OFEV(nintedanib)尼达尼布胶囊

适应证和用途
OFEV是一种激酶抑制剂适用为特发性肺纤维化(IPF)的治疗。

剂量和给药方法
⑴ 推荐剂量：150mg每天2次间隔约12小时与食物服用。
⑵ 考虑暂时剂量减低至100mg，治疗中断，或终止为处理不良反应。
⑶ 治疗前，进行肝功能检验。

剂型和规格
胶囊：150mg和100mg

禁忌证
无

警告和注意事项
⑴ 肝酶升高：用OFEV曾发生ALT，AST，和胆红素升高。治疗前和期间监视ALT，AST，和胆红素。可能需要暂时减低剂量或终止。
⑵ 胃肠道疾病：用OFEV曾发生腹泻，恶心，和呕吐。第一个征象用充分水化和止泻药(如，洛哌丁胺[loperamide])或抗吐药治疗患者。如尽管对症治疗严重腹泻，恶心，或呕吐持续终止OFEV。
⑶ 胚胎胎儿毒性：应劝告育龄妇女对胎儿潜在危害和避免成为妊娠。
⑷ 曾报道动脉血栓栓塞事件。当治疗患者处于较高心血管风险包括已知冠状动脉疾病谨慎使用。
⑸ 曾报道出血事件。只有已知出血风险患者期望获益胜过潜在风险时使用FEV。
⑹ 曾报道胃肠道穿孔。最近腹部手术治疗患者谨慎使用OFEV。发生胃肠道穿孔患者终止OFEV。只有有已知胃肠道穿孔风险如期望获益胜过潜在风险才使用OFEV。

不良反应
最常见不良反应(≥5%)是：腹泻，恶心，腹痛，呕吐，肝酶升高，食欲减退，头痛，体重减轻，和高血压。

药物相互作用
P-gp和CYP3A4抑制剂共同给药可能增加nintedanib暴露。密切监视患者对OFEV耐受性。

特殊人群中使用
⑴ 哺乳母亲：终止哺乳或终止药物，考虑药物对母亲重要性。
⑵ 肝受损：对有轻度肝受损患者监视不良反应和需要时考虑调整剂量或终止OFEV。有中度或严重肝受损患者中不建议使用OFEV。
⑶ 肾受损：未曾在有严重肾受损和肾病终末期患者研究OFEV的安全性和疗效。
⑷ 吸烟者：曾注意到吸烟者减低暴露可能改变OFEV疗效图形 .

产品资料

2014年11月26日，继今年10月获得FDA批准，勃林格殷格翰（Boehringer Ingelheim）特发性肺纤维化（IPF）口服药物Ofev（nintedanib）胶囊获欧洲药品管理局（EMA）人用医药产品委员会（CHMP）已建议批准Ofev用于特发性肺纤维化（IPF）患者的治疗，欧盟委员会（EC）预计将在2个月内批准Ofe在欧盟上市。此前，EMA于今年6月接受审查nintedanib治疗IPF上市许可申请（MAA）并授予加速评估资格。

nintedanib MAA包括来自2项III期研究（INPULSIS-1和INPULSIS-2）的数据，在这些研究中，nintedanib显著延缓了广泛特发性肺纤维化（IPF）患者病情的恶化，均达到了研究的主要终点。相关数据已于今年5月发表于《新英格兰医学杂志》（New England Journal of Medicine）。

在美国，Ofev（nintedanib）已于今年10月获FDA批准，同时获批的还有罗氏和InterMune的另一款特发性肺纤维化（IPF）药物Esbriet（比非尼酮）。
特发性肺纤维化（IPF）是一种罕见的肺部疾病，根据肺纤维化联盟（CPF）数据，每年IPF死亡病例达40000例。分析师预计，IPF药物市场的年销售将超过20亿美元，现在2家公司的药物同时获批上市，究竟哪家公司能夺取更大的市场份额，还不太好说。而且从疗效方面看，在关键性III期试验中，2种药物与安慰剂相比都显著改善了肺功能；而在安全性方面，2种药物均禁忌用于伴有肝脏问题的患者群体。

Nintedanib是一种口服三联血管激酶抑制剂，可同时阻断3种生长因子受体：血管内皮生长因子受体（VEGFR 1-3）、血小板源性生长因子受体（PDGFR α和β）、成纤维细胞生长因子受体（FGFR 1-3）。所有这3种受体在血管生成和肿瘤生长过程中均发挥着重要作用。这些受体的阻断，可能导致血管生成的抑制，而血管生成在肿瘤生长中起着关键作用。

目前，勃林格殷格翰正在多种实体瘤中评价nintedanib，其中晚期非小细胞肺癌（NSCLC）、结直肠癌、卵巢癌已处于III期临床，间皮瘤、肾癌（肾细胞癌）、肝癌（肝细胞癌）处于II期临床。

在欧盟，除特发性肺纤维化（IPF）外，CHMP此前已建议批准nintedanib联合多西他赛（docetaxel）用于既往经一线化疗治疗的局部晚期、转移性或局部复发性腺癌组织学非小细胞肺癌（NSCLC）患者的治疗。

 Generic Name: nintedanib (nin TED a nib)

Brand Name: Ofev

Pronunciation

(nin TED a nib)

Index TermsBIBF1120Nintedanib Esylate

Dosage Forms

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

Capsule, Oral:

Ofev: 100 mg, 150 mg

Brand Names: U.S.OfevPharmacologic CategoryTyrosine Kinase InhibitorPharmacology

Inhibits multiple receptor tyrosine kinases (RTKs) and nonreceptor tyrosine kinases (nRTKs), including platelet-derived growth factor (PDGFR alpha and PDGFR beta); fibroblast growth factor receptor (FGFR1, FGFR2, FGFR3); vascular endothelial growth factor (VEGFR1, VEGFR2, and VEGFR3); and Fms-like tyrosine kinase-3 (FLT3). Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signaling which is crucial for the proliferation, migration, and transformation of fibroblasts.

Absorption

Food increases exposure ~20% and delays absorption

Distribution

Vss: 1050 L

Metabolism

Hydrolytic cleavage by esterases to free acid moiety BIBF 1202, which is then glucuronidated by UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide; CYP 3A4 (minor)

Excretion

Feces (~93%); urine (<1%)

Time to Peak

2 hours (4 hours with food)

Half-Life Elimination

9.5 hours

Protein Binding

~98%

Special Populations: Hepatic Function Impairment

In patients with mild hepatic impairment (Child-Pugh class A) and moderate impairment (Child-Pugh class B), the AUC is increased 2.2 fold and 7.6 fold, respectively, compared to patients with normal hepatic function.

Special Populations Note

Cigarette smoking: Exposure was 21% lower in smokers.

Use: Labeled Indications

Idiopathic pulmonary fibrosis: Treatment of idiopathic pulmonary fibrosis (IPF).

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to nintedanib, peanut, or soya or any component of the formulation; pregnancy

Dosing: Adult

Idiopathic pulmonary fibrosis (IPF): Oral: 150 mg every 12 hours (maximum: 300 mg/day)

Missed dose: If a dose is missed, the next dose should be taken at the next scheduled time. Do not make up a missed dose.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥30 mL/minute: No initial dosage adjustment necessary.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

ESRD: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Hepatic impairment at baseline:

Mild impairment (Child-Pugh class A): 100 mg every 12 hours.

Moderate to severe impairment (Child-Pugh class B or C): Use is not recommended (exposure is increased in moderate impairment; has not been studied in severe impairment).

Hepatotoxicity during treatment:

AST or ALT >3 times to <5 times ULN (without signs of severe liver damage): Interrupt treatment or reduce dosage to 100 mg every 12 hours. Once liver enzymes have returned to baseline values after treatment interruption, reintroduce therapy at 100 mg every 12 hours; may be subsequently increased to 150 mg every 12 hours. If a patient does not tolerate 100 mg every 12 hours, consider treatment interruption or discontinue treatment to manage adverse reactions.

AST or ALT >5 times ULN or >3 times ULN with signs or symptoms of severe liver damage: Discontinue therapy.

Dosing: Adjustment for Toxicity

Gastrointestinal toxicity (eg, diarrhea, nausea, vomiting) or other adverse reactions/toxicity: Dose reduction or temporary interruption may be needed. Treatment may be resumed at 150 mg every 12 hours or 100 mg every 12 hours, which may subsequently be increased to 150 mg every 12 hours. If a patient does not tolerate 100 mg every 12 hours, discontinue treatment.

Administration

Oral: Administer with food. Swallow capsules whole with liquid; do not chew or crush (bitter taste).

Storage

Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Protect from high humidity and avoid excessive heat.

Drug Interactions

Anticoagulants: May enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Monitor therapy

Combined Inducers of CYP3A4 and P-glycoprotein: May decrease the serum concentration of Nintedanib. Avoid combination

Combined Inhibitors of CYP3A4 and P-glycoprotein: May increase the serum concentration of Nintedanib. Monitor therapy

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Pirfenidone: May decrease the serum concentration of Nintedanib. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Adverse Reactions

>10%:

Gastrointestinal: Diarrhea (62%), nausea (24%), abdominal pain (15%), vomiting (12%), decreased appetite (11%)

Hepatic: Increased liver enzymes (14%)

1% to 10%:

Cardiovascular: Hypertension (5%), arterial thrombosis (3%), myocardial infarction (2%)

Central nervous system: Headache (8%)

Endocrine & metabolic: Weight loss (10%), hypothyroidism (1%)

Hematologic and oncologic: Hemorrhage (10%)

Respiratory: Bronchitis (1%)

<1% (Limited to important or life-threatening): Gastrointestinal perforation, hepatotoxicity, major hemorrhage, pancreatitis, thrombocytopenia

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: May increase the risk of bleeding. Use in patients with known risk of bleeding only if the benefit outweighs the risk.

• Cardiovascular effects: Arterial thromboembolic events, including MI, have been reported. Use caution in patients at high cardiovascular risk, including in patients with known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.

• GI effects: Diarrhea, nausea, and vomiting may occur. Diarrhea occurred in over 50% of nintedanib-treated patients, and was generally of mild to moderate intensity and occurred within the first 3 months of treatment. Treat with appropriate supportive care (eg, adequate hydration, antidiarrheals, antiemetics); dose reduction and/or treatment interruption may be required. If GI effects do not resolve, discontinue treatment. In addition, nintedanib may increase the risk of GI perforation; only use in patients at risk of perforation if the benefit outweighs the risk. Use caution in patients with recent abdominal surgery. It has been recommended to wait at least 4 weeks following abdominal surgery before initiating therapy (OFEV Canadian product labeling 2017). Discontinue if perforation develops.

• Hepatic effects: Drug-induced liver injury has been observed. Elevations of ALT, AST, GGT, alkaline phosphatase, and bilirubin were reversible with dose modification or interruption. Obtain liver function tests prior to treatment then as clinically indicated. Dosage modifications or interruption may be necessary; if serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly interrupt therapy.

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.

Special populations:

• Hepatic impairment: Nintedanib is primarily eliminated through biliary/fecal excretion; use is not recommended in patients with moderate or severe hepatic impairment. Dose reduction is recommended in patients with mild impairment; if adverse reactions occur, consider treatment interruption or discontinuation.

• Smokers: Smoking may decrease exposure to nintedanib; patients should stop smoking prior to treatment and avoid smoking during therapy.

Monitoring Parameters

Obtain liver function tests prior to treatment and as clinically indicated; obtain pregnancy test prior to treatment. Monitor for gastrointestinal events (eg, diarrhea, nausea, vomiting), arterial thromboembolic events, bleeding, and gastrointestinal perforation.

Pregnancy Considerations

Based on the mechanism of action and adverse events observed in animal reproduction studies, nintedanib may be expected to cause fetal harm if used during pregnancy. Women of reproductive potential should use adequate contraception during therapy; pregnancy status should be obtained before treatment and pregnancy should be avoided; effective contraception should be used during therapy and for at least 3 months after the last dose. Based on animal studies, nintedanib may reduce female fertility.

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 lack of appetite or weight loss. Have patient report immediately to prescriber 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 severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of a heart attack (angina; pain in arms, back, neck, jaw, or abdomen; shortness of breath; cold sweats; severe dizziness; passing out; or severe nausea or vomiting), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), severe diarrhea, persistent diarrhea, severe nausea, vomiting, severe abdominal pain, abdominal edema, severe headache, severe dizziness, passing out, or vision changes (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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