stivarga

Important safety information

Hepatotoxicity : Monitor liver function tests. Withhold and then reduce or discontinue STIVARGA based on severity and duration. ( 5.1 ) • Infections : Withhold STIVARGA in patients with worsening or severe infections. ( 5.2 ) • Hemorrhage : Permanently discontinue STIVARGA for severe or life-threatening hemorrhage. ( 5.3 ) • Gastrointestinal perforation or fistula : Discontinue STIVARGA. ( 5.4 ) • Dermatologic toxicity : Withhold and then reduce or discontinue STIVARGA depending on severity and persistence of dermatologic toxicity. ( 5.5 ) • Hypertension : Temporarily or permanently withhold STIVARGA for severe or uncontrolled hypertension. ( 5.6) • Cardiac ischemia and infarction : Withhold STIVARGA for new or acute cardiac ischemia/infarction and resume only after resolution of acute ischemic events. ( 5.7) • Reversible posterior leukoencephalopathy syndrome (RPLS) : Discontinue STIVARGA. ( 5.8) • Risk of impaired wound healing : Withhold for at least 2 weeks prior to elective surgery. Do not administer for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of STIVARGA after resolution of wound healing complications has not been established. ( 5.9 ) • Embryo-fetal toxicity : Can cause fetal harm. Advise women of potential risk to a fetus and to use effective contraception during treatment and for 2 months after the final dose. Advise males to use effective contraception for 2 months after the final dose. ( 5.10 , 8.1 , 8.3 ) 5.1 Hepatotoxicity Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients in clinical trials. In most cases, liver dysfunction occurred within the first 2 months of therapy and was characterized by a hepatocellular pattern of injury. Additionally, hyperammonemic encephalopathy, including fatal cases, have been reported in the postmarketing setting in patients treated with STIVARGA. The risk of hyperammonemic encephalopathy appears increased in patients with liver dysfunction, liver metastases, or primary liver cancer. In the CORRECT study, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 0.4% of patients in the placebo arm. In the GRID study , fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm. In the RESORCE study, there was no increase in the incidence of fatal hepatic failure as compared to placebo [see Adverse Reactions ( 6.1 )] . Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every two weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline. For patients who develop unexplained lethargy or changes in mental status, measure ammonia level and initiate appropriate clinical management. Temporarily hold and then reduce or permanently discontinue STIVARGA depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )] . If hyperammonemic encephalopathy is confirmed, withhold and consider permanent discontinuation of STIVARGA. 5.2 Infections STIVARGA caused an increased risk of infections. The overall incidence of infection (Grades 1-5) was higher (32% vs. 17%) in 1142 STIVARGA-treated patients as compared to the control arm in randomized placebo‑controlled trials.The incidence of grade 3 or greater infections in STIVARGA treated patients was 9%. The most common infections were urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) and pneumonia (2.6%). Fatal outcomes caused by infection occurred more often in patients treated with STIVARGA (1.0%) as compared to patients receiving placebo (0.3%); the most common fatal infections were respiratory (0.6% in STIVARGA-treated patients vs 0.2% in patients receiving placebo). Withhold STIVARGA for Grade 3 or 4 infections, or worsening infection of any grade. Resume STIVARGA at the same dose following resolution of infection [see Dosage and Administration ( 2.2 )] . 5.3 Hemorrhage STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 18.2% in 1142 patients treated with STIVARGA and 9.5% in patients receiving placebo in randomized, placebo‑controlled trials. The incidence of grade 3 or greater hemorrhage in patients treated with STIVARGA was 3.0%. The incidence of fatal hemorrhagic events was 0.7%, involving the central nervous system or the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage. Monitor INR levels more frequently in patients receiving warfarin [see Clinical Pharmacology ( 12.3 )] . 5.4 Gastrointestinal Perforation or Fistula Gastrointestinal perforation occurred in 0.6% of 4518 patients treated with STIVARGA across all clinical trials of STIVARGA administered as a single agent; this included eight fatal events. Gastrointestinal fistula occurred in 0.8% of patients treated with STIVARGA and 0.2% of patients in placebo arm across randomized, placebo-controlled trials. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula. 5.5 Dermatologic Toxicity In randomized, placebo-controlled trials, adverse skin reactions occurred in 71.9% of patients in the regorafenib arm and in 25.5% of patients in the placebo arm, including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia syndrome (PPES), and severe rash requiring dose modification. In the randomized, placebo-controlled trials, the overall incidence of HFSR was higher in 1142 STIVARGA-treated patients (53%) than in the placebo-treated patients (8%). Most cases of HFSR in STIVARGA-treated patients appeared during the first cycle of treatment. The incidences of Grade 3 HFSR (16% versus <1%), Grade 3 rash (3% versus <1%), serious adverse reactions of erythema multiforme (<0.1% vs. 0%) and Stevens-Johnson Syndrome (<0.1% vs. 0%) were also higher in STIVARGA-treated patients [see Adverse Reactions (6.1)] . Across all trials, a higher incidence of HFSR was observed in Asian patients treated with STIVARGA (all grades: 72%; Grade 3: 18%) [see Use in Specific Populations ( 8.8 )] . Toxic epidermal necrolysis occurred in 0.02% of 4518 STIVARGA-treated patients across all clinical trials of STIVARGA administered as a single agent. Withhold STIVARGA, reduce the dose, or permanently discontinue STIVARGA depending on the severity and persistence of dermatologic toxicity [see Dosage and Administration ( 2.2 )] . Institute supportive measures for symptomatic relief. 5.6 Hypertension In randomized, placebo-controlled trials, hypertensive crisis occurred in 0.2% of patients in the regorafenib arms and in none of the patients in the placebo arms. STIVARGA caused an increased incidence of hypertension (30% versus 8% in CORRECT, 59% versus 27% in GRID, and 31% versus 6% in RESORCE) [see Adverse Reactions ( 6.1)]. The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (67% in randomized, placebo-controlled trials). Do not initiate STIVARGA unless 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 )]. 5.7 Cardiac Ischemia and Infarction STIVARGA increased the incidence of myocardial ischemia and infarction (0.9% vs 0.2%) in randomized placebo-controlled trials [see Adverse Reactions ( 6.1 )] . Withhold STIVARGA in patients who develop new or acute onset…