WARNINGS AND PRECAUTIONS
Risk of Cardiac Ischemia and/or Infarction
In the HCC study, the incidence of cardiac ischemia/infarction was 2.7% in NEXAVAR patients compared with 1.3% in the placebo group and in RCC Study 1, the incidence of cardiac ischemia/infarction was higher in the NEXAVAR group (2.9%) compared with the placebo 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 patients and 4% in placebo patients. Bleeding with a fatal outcome from any site was reported in 2.4% of NEXAVAR patients and 4% in placebo patients. In RCC Study 1, bleeding regardless of causality was reported in 15.3% of patients in the NEXAVAR group and 8.2% of patients in the placebo group. The incidence of CTCAE Grade 3 and 4 bleeding was 2% and 0%, respectively, in NEXAVAR patients, and 1.3% and 0.2%, respectively, in placebo 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
Blood pressure should be monitored weekly during the first 6 weeks of NEXAVAR therapy and thereafter monitored and treated, 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 group. In RCC Study 1, hypertension was reported in approximately 16.9% of NEXAVAR-treated patients and 1.8% of patients in the placebo 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, temporary or permanent discontinuation of NEXAVAR should be considered. Permanent discontinuation due to hypertension occurred in 1 of 297 NEXAVAR patients in the HCC study and 1 of 451 NEXAVAR 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 HCC patients and 3 of 451 NEXAVAR RCC patients.
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, NEXAVAR therapy should be discontinued.
Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on NEXAVAR therapy. Patients taking concomitant warfarin should be monitored regularly for changes in prothrombin time, 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 therapy is recommended in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of NEXAVAR therapy following major surgical intervention. Therefore, the decision to resume NEXAVAR therapy following a major surgical intervention should be based on clinical judgment of adequate wound healing.
Interactions with UGT1A1 Substrates
Sorafenib can cause increases in plasma concentrations of drugs that are substrates of UGT1A1. Caution is recommended when administering NEXAVAR with compounds that are metabolized/eliminated predominantly by the UGT1A1 pathway (e.g. irinotecan) [see Drug Interactions ].
5.9 Interaction with Docetaxel
Sorafenib can cause increases in plasma concentrations of docetaxel. Caution is recommended when NEXAVAR is co-administered with docetaxel [see Drug Interactions].
5.10 Interaction with Doxorubicin
Sorafenib can cause increases in plasma concentrations of doxorubicin. Caution is recommended when NEXAVAR is co-administered with doxorubicin [see Drug Interactions ].
Pregnancy Category D
Sorafenib may cause fetal harm when administered to a pregnant woman. In rats and rabbits, sorafenib has been shown to be teratogenic and to induce 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 ≥1.2 mg/m2/day in rats and 3.6 mg/m2/day in rabbits (approximately 0.008 times the AUC seen in cancer 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.
There are no adequate and well-controlled studies in pregnant women using NEXAVAR. Women of childbearing potential should be advised to avoid becoming pregnant while on NEXAVAR. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
5.12 Hepatic Impairment
Hepatic impairment may reduce plasma concentrations of sorafenib. Comparison of data across studies suggests that sorafenib levels are lower in HCC patients than in non-HCC patients (without hepatic impairment). The AUC of sorafenib is similar between HCC patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. The optimal dose in non-HCC patients with hepatic impairment is not established [see Use in Specific Populations (8.6) and Clinical Pharmacology].
USE IN SPECIFIC POPULATIONS
Pregnancy Category D
[see Warnings and Precautions ].
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 vitro and in vivo data indicate that sorafenib is primarily metabolized by the liver. Comparison of data across studies suggests that patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment have sorafenib AUCs that may be 23- 65% lower than subjects with normal hepatic function. Systemic exposure and safety data were comparable in HCC patients with Child-Pugh A and B hepatic impairment. NEXAVAR has not been studied in patients with Child-Pugh C hepatic impairment [see Warnings and Precautions and Clinical Pharmacology].
Patients with Renal Impairment
NEXAVAR has not been studied in patients undergoing dialysis. No dosage adjustment is necessary when administering NEXAVAR to patients with mild, moderate or severe renal impairment not undergoing dialysis. Monitoring of fluid balance and electrolytes in patients at risk with renal dysfunction is advised [see Clinical Pharmacology].