化疗)失败的晚期肾癌病人随机分为两 组，一组接受Sorafenib，另一组接受安慰剂治疗。中期分析时已发生222例死亡事件，结果表明两组的客观有效率分别为10%和2%，另分别有 74%和53%的病人肿瘤保持稳定。Sorafenib组的无进展生存期较安慰剂组延长一倍(5.8vs2.8个月，风险比为0.51)，且 Sorafenib较安慰剂治疗显著改善了病人的生活质量。Sorafinib组的生存期较安慰剂组长，风险比为0.72，但这一差异尚未达到统计学意 义，由于这只是中期分析的结果，因此需到试验最终分析时才能对生存期作最后的比较。 

Sorafenib治疗的耐受性良好，主要的不良反应为可控制的腹泻、皮疹、疲乏、手足综合征、高血压、脱发、恶心/呕吐和食欲不振。 
美国FDA正是基于这一临床试验的结果快速批准了Sorafenib作为晚期肾癌治疗的药物，“这是近10多年来唯一被FDA批准的用于治疗肾癌的新药”，也是肾癌治疗取得的一个重大进展。 
至 今，临床试验考察了Sorafenib对20多种恶性肿瘤的疗效，已接受其治疗的病人已超过4000多例。目前正在开展Sorafenib治疗肝癌、转移 性黑色素瘤和皮肤癌的III期临床试验。

Sorafenib是目前世界上第一个被批准应用于临床的一个多靶点的靶向治疗药物。目前Sorafenib正在由中国医学科学院肿瘤医院的孙燕院 士作为主要研究者在亚洲开展临床试验。我国有四家单位参与这一工作，试验的主要对象是有病理证实的无法手术切除和/或转移的晚期肾透明细胞癌，这些患者既 往最多可以接受过一次系统的治疗。 

Pronunciation

(sor AF e nib)

Index TermsBAY 43-9006Sorafenib Tosylate

Dosage Forms

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

Tablet, Oral:

NexAVAR: 200 mg

Brand Names: U.S.NexAVARPharmacologic CategoryAntineoplastic Agent, Tyrosine Kinase InhibitorAntineoplastic Agent, Vascular Endothelial Growth Factor (VEGF) InhibitorPharmacology

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

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

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

Bosentan: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations 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

Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. 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

CYP2C9 Substrates (High risk with Inhibitors): CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates (High risk with Inhibitors). 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

Dronabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol.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

Fluorouracil (Systemic): SORAfenib may decrease the serum concentration of Fluorouracil (Systemic). SORAfenib may increase the serum concentration of Fluorouracil (Systemic). Monitor therapy

Fluorouracil (Topical): SORAfenib may decrease the serum concentration of Fluorouracil (Topical). SORAfenib may increase the serum concentration of Fluorouracil (Topical). 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

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

Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. 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% (Limited to important or life-threatening): Acute renal failure, amyotrophy, anaphylaxis, angioedema, aortic dissection, 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), malignant neoplasm of skin (keratoacanthomas), nephrotic syndrome, ostealgia, osteonecrosis (jaw), pancreatitis, pleural effusion, prolonged QT interval on ECG, respiratory tract hemorrhage, reversible posterior leukoencephalopathy syndrome (RPLS), rhabdomyolysis, Stevens-Johnson syndrome, thromboembolism, toxic epidermal necrolysis (TEN), 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 constipation, dry skin, hair loss, lack of appetite, itching, weight loss, muscle pain, or joint pain. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of bleeding (vomiting blood or vomit that looks like coffee grounds, coughing up blood, blood in the urine, black, red, or tarry stools, bleeding from the gums, abnormal vaginal bleeding, bruises without a reason or that get bigger, or any bleeding that is very bad or that will not stop), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), shortness of breath, sweating a lot, confusion, vision changes, tachycardia, severe dizziness, passing out, angina, severe headache, severe abdominal pain, severe nausea, severe vomiting, severe diarrhea, 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.

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