5.4 Hypertension
 
Stivarga caused an increased incidence of hypertension (30% of Stivarga-treated patients vs. 8% of placebo-treated patients in Study 1) [see Adverse Reactions (6.1)]. Hypertensive crisis occurred in 0.18% of 1100 Stivarga-treated patients across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients. Do not initiate Stivarga until blood pressure is adequately controlled.
 
Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold Stivarga for severe or uncontrolled hypertension [see Dosage and Administration (2.2)].

5.5 Cardiac Ischemia and Infarction
 
Stivarga increased the incidence of myocardial ischemia and infarction (1.2% for Stivarga-treated patients vs. 0.4% of placebo-treated patients) [see Adverse Reactions (6.1)].
 
Withhold Stivarga in patients who develop new or acute onset cardiac ischemia or infarction. Resume Stivarga only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia.

5.6 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
 
RPLS (also known as posterior reversible encephalopathy syndrome) occurred in one of 1100 Stivarga-treated patients across all clinical trials. Confirm the diagnosis of RPLS with MRI and discontinue Stivarga in patients who develop RPLS.
 
5.7 Gastrointestinal Perforation or Fistula
 
Gastrointestinal perforation or fistula occurred in 0.6% of 1100 patients treated with Stivarga across clinical trials. Permanently discontinue Stivarga in patients who develop gastrointestinal perforation or fistula..

5.8 Wound Healing Complications
 
No formal studies of the effect of regorafenib on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as regorafenib can impair wound healing, treatment with regorafenib should be stopped at least 2 weeks prior to scheduled surgery. The decision to resume regorafenib after surgery should be based on clinical judgment of adequate wound healing. Regorafenib should be discontinued in patients with wound dehiscence.
 
5.9 Embryo-Fetal Toxicity
 
Stivarga can cause fetal harm when administered to a pregnant woman. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. 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 a fetus [see Use in Specific Populations (8.1)].
 
6 ADVERSE REACTIONS
 
The following serious adverse reactions are discussed elsewhere in the labeling:
 
6.1 Clinical Trials Experience
 
Because clinical trials are conducted under widely varying condit