IMPORTANT SAFETY INFORMATION

NEXAVAR in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer. Nexavar may cause fetal harm when administered to a pregnant woman. Women of childbearing potential are advised to avoid becoming pregnant and female patients should also be advised against breastfeeding while receiving Nexavar. Cardiac ischemia and/or myocardial infarction may occur. continue reading below »

Multiple signaling pathways are thought to be involved in the tumorigenesis of HCC.^1,2

2 important pathways: angiogenesis and tumor cell proliferation

Antiangiogenic activity in HCC

In preclinical data, Nexavar was shown to inhibit molecular pathways involved in HCC neoangiogenesis^3,4:

VEGF signaling at the VEGFR-1, -2, and -3 receptor tyrosine kinase level
PDGF signaling at the PDGFR-β receptor tyrosine kinase level
RAF signaling along the RAS/RAF/MEK/ERK pathway within vascular endothelial cells

Tumor cell proliferation and apoptotic activity in HCC

In preclinical data, Nexavar was shown to inhibit molecular signaling involved in HCC tumor progression and to^3,4:

Interrupt some RAF signaling along the RAS/RAF/MEK/ERK pathway in tumor cells
Induce tumor stasis and increase tumor cell apoptosis

The mechanism of action of Nexavar has been elucidated primarily in preclinical models (in vitro and animal). Its clinical significance is unknown.

Indication

Nexavar is indicated for the treatment of patients with unresectable hepatocellular carcinoma.

Important Safety Considerations

Nexavar in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer
Nexavar may cause fetal harm when administered to a pregnant woman. Women of childbearing potential are advised to avoid becoming pregnant and female patients should also be advised against breastfeeding while receiving Nexavar
Cardiac ischemia and/or myocardial infarction may occur. Temporary or permanent discontinuation of Nexavar should be considered in patients who develop cardiac ischemia and/or myocardial infarction
Gastrointestinal perforation was an uncommon adverse reaction and has been reported in less than 1% of patients taking Nexavar
Uncommon but serious adverse reactions, including keratoacanthomas/squamous cell cancer of the skin and Stevens-Johnson Syndrome, have been reported in clinical trials
An increased risk of bleeding may occur following Nexavar administration. If bleeding necessitates medical intervention, consider discontinuation of Nexavar
Hypertension may occur early in the course of treatment. Monitor blood pressure weekly during the first 6 weeks and periodically thereafter and treat, as required
Hand-foot skin reaction and rash are common and management may include topical therapies for symptomatic relief. In cases of any severe or persistent adverse reactions, temporary treatment interruption, dose modification, or permanent discontinuation of Nexavar should be considered. Temporary interruption of Nexavar therapy is recommended in patients undergoing major surgical procedures
Nexavar can prolong the QT/QTc interval and increase the risk for ventricular arrhythmias. Avoid use in patients with congenital long QT syndrome and monitor patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities
Elevations in serum lipase and reductions in serum phosphate of unknown etiology have been associated with Nexavar. Monitor patients taking concomitant warfarin regularly for changes in prothrombin time, INR, or clinical bleeding episodes. Avoid concomitant use of strong CYP3A4 inducers, when possible, because inducers can decrease the systemic exposure of sorafenib. Nexavar exposure decreases when co-administered with oral neomycin. Effects of other antibiotics on Nexavar pharmacokinetics have not been studied
Most common adverse reactions reported for Nexavar-treated patients vs placebo-treated patients in unresectable HCC, respectively, were: diarrhea (55% vs 25%), fatigue (46% vs 45%), abdominal pain (31% vs 26%), weight loss (30% vs 10%), anorexia (29% vs 18%), nausea (24% vs 20%), and hand-foot skin reaction (21% vs 3%). Grade 3/4 adverse reactions were 45% vs 32%
During postapproval use of Nexavar, the following adverse drug reactions have been identified: angioedema and drug-induced hepatitis, including reports of hepatic failure and death

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1.800.FDA.1088. For important risk and use information, please see the full Prescribing Information.

References: 1. Kerbel RS, Ellis LM. Angiogenesis. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:103-116. 2. Faivre S, Demetri G, Sargent W, Raymond E. Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov. 2007;6(9):734-745. 3. Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model. Cancer Res. 2006;66(24):11851-11858. 4. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7(10):3129-3140.

VEGF=vascular endothelial growth factor; PDGF=platelet-derived growth factor.
RAS=rat sarcoma
RAF=rat sarcoma activated factor.
MEK=mitogen-activated protein kinase.
ERK=extracellular signal-regulated kinase.