Cometriq(cabozantinib)

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Pharmacological Class:
Kinase inhibitor.

Active Ingredient(s):
Cabozantinib 20mg, 80mg; caps.

Company
Exelixis, Inc.

Indication(s):

Treatment of progressive, metastatic medullary thyroid cancer (MTC).

Pharmacology:

Cabozantinib inhibits the tyrosine kinase activity of RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

Clinical Trials:

The safety and efficacy of Cometriq was assessed in a double-blind, controlled trial of 330 patients. The main efficacy outcome measures were progression-free survival (PFS), objective response (OR), and response duration. A statistically significant prolongation in PFS was demonstrated among Cometriq-treated patients compared to those receiving placebo [HR 0.28 (95% CI: 0.19, 0.40); p <0.0001], with median PFS times of 11.2 months and 4 months in the Cometriq and placebo arms, respectively. Partial responses were observed only among patients in the Cometriq arm (27% vs. 0; p<0.0001). The median duration of objective responses was 14.7 months (95% CI: 11.1, 19.3) for patients treated with Cometriq. There was no statistically significant difference in overall survival between the treatment arms at the planned interim analysis.

Legal Classification:

Rx

Adults:

Swallow whole. 140mg daily. Do not eat at least 2 hours before or 1 hour after dose. Continue until disease progression or unacceptable toxicity. Withhold for Grade 4 hematologic adverse reactions, ≥Grade 3 non-hematologic reactions or intolerable Grade 2 reactions. Upon improvement to Grade 1 or to baseline, reduce dose as follows: previously on 140mg daily, resume at 100mg daily; previously on 100mg daily, resume at 60mg daily; previously on 60mg daily, resume at 60mg if tolerated, otherwise discontinue. Concom­itant strong CYP3A4 inhibitor: reduce daily dose by 40mg; resume dose used prior to starting inhibitor 2–3 days after dis­con­tin­u­a­tion of inhibitor. Con­com­itant strong CYP3A4 i­nducers: increase daily dose by 40mg; resume dose used prior to starting inducer 2–3 days after discontinuation of inducer. Max daily dose: 180mg.

Children:

Not studied.

Warnings/Precautions:

Permanently discontinue if the following occurs: GI or non-GI perforation/fistula formation, severe hemorrhage, serious arterial thrombo­em­bolic events (eg, MI, cerebral infarction), nephrotic syndrome, malignant hypertension, ­hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management, osteonecrosis of the jaw, reversible posterior leukoencephalopathy syndrome. Moderate-to-severe hepatic impairment: not recommended. Recent history of hemorrhage, hemoptysis: avoid. Stop treatment at least 28 days prior to scheduled surgery (including invasive dental procedures); withhold dose if dehiscence or wound healing complications require medical intervention. Monitor for bleeding, hypertension, proteinuria (measure urine protein regularly). Use effective contraception during and up to 4 months after completion of therapy. Pregnancy (Cat. D). Nursing mothers: not recommended.

Interaction(s)

Avoid concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarith­ro­mycin, atazanavir, nefazodone, saquinavir, telith­romycin, ritonavir, indinavir, nelfinavir, voriconazole, grapefruit or grapefruit juice) and strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort): see Adult dose.

Adverse Reaction(s)

Diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, decreased weight/appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, constipation, increased AST, ALT, alkaline phospha­tase, lymphopenia, hypocalcemia, neutro­penia, thrombocytopenia, hypophospha­te­mia, hyper­bilirubinemia.

How Supplied:

140mg daily-dose carton—4 blister cards (each: 7x80mg and 21x20mg caps); 100mg daily-dose carton—4 blister cards (each: 7x80mg and 7x20mg caps); 60mg daily-dose carton—4 blister cards (each: 21x20mg caps)

LAST UPDATED:

1/18/2013

治疗转移性甲状腺髓样癌新药获美批准上市
2012年11月29日，美国食品与药物管理局（FDA）发布公告，批准了cabozantinib用于治疗（转移性）甲状腺髓样癌患者。
Cabozantinib是一种激酶抑制剂，可抑制髓质癌细胞生长和发展的异常激酶蛋白。
一项纳入330例甲状腺髓样癌患者的临床试验评估了Cabozantinib的安全性和有效性。结果显示，与安慰剂相比，Cabozantinib可延长患者的无癌症进展生存期长达8.2个月，并且可减小一些患者的肿瘤尺寸。但接受Cabozantinib治疗的患者寿命无延长。
Cabozantinib包括一项加框警告，提示医务人员此药可在某些患者身上发生严重和致命的结肠出血和穿孔。
该药最常见的不良反应包括腹泻，口腔炎或溃疡，手足综合征，体重减轻，食欲降低，恶心，乏力，口腔痛，头发变灰白且脱发，味觉变差，新发高血压或恶化，腹痛和便秘。实验室最常见的异常包括肝酶升高，低血钙和低血磷，白细胞和血小板降低。
cabozantinib是第二个被批准用于甲状腺髓样癌治疗的药物，vandetanib是FDA于去年4月第一个批准治疗该病的药物。