ダブラフェニブ

Warning

H361 (22.2%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]；H361fd (77.8%): Suspected of damaging fertility; Suspected of damaging the unborn child [Warning Reproductive toxicity]；H373 (88.9%): May causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]；H400 (100%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]；H410 (11.1%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]；H411 (88.9%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

P203, P260, P273, P280, P318, P319, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 9 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

Elevations in serum ALT levels were reported in 11% of patients treated with dabrafenib alone, but all elevations were above 5 times ULN. When dabrafenib was given in combination with trametinib, serum ALT elevations occurred in 35% to 42% of patients and were above 5 times ULN in 4%. Similarly, serum alkaline phosphatase elevations occurred in 26% of patients given dabrafenib alone, but in 60% to 67% given dabrafenib and trametinib. These abnormalities were largely asymptomatic and fully reversible. There were no instances of clinically apparent acute liver injury or hepatic failure reported in prelicensure studies of dabrafenib and, since its approval and more wide spread use, there have been no published reports of dabrafenib hepatotoxicity.；Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

L01XE23

L - Antineoplastic and immunomodulating agents；L01 - Antineoplastic agents；L01E - Protein kinase inhibitors；L01EC - B-raf serine-threonine kinase (braf) inhibitors；L01EC02 - Dabrafenib

QL - Antineoplastic and immunomodulating agents；QL01 - Antineoplastic agents；QL01E - Protein kinase inhibitors；QL01EC - B-raf serine-threonine kinase (braf) inhibitors；QL01EC02 - Dabrafenib

Dabrafenib is a kinase inhibitor that is mainly used to target BRAF V600E mutation in multiple types of cancer. Although dabrafenib and [trametinib] both inhibit the RAS/RAF/MEK/ERK pathway, they inhibit different effectors of the pathway, thus increasing response rate and mitigating resistance without cumulative toxicity. The melanoma approval for use with [trametinib] is based on results from COMBI-AD, a Phase III study of 870 patients with Stage III BRAF V600E/K mutation-positive melanoma treated with dabrafenib + trametinib after complete surgical resection. Patients received doses of dabrafenib (150 mg BID) + trametinib (2 mg QD) combination (n = 438) or matching placebos (n = 432). After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival (RFS) was met. In the case of thyroid cancer, Dabrafenib plus Trametinib is the first regimen demonstrated to have potent clinical activity in BRAF V600E–mutated anaplastic thyroid cancer and is well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.

Dabrafenib is a competitive and selective BRAF inhibitor by binding to its ATP pocket. Although dabrafenib can inhibit wild-type BRAF, it has a higher affinity for mutant forms of BRAF, including BRAF V600E, BRAF V600K, and BRAF V600D. BRAF is a serine/threonine protein kinase and is involved in activating the RAS/RAF/MEK/ERK or MAPK pathway, a pathway that is implicated in cell cycle progression, cell proliferation, and arresting apoptosis.Therefore, constitutive active mutation of BRAF such as BRAF V600E is frequently observed in many types of cancer, including melanoma, lung cancer, and colon cancer.