Safety in the TARGET Study

Hemorrhage: An increased risk of bleeding may occur following NEXAVAR administration. In the SHARP (HCC) study, the rates of bleeding from esophageal varices (2.4% and 4%) and of bleeding with a fatal outcome from any site (2.4% and 4%) were similar in NEXAVAR-treated patients and those receiving placebo, respectively. In the TARGET (RCC) study, bleeding was reported in 15.3% of patients in the NEXAVAR-treated group and 8.2% of patients receiving placebo. The incidence of Grade 3 and 4 bleeding was 2% and 0%, respectively, in NEXAVAR-treated patients, and 1.3% and 0.2%, respectively, in those receiving placebo. There was one fatal hemorrhage in each treatment group in the TARGET (RCC) study. In the DECISION (DTC) study, bleeding was reported in 17.4% of NEXAVAR-treated patients and 9.6% of those receiving placebo; however, the incidence of Grade 3 bleeding was similar (1% and 1.4%) in NEXAVAR-treated patients and in those receiving placebo. If any bleeding necessitates medical intervention, consider permanent discontinuation of NEXAVAR.

Hypertension: In the SHARP (HCC) study, hypertension was reported in 9.4% of NEXAVAR-treated patients and 4.3% of patients in the placebo-treated group. In the TARGET (RCC) study, hypertension was reported in 16.9% of NEXAVAR-treated patients and 1.8% of patients in the placebo-treated group. In the DECISION (DTC) study, hypertension was reported in 40.6% of NEXAVAR-treated patients and 12.4% of placebo-treated patients. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was managed with standard antihypertensive therapy. Monitor blood pressure weekly during the first 6 weeks of NEXAVAR. Thereafter, monitor blood pressure and treat hypertension, if required, in accordance with standard medical practice. In cases of severe or persistent hypertension despite institution of antihypertensive therapy, consider temporary or permanent discontinuation of NEXAVAR.

Dermatologic Toxicities: Hand-foot skin reaction and rash are the most common adverse reactions attributed to NEXAVAR. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of NEXAVAR, or in severe or persistent cases, permanent discontinuation of NEXAVAR. There have been reports of severe dermatologic toxicities, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These cases may be life-threatening. Discontinue NEXAVAR if SJS or TEN are suspected.

Gastrointestinal Perforation: Gastrointestinal perforation has been reported in less than 1% of patients taking NEXAVAR. In the event of a gastrointestinal perforation, permanently discontinue NEXAVAR.

Increased Risk of Bleeding with Concomitant Use of Warfarin: Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on NEXAVAR. Monitor patients taking concomitant warfarin regularly for changes in prothrombin time (PT), INR, or clinical bleeding episodes.

Risk of Impaired Wound Healing: Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, NEXAVAR has the potential to adversely affect wound healing. Withhold NEXAVAR for at least 10 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of NEXAVAR after resolution of wound healing complications has not been established.

Increased Mortality, Concomitant Administration with Carboplatin/Paclitaxel & Gemcitabine/Cisplatin in Squamous Cell Lung Cancer: In a subset analysis of two randomized controlled trials in chemo-naïve patients with Stage IIIB-IV non-small cell lung cancer, patients with squamous cell carcinoma experienced higher mortality with the addition of NEXAVAR compared to those treated with carboplatin/paclitaxel alone (HR 1.81, 95% CI 1.19-2.74) and gemcitabine/cisplatin alone (HR 1.22, 95% CI 0.82-1.80). 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.

QT Interval Prolongation: NEXAVAR can prolong the QT/QTc interval. QT/QTc interval prolongation increases the risk for ventricular arrhythmias. Avoid use in patients with congenital long QT syndrome. Monitor electrolytes and electrocardiograms in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Correct electrolyte abnormalities (magnesium, potassium, calcium). Interrupt NEXAVAR if QTc interval is greater than 500 milliseconds or for an increase from baseline of 60 milliseconds or greater.

Drug-Induced Liver Injury: Sorafenib-induced hepatitis is characterized by a hepatocellular pattern of liver damage with significant increases of transaminases which may result in hepatic failure and death. Increases in bilirubin and INR may also occur. Liver function tests should be monitored regularly and in cases of increased transaminases without alternative explanation NEXAVAR should be discontinued.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, NEXAVAR may cause fetal harm when administered to a pregnant woman. Sorafenib caused embryo-fetal toxicities in animals at maternal exposures that were significantly lower than the human exposures at the recommended dose of 400 mg twice daily. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiation of NEXAVAR. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of NEXAVAR. Advise male patients with female partners of reproductive potential and pregnant partners to use effective contraception during treatment and for 3 months following the last dose of NEXAVAR.

Impairment of Thyroid Stimulating Hormone Suppression in Differentiated Thyroid Carcinoma: NEXAVAR impairs exogenous thyroid suppression. In the DECISION (DTC) study, 99% of patients had a baseline thyroid stimulating hormone (TSH) level less than 0.5 mU/L. Elevation of TSH level above 0.5 mU/L was observed in 41% of NEXAVAR-treated patients as compared with 16% of placebo-treated patients. For patients with impaired TSH suppression while receiving NEXAVAR, the median maximal TSH was 1.6 mU/L and 25% had TSH levels greater than 4.4 mU/L. Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC.

Laboratory Abnormalities: In the HCC study, the most common laboratory abnormalities observed in the NEXAVAR arm versus the placebo arm, respectively, were hypoalbuminemia (59% vs. 47%), lymphopenia (47% vs. 42%), thrombocytopenia (46% vs. 41%), elevation in INR (42% vs. 34%), elevated lipase (40% vs. 37%), hypophosphatemia (35% vs. 11%), elevated amylase (34% vs. 29%), hypocalcemia (27% vs. 15%), and hypokalemia (10% vs. 6%).

In the RCC study, the most common laboratory abnormalities observed in the NEXAVAR arm versus the placebo arm, respectively, were hypophosphatemia (45% vs. 11%), anemia (44% vs. 49%), elevated lipase (41% vs. 30%), elevated amylase (30% vs. 23%), lymphopenia (23% vs. 13%), neutropenia (18% vs. 10%), thrombocytopenia (12% vs. 5%), hypocalcemia (12% vs. 8%), and hypokalemia (5% vs. <1%).

In the DTC study, the most common laboratory abnormalities observed in the NEXAVAR arm versus the placebo arm, respectively, were elevated ALT (59% vs. 24%), elevated AST (54% vs. 15%), and hypocalcemia (36% vs. 11%). The relative increase for the following laboratory abnormalities observed in NEXAVAR-treated DTC patients as compared to placebo-treated patients is similar to that observed in the RCC and HCC studies: lipase, amylase, hypokalemia, hypophosphatemia, neutropenia, lymphopenia, anemia, and thrombocytopenia.

Most Frequently Observed Adverse Drug Reactions (≥20%): The most common adverse reactions reported in ≥20% of patients and at a higher rate in the NEXAVAR arm versus the placebo arm, respectively, in the SHARP (HCC) study included: 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%.

The most common adverse reactions reported in ≥20% of patients and at a higher rate in the NEXAVAR arm versus the placebo arm, respectively, in the TARGET (RCC) study included: diarrhea (43% vs. 14%), 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%), anorexia (29% vs. 18%), nausea (23% vs. 19%). Grade 3/4 adverse reactions were 38% vs. 28%.

The most common adverse reactions reported in ≥20% of patients and at a higher rate in the NEXAVAR arm versus the placebo arm, respectively, in the DECISION (DTC) study included: 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%.

Drug Interactions: Avoid concomitant use of NEXAVAR with strong CYP3A4 inducers, when possible, because these drugs can decrease the systemic exposure to sorafenib. Avoid concomitant use of NEXAVAR with neomycin. The effects of other antibiotics on the pharmacokinetics of sorafenib have not been studied. The concomitant use of NEXAVAR and warfarin may increase the risk of bleeding or increased the INR. Monitor INR and for clinical bleeding episodes in patients taking warfarin while receiving NEXAVAR. NEXAVAR is associated with QTc interval prolongation. Avoid coadministration of NEXAVAR with medicinal products with a known potential to prolong QT/QTc interval.

Lactation: Because of the potential for serious adverse reactions in a breastfed child from NEXAVAR, advise lactating women not to breastfeed during treatment with NEXAVAR and for 2 weeks after the last dose.

For important risk and use information about NEXAVAR, please see the full Prescribing Information.