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Risk of Cardiac Ischemia and/or Infarction
In the HCC study, the incidence of cardiac ischemia/infarction was 2.7% in NEXAVAR-treated patients compared with 1.3% in the placebo-treated group and in RCC Study 1, the incidence of cardiac ischemia/infarction was higher in the NEXAVAR-treated group (2.9%) compared with the placebo-treated group (0.4%). Patients with unstable coronary artery disease or recent myocardial infarction were excluded from this study. Temporary or permanent discontinuation of NEXAVAR should be considered in patients who develop cardiac ischemia and/or infarction.
Risk of Hemorrhage
An increased risk of bleeding may occur following NEXAVAR administration. In the HCC study, an excess of bleeding regardless of causality was not apparent and the rate of bleeding from esophageal varices was 2.4% in NEXAVAR-treated patients and 4% in placebo-treated patients. Bleeding with a fatal outcome from any site was reported in 2.4% of NEXAVAR-treated patients and 4% in placebo-treated patients. In RCC Study 1, bleeding regardless of causality was reported in 15.3% of patients in the NEXAVAR-treated group and 8.2% of patients in the placebo-treated group. The incidence of CTCAE Grade 3 and 4 bleeding was 2% and 0%, respectively, in NEXAVAR-treated patients, and 1.3% and 0.2%, respectively, in placebo-treated patients. There was one fatal hemorrhage in each treatment group in RCC Study 1. If any bleeding necessitates medical intervention, permanent discontinuation of NEXAVAR should be considered.
Risk of Hypertension
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 the HCC study, hypertension was reported in approximately 9.4% of NEXAVAR-treated patients and 4.3% of patients in the placebo-treated group. In RCC Study 1, hypertension was reported in approximately 16.9% of NEXAVAR-treated patients and 1.8% of patients in the placebo-treated group. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was managed with standard antihypertensive therapy. In cases of severe or persistent hypertension despite institution of antihypertensive therapy, consider temporary or permanent discontinuation of NEXAVAR. Permanent discontinuation due to hypertension occurred in 1 of 297 NEXAVAR-treated patients in the HCC study and 1 of 451 NEXAVAR-treated patients in RCC Study 1.
Risk of Dermatologic Toxicities
Hand-foot skin reaction and rash represent the most common adverse reactions attributed to NEXAVAR. Rash and hand-foot skin reaction are usually CTCAE Grade 1 and 2 and generally appear during the first six weeks of treatment with 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. Permanent discontinuation of therapy due to hand-foot skin reaction occurred in 4 of 297 NEXAVAR-treated patients with HCC and 3 of 451 NEXAVAR-treated patients with RCC.
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.
Risk of Gastrointestinal Perforation
Gastrointestinal perforation is an uncommon adverse reaction and has been reported in less than 1% of patients taking NEXAVAR. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastrointestinal perforation, discontinue NEXAVAR.
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.
Wound Healing Complications
No formal studies of the effect of NEXAVAR on wound healing have been conducted. Temporary interruption of NEXAVAR is recommended in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of NEXAVAR following major surgical intervention. Therefore, the decision to resume NEXAVAR following a major surgical intervention should be based on clinical judgment of adequate wound healing.
Increased Mortality Observed with NEXAVAR Administered in Combination with Carboplatin/Paclitaxel and Gemcitabine/Cisplatin in Squamous Cell Lung Cancer
In a subset analysis of two randomized controlled trials in chemo-naive patients with Stage IIIB-IV non-small cell lung cancer, patients with squamous cell carcinoma experienced higher mortality with the addition of sorafenib 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). The use of sorafenib in combination with carboplatin/paclitaxel is contraindicated in patients with squamous cell lung cancer. Sorafenib 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.
Risk of QT Interval Prolongation
NEXAVAR can prolong the QT/QTc interval. QT/QTc interval prolongation increases the risk for ventricular arrhythmias. Avoid NEXAVAR in patients with congenital long QT syndrome. Monitor patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities with on-treatment electrocardiograms and electrolytes (magnesium, potassium, calcium) [see CLINICAL PHARMACOLOGY].
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. Monitor liver function tests regularly. In case of significantly increased transaminases without alternative explanation such as viral hepatitis or progressing underlying malignancy, discontinue NEXAVAR.
Risk of Fetal Harm
There are no adequate and well-controlled studies in pregnant women using NEXAVAR. However, 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 women of childbearing potential to avoid becoming pregnant while on NEXAVAR because of the potential hazard to the fetus [see Use in Specific Populations].
Patient Counseling Information
See FDA-approved Patient Labeling
Cardiac Ischemia; Infarction
Discuss with patients that cardiac ischemia and/or infarction has been reported during NEXAVAR treatment, and that they should immediately report any episodes of chest pain or other symptoms of cardiac ischemia [see WARNINGS AND PRECAUTIONS].
Inform patients that NEXAVAR can increase the risk of bleeding and that they should promptly report any episodes of bleeding [see WARNINGS AND PRECAUTIONS].
Inform patients that bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on NEXAVAR and that their INR should be monitored regularly [see WARNINGS AND PRECAUTIONS].
Inform patients that hypertension can develop during NEXAVAR treatment, especially during the first six weeks of therapy, and that blood pressure should be monitored regularly during treatment [see WARNINGS AND PRECAUTIONS].
Advise patients of the possible occurrence of hand-foot skin reaction and rash during NEXAVAR treatment and appropriate countermeasures [see WARNINGS AND PRECAUTIONS].
Advise patients that cases of gastrointestinal perforation have been reported in patients taking NEXAVAR [see WARNINGS AND PRECAUTIONS].
Wound Healing Complications
Inform patients that temporary interruption of NEXAVAR is recommended in patients undergoing major surgical procedures [see WARNINGS AND PRECAUTIONS].
QT Interval Prolongation
Inform patients with a history of prolonged QT interval that NEXAVAR can worsen the condition [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Inform patients that NEXAVAR can cause hepatitis which may result in hepatic failure and death. Advise patients that liver function tests should be monitored regularly during treatment and to report signs and symptoms of hepatitis [see WARNINGS AND PRECAUTIONS].
Birth Defects and Fetal Loss
Inform patients that NEXAVAR can cause birth defects or fetal loss. Counsel both male and female patients to use effective birth control during treatment with NEXAVAR and for at least 2 weeks after stopping treatment. Inform female patients to contact their healthcare provider if they become pregnant while taking NEXAVAR [see WARNINGS AND PRECAUTIONS, Use in Specific Populations].
Advise mothers not to breast-feed while taking NEXAVAR [see Use In Specific Populations].
Instruct patients that if a dose of NEXAVAR is missed, to take the next dose at the regularly scheduled time, and not double the dose. Instruct patients to contact their healthcare provider immediately if they take too much NEXAVAR.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been performed with sorafenib.
Sorafenib was clastogenic when tested in an in vitro mammalian cell assay (Chinese hamster ovary) in the presence of metabolic activation. Sorafenib was not mutagenic in the in vitro Ames bacterial cell assay or clastogenic in an in vivo mouse micronucleus assay. One intermediate in the manufacturing process, which is also present in the final drug substance ( < 0.15%), was positive for mutagenesis in an in vitro bacterial cell assay (Ames test) when tested independently.
No specific studies with sorafenib have been conducted in animals to evaluate the effect on fertility. However, results from the repeat-dose toxicity studies suggest there is a potential for sorafenib to impair reproductive function and fertility. Multiple adverse effects were observed in male and female reproductive organs, with the rat being more susceptible than mice or dogs. Typical changes in rats consisted of testicular atrophy or degeneration, degeneration of epididymis, prostate, and seminal vesicles, central necrosis of the corpora lutea and arrested follicular development. Sorafenib-related effects on the reproductive organs of rats were manifested at daily oral doses ≥ 5 mg/kg (30 mg/m²). This dose results in an exposure (AUC) that is approximately 0.5 times the AUC in patients at the recommended human dose. Dogs showed tubular degeneration in the testes at 30 mg/kg/day (600 mg/m²/day). This dose results in an exposure that is approximately 0.3 times the AUC at the recommended human dose. Oligospermia was observed in dogs at 60 mg/kg/day (1200 mg/m²/day) of sorafenib.
Adequate contraception should be used during therapy and for at least 2 weeks after completing therapy.
Use In Specific Populations
Pregnancy Category D
[see WARNINGS AND PRECAUTIONS].
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. There are no adequate and well-controlled studies in pregnant women using NEXAVAR. Inform patients of childbearing potential that NEXAVAR can cause birth defects or fetal loss. Instruct both men and women of childbearing potential to use effective birth control during treatment with NEXAVAR and for at least 2 weeks after stopping treatment. Counsel female patients to contact their healthcare provider if they become pregnant while taking NEXAVAR.
When administered to rats and rabbits during the period of organogenesis, sorafenib was teratogenic and induced embryo-fetal toxicity (including increased post-implantation loss, resorptions, skeletal retardations, and retarded fetal weight). The effects occurred at doses considerably below the recommended human dose of 400 mg twice daily (approximately 500 mg/m²/day on a body surface area basis). Adverse intrauterine development effects were seen at doses ≥ 0.2 mg/kg/day (1.2 mg/m²/day) in rats and 0.3 mg/kg/day (3.6 mg/m²/day) in rabbits. These doses result in exposures (AUC) approximately 0.008 times the AUC seen in patients at the recommended human dose. A NOAEL (no observed adverse effect level) was not defined for either species, since lower doses were not tested.
It is not known whether sorafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from NEXAVAR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Following administration of radiolabeled sorafenib to lactating Wistar rats, approximately 27% of the radioactivity was secreted into the milk. The milk to plasma AUC ratio was approximately 5:1.
The safety and effectiveness of NEXAVAR in pediatric patients have not been studied.
Repeat dosing of sorafenib to young and growing dogs resulted in irregular thickening of the femoral growth plate at daily sorafenib doses ≥ 600 mg/m² (approximately 0.3 times the AUC at the recommended human dose), hypocellularity of the bone marrow adjoining the growth plate at 200 mg/m²/day (approximately 0.1 times the AUC at the recommended human dose), and alterations of the dentin composition at 600 mg/m²/day. Similar effects were not observed in adult dogs when dosed for 4 weeks or less.
In total, 59% of HCC patients treated with NEXAVAR were age 65 years or older, and 19% were 75 and older. In total, 32% of RCC patients treated with NEXAVAR were age 65 years or older, and 4% were 75 and older. No differences in safety or efficacy were observed between older and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Patients with Hepatic Impairment
In a trial of HCC patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, the systemic exposure (AUC) of sorafenib was within the range observed in patients without hepatic impairment. In another trial in subjects without HCC, the mean AUC was similar for subjects with mild (n=15) and moderate (n=14) hepatic impairment compared to subjects (n=15) with normal hepatic function. No dose adjustment is necessary for patients with mild or moderate hepatic impairment. The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh C) hepatic impairment [see CLINICAL PHARMACOLOGY].
Patients with Renal Impairment
No correlation between sorafenib exposure and renal function was observed following administration of a single oral dose of NEXAVAR 400 mg to subjects with normal renal function and subjects with mild (CrCl 50–80 mL/min), moderate (CrCl 30– < 50 mL/min), or severe (CrCl < 30 mL/min) renal impairment who are not on dialysis. No dose adjustment is necessary for patients with mild, moderate or severe renal impairment who are not on dialysis. The pharmacokinetics of sorafenib have not been studied in patients who are on dialysis [see CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 12/2/2013
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