Nexavar ® (sorafenib) Tablets
NEXAVAR® (sorafenib) is approved in the U.S. for the treatment of patients with unresectable hepatocellular carcinoma, patients with advanced renal cell carcinoma and patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment.
NEXAVAR is currently approved in more than 100 countries.
NEXAVAR is a kinase inhibitor that decreases tumor cell proliferation in vitro. NEXAVAR also inhibits other tyrosine kinases such as c-KIT, RET and FLT-3. NEXAVAR is a kinase inhibitor that decreases tumor cell proliferation in vitro. NEXAVAR was shown to inhibit multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-ß). Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis, and apoptosis. NEXAVAR inhibited tumor growth of human hepatocellular carcinoma and renal cell carcinoma and DTC human tumor xenografts in immunocompromised mice. Reductions in tumor angiogenesis were seen in models of HCC and RCC upon Nexavar treatment, and increases in tumor apoptosis were observed in models of HCC, RCC, and DTC.
Onyx and Bayer develop and market Nexavar under collaboration and co-promotion agreements. According to these agreements, Onyx and Bayer each fund 50 percent of the development costs for Nexavar worldwide, excluding Japan, where Bayer funds all product development. Onyx and Bayer co-promote Nexavar in the U.S. and share equally in any profits or losses. Outside of the U.S., Bayer has exclusive marketing rights and Onyx and Bayer share profits 50/50 globally, excluding Japan, where Bayer paid Onyx a one-time payment of $160 million in 2011, as part of its expanded collaboration agreement.
Important Safety Considerations
- NEXAVAR in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer
- Cardiac ischemia and/or myocardial infarction may occur. The incidence of cardiac ischemia/infarction in NEXAVAR-treated vs placebo-treated patients was 2.7% vs 1.3%, 2.9% vs 0.4%, and 1.9% vs 0% in the HCC, RCC, and DTC studies, respectively. Temporary or permanent discontinuation of NEXAVAR should be considered in patients who develop cardiac ischemia and/or myocardial infarction
- An increased risk of bleeding may occur following NEXAVAR administration. The following bleeding adverse reactions were reported in the NEXAVAR-treated vs placebo-treated patients, respectively, in the HCC study: bleeding from esophageal varices (2.4% vs 4%) and bleeding with fatal outcome at any site (2.4% vs 4%); in the RCC study: bleeding regardless of causality (15.3% vs 8.2%), Grade 3 bleeding (2.0% vs 1.3%), Grade 4 bleeding (0% vs 0.2%), and one fatal hemorrhage in each treatment group; in the DTC study: bleeding (17.4% vs 9.6%) and Grade 3 bleeding (1% vs 1.4%). If bleeding necessitates medical intervention, consider permanent 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, if 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. NEXAVAR should be discontinued if Stevens-Johnson syndrome or toxic epidermal necrolysis are suspected as these may be life-threatening
- Gastrointestinal perforation was an uncommon adverse reaction and has been reported in less than 1% of patients taking NEXAVAR. Discontinue NEXAVAR in the event of a gastrointestinal perforation
- Patients taking concomitant warfarin should be monitored regularly for changes in prothrombin time (PT), International Normalized Ratio (INR), or clinical bleeding episodes
- Temporary interruption of NEXAVAR therapy is recommended in patients undergoing major surgical procedures
- NEXAVAR, in combination with gemcitabine/cisplatin, is not recommended in patients with squamous cell lung cancer. The safety and effectiveness of NEXAVAR has not been established in patients with non-small cell lung cancer
- 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. Interrupt NEXAVAR if QTc interval is greater than 500 milliseconds or for an increase from baseline of 60 milliseconds or greater
- Drug-induced hepatitis with NEXAVAR may result in hepatic failure and death. Liver function tests should be monitored regularly and in cases of increased transaminases without alternative explanation NEXAVAR should be discontinued
- NEXAVAR may cause fetal harm when administered to a pregnant woman. Women of child-bearing potential should be advised to avoid becoming pregnant while on NEXAVAR and female patients should also be advised against breastfeeding while receiving NEXAVAR
- In DTC, NEXAVAR impairs exogenous thyroid suppression. Elevation of thyroid stimulating hormone (TSH) level above 0.5 mU/L was observed in 41% of NEXAVAR-treated patients as compared with 16% of placebo-treated patients in the DTC study. Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC
- Elevations in serum lipase and reductions in serum phosphate of unknown etiology have been associated with NEXAVAR
- 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%
- Most common adverse reactions reported for NEXAVAR-treated patients vs placebo-treated patients in advanced RCC, respectively, were: diarrhea (43% vs 13%), rash/desquamation (40% vs 16%), fatigue (37% vs 28%), hand-foot skin reaction (30% vs 7%), alopecia (27% vs 3%),and nausea (23% vs 19%). Grade 3/4 adverse reactions were 38% vs 28%
- Most common adverse reactions reported for NEXAVAR-treated patients vs placebo-treated patients in DTC, respectively, were: Palmar-plantar erythrodysesthesia syndrome (PPES) (69% vs 8%), diarrhea (68% vs 15%), alopecia (67% vs 8%), weight loss (49% vs 14%), fatigue (41% vs 20%), hypertension (41% vs 12%), rash (35% vs 7%), decreased appetite (30% vs 5%), stomatitis (24% vs 3%), nausea (21% vs 12%), pruritus (20% vs 11%), and abdominal pain (20% vs 7%). Grade 3/4 adverse reactions were 65% vs 30%