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hemorrhagic events was 0.7%, involving the central nervous system or the respiratory, gastrointestinal, or genitourinarytracts.Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage. Monitor INR levels morefrequently in patients receiving warfarin [see Clinical Pharmacology (12.3)].5.4 Gastrointestinal Perforation or FistulaGastrointestinal perforation occurred in 0.6% of 4518 patients treated with STIVARGA across all clinical trials ofSTIVARGA 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 acrossrandomized, placebo-controlled trials. Permanently discontinue STIVARGA in patients who develop gastrointestinalperforation or fistula.5.5 Dermatologic ToxicityIn randomized, placebo-controlled trials, adverse skin reactions occurred in 71.9% of patients in the regorafenib arm andin 25.5% of patients in the placebo arm, including hand-foot skin reaction (HFSR) also known as palmar-plantarerythrodysesthesia syndrome (PPES), and severe rash requiring dose modification.In the randomized, placebo-controlled trials, the overall incidence of HFSR was higher in 1142 STIVARGA-treatedpatients (53%) than in the placebo-treated patients (8%). Most cases of HFSR in STIVARGA-treated patients appearedduring 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%) werealso higher in STIVARGA-treated patients [see Adverse Reactions (6.1)]. Across all trials, a higher incidence of HFSRwas observed in Asian patients treated with STIVARGA (all grades: 72%; Grade 3: 18%) [see Use in SpecificPopulations (8.8 )].Toxic epidermal necrolysis occurred in 0.02% of 4518 STIVARGA-treated patients across all clinical trials ofSTIVARGA administered as a single agent.Withhold STIVARGA, reduce the dose, or permanently discontinue STIVARGA depending on the severity andpersistence of dermatologic toxicity [see Dosage and Administration (2.2)]. Institute supportive measures forsymptomatic relief.5.6 HypertensionIn randomized, placebo-controlled trials, hypertensive crisis occurred in 0.2% of patients in the regorafenib arms and innone of the patients in the placebo arms. STIVARGA caused an increased incidence of hypertension (30% versus 8% inCORRECT, 59% versus 27% in GRID, and 31% versus 6% in RESORCE) [see Adverse Reactions (6.1)]. The onset ofhypertension occurred during the first cycle of treatment in most patients who developed hypertension (67% inrandomized, placebo-controlled trials).Do not initiate STIVARGA unless blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withholdSTIVARGA for severe or uncontrolled hypertension [see Dosage and Administration (2.2)].5.7 Cardiac Ischemia and InfarctionSTIVARGA increased the incidence of myocardial ischemia and infarction (0.9% vs 0.2%) in randomized placebocontrolled trials [see Adverse Reactions (6.1)]. Withhold STIVARGA in patients who develop new or acute onset cardiacischemia or infarction. Resume STIVARGA only after resolution of acute cardiac ischemic events, if the potentialbenefits outweigh the risks of further cardiac ischemia.5.8 Reversible Posterior Leukoencephalopathy SyndromeReversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed bycharacteristic finding on MRI, occurred in one of 4800 STIVARGA-treated patients across all clinical trials. Perform anevaluation for RPLS in any patient presenting with seizures, severe headache, visual disturbances, confusion or alteredmental function. Discontinue STIVARGA in patients who develop RPLS.5

5.9 Risk of Impaired Wound HealingImpaired wound healing complications can occur in patients who receive drugs that inhibit the VEGF signaling pathway.Therefore, STIVARGA has the potential to adversely affect wound healing.Withhold STIVARGA for at least 2 weeks prior to elective surgery. Do not administer for at least 2 weeks followingmajor surgery and until adequate wound healing. The safety of resumption of STIVARGA after resolution of woundhealing complications has not been established.5.10 Embryo-Fetal ToxicityBased on animal studies and its mechanism of action, STIVARGA can cause fetal harm when administered to a pregnantwoman. There are no available data on STIVARGA use in pregnant women. Regorafenib was embryolethal andteratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increasedincidences of cardiovascular, genitourinary, and skeletal malformations. Advise pregnant women of the potential risk to afetus.Advise females of reproductive potential to use effective contraception during treatment with STIVARGA and for 2months after the final dose. Advise males with female partners of reproductive potential to use effective contraceptionduring treatment with STIVARGA and for 2 months after the final dose [see Use in Specific Populations (8.1), (8.3)].6 ADVERSE REACTIONSThe following serious adverse reactions are discussed elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions (5.1)] Infections [see Warnings and Precautions (5.2)] Hemorrhage [see Warnings and Precautions (5.3)] Gastrointestinal Perforation or Fistula [see Warnings and Precautions (5.4)] Dermatological Toxicity [see Warnings and Precautions (5.5)] Hypertension [see Warnings and Precautions (5.6)] Cardiac Ischemia and Infarction [see Warnings and Precautions (5.7)] Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions (5.8)]6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trialsof a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed inpractice.The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to STIVARGA in more than 4800patients who were enrolled in four randomized, placebo-controlled trials (n 1142), an expanded access program(CONSIGN, n 2864), or single arm clinical trials (single agent or in combination with other agents). There were 4518patients who received STIVARGA as a single agent; the distribution of underlying malignancies was 80% CRC, 4%GIST, 10% HCC, 6% other solid tumors; and 74% were White, 11% Asian, and 15% race not known. Among these 4518patients, 83% received STIVARGA for at least 21 days and 20% received STIVARGA for 6 months or longer.In randomized placebo-controlled trials (CORRECT, GRID, RESORCE and CONCUR), the most frequently observedadverse drug reactions ( 20%) in patients receiving STIVARGA are pain (including gastrointestinal and abdominal pain),HFSR, asthenia/fatigue, diarrhea, decreased appetite/food intake, hypertension, infection, dysphonia, hyperbilirubinemia,fever, mucositis, weight loss, rash, and nausea.6

Colorectal CancerThe safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebocontrolled trial (CORRECT) in which 500 patients (median age 61 years; 61% men) with previously-treated metastaticcolorectal cancer (CRC) received STIVARGA as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The median duration of therapywas 1.7 months (range 2 days, 10.8 months) for patients receiving STIVARGA. Due to adverse reactions, 61% of thepatients receiving STIVARGA required a dose interruption and 38% of the patients had their dose reduced. Adversereactions that resulted in treatment discontinuation occurred in 8.2% of STIVARGA-treated patients compared to 1.2% ofpatients who received placebo. Hand-foot skin reaction (HFSR) and rash were the most common reasons for permanentdiscontinuation of STIVARGA.Table 1 provides the incidence of adverse reactions ( 10%) in patients in CORRECT.Table 1: Adverse drug reactions reported in 10% of patients treated with STIVARGA in CORRECT andreported more commonly than in patients receiving placeboaSTIVARGA(N 500)GradeAdverse ReactionsGeneral disorders and administrationsite conditionsAsthenia/fatiguePainFeverMetabolism and nutrition disordersDecreased appetite and food intakeabcPlacebo(N 253)GradeAll% 3%All% 3%6459281592464815970475284Skin and subcutaneous tissue disorders451770HFSR/PPESbRash2664 1Gastrointestinal sWeight loss32 1100Infections and infestationsInfection c319176Vascular disordersHypertension3088 1Hemorrhage c2128 1Respiratory, thoracic and mediastinaldisordersDysphonia30060Nervous system disordersHeadache10 170Adverse reactions graded according to National Cancer Institute Common Toxicity for Adverse Events version 3.0(NCI CTCAE v3.0).The term rash represents reports of events of drug eruption, rash, erythematous rash, generalized rash, macular rash,maculo-papular rash, papular rash, and pruritic rash.Fatal outcomes observed.7

Table 2 provides laboratory abnormalities observed in CORRECT.Table 2: Laboratory test abnormalities reported in CORRECTSTIVARGA(N 500 a)Grade bLaboratory ParameterAll%abcd3%Placebo(N 253 a)Grade b4%All%3%4%Blood and lymphatic systemdisordersAnemia79516630Thrombocytopenia412 117 10Neutropenia310000Lymphopenia5490354 1Metabolism and nutritiondisordersHypocalcemia591 11810Hypokalemia26408 atobiliary disordersHyperbilirubinemia451031753Increased AST65514641Increased ALT4551303 1Renal and urinary ed INRd244N/A172N/AIncreased Lipase46921932Increased Amylase262 1172 1% based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo).NCI CTCAE v3.0.Based on urine protein-creatinine ratio data.International normalized ratio: No Grade 4 denoted in NCI CTCAE, v3.0.Gastrointestinal Stromal TumorsThe safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (GRID) inwhich 132 patients (median age 60 years; 64% men) with previously-treated GIST received STIVARGA as a single agentat a dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 66 patients (median age 61 years; 64%men) received placebo. The median duration of therapy was 5.7 months (range 1 day, 11.7 months) for patients receivingSTIVARGA. Dose interruptions for adverse events were required in 58% of patients receiving STIVARGA and 50% ofpatients had their dose reduced. Adverse reactions that resulted in treatment discontinuation were reported in 2.3% ofSTIVARGA-treated patients compared to 1.5% of patients who received placebo.Table 3 provides the incidence of adverse reactions ( 10%) in patients in GRID.8

Table 3: Adverse reactions reported in 10% patients treated with STIVARGA in GRID and reportedmore commonly than in patients receiving placeboaAdverse ReactionsSkin and subcutaneous tissue disordersHFSR/PPERash bAlopeciaabcdSTIVARGA(N 132)Placebo(N 66)GradeGradeAll% 3%All% 3%67302422721232200General disorders and administrationsite r ntestinal sea202122Vomiting17 180Respiratory, thoracic and mediastinaldisordersDysphonia39090Infections and infestationsInfection c32550Metabolism and nutrition disordersDecreased appetite and food intake31 1213dHypothyroidism18060Nervous system disordersHeadache16090InvestigationsWeight loss14080Musculoskeletal and connective tissuedisordersMuscle spasms14030Adverse reactions graded according to NCI CTCAE v4.0.The term rash represents reports of events of rash, erythematous rash, macular rash, maculo-papular rash, papular rashand pruritic rash.Fatal outcomes observed.Hypothyroidism incidence based on subset of patients with normal TSH and no thyroid supplementation at baseline.Table 4 provides laboratory abnormalities observed in GRID.9

Table 4: Laboratory test abnormalities reported in GRIDAll%STIVARGA(N 132 a)Grade b3%4%131630128172155335839Laboratory ParameterBlood and lymphaticsystem abolism and hatemiaHepatobiliary disordersHyperbilirubinemiaIncreased ASTIncreased ALTAll%Placebo(N 66 a)Grade 000Renal and urinarydisordersProteinuria c593-d533-dInvestigationsIncreased Lipase1401500aPercent based on number of patients with post-baseline samples which may be less than 132 (regorafenib) or66 (placebo).bNCI CTCAE v4.0.cBased on urine protein-creatinine ratio data.dNo Grade 4 denoted in NCI CTCAE v4.0.Hepatocellular CarcinomaThe safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (RESORCE)in which patients with previously-treated HCC received either STIVARGA (n 374) 160 mg orally on days 1-21 of each 4week treatment cycle or placebo (n 193). The median age was 63 years, 88% were men, 98% had Child-Pugh A cirrhosis,66% had an ECOG performance status (PS) of 0 and 34% had PS of 1. The median duration of therapy was 3.5 months(range 1 day to 29.4 months) for patients receiving STIVARGA. Of the patients receiving STIVARGA, 33% wereexposed to STIVARGA for greater than or equal to 6 months and 14% were exposed to STIVARGA for greater than orequal to 12 months. Dose interruptions for adverse events were required in 58.3% of patients receiving STIVARGA and48% of patients had their dose reduced. The most common adverse reactions requiring dose modification (interruption ordose reduction) were HFSR/PPES (20.6%), blood bilirubin increase (5.9%), fatigue (5.1%) and diarrhea (5.3%). Adversereactions that resulted in treatment discontinuation were reported in 10.4% of STIVARGA-treated patients compared to3.6% of patients who received placebo; the most common adverse reactions requiring discontinuation of STIVARGAwere HFSR/PPES (1.9%) and AST increased (1.6%).Table 5 provides the incidence of adverse reactions ( 10%) in patients in RESORCE.10

Table 5: Adverse reactions reported in 10% of patients treated with STIVARGA in RESORCE andreported more commonly than in patients receiving placeboaAdverse ReactionsSkin and subcutaneous tissuedisordersHFSR/PPEGeneral disorders andadministration site conditionsPainAsthenia/FatigueFeverVascular disordersHypertensionHemorrhage bGastrointestinal y, thoracic andmediastinal disordersDysphoniaInfections and infestationsInfection bMetabolism and nutritiondisordersDecreased appetite and foodintakeInvestigationsWeight lossabSTIVARGA(N 374)Placebo(N 193)GradeGradeAll% 3%All% 3%51127 1554220910044337850311815561658411713133 1 1115137200 1 11802031818631315213240020Musculoskeletal andconnective tissue disordersMuscle spasms10Adverse reactions graded according to NCI CTCAE v4.0.Fatal outcomes observed.Other clinically significant adverse reactions observed in less than 10% of STIVARGA-treated patients were: alopecia(7%), hypothyroidism (6.4%), pancreatitis (1.6%), exfoliative rash (1.3%), tremor (1.3%), erythema multiforme (0.8%),myocardial ischemia (0.8%), gastrointestinal fistula (0.3%), and myocardial infarction (0.3%).Table 6 provides laboratory abnormalities observed in RESORCE.11

Table 6: Laboratory test abnormalities reported in RESORCEAll%STIVARGA(N 374 a)Grade b3%4%6314685316233170789370Laboratory ParameterBlood and lymphaticsystem abolism and hatemiaHepatobiliary disordersHyperbilirubinemiaIncreased ASTIncreased ALTAll%Placebo(N 193 a)Grade b3%4% 1025015590 1110 1 1 14320 12109310270001316632 155845911175530Renal and urinarydisordersProteinuria c5117-d373-dInvestigationsIncreased INR44 1-d352-dIncreased Lipase411132781Increased Amylase233 1192 1aPercent based on number of patients with post-baseline samples which may be less than 374 (regorafenib) or 193(placebo).bNCI CTCAE v4.0.cBased on dipstick data.dNo Grade 4 denoted in NCI CTCAE v4.0.6.2 Postmarketing ExperienceThe following adverse reaction has been identified during postapproval use of STIVARGA. Because these reactions arereported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency orestablish a causal relationship to drug exposure: hypersensitivity reaction nephrotic syndrome cardiac failure arterial (including aortic) aneurysms, dissections, and rupture7 DRUG INTERACTIONS7.1 Effect of Strong CYP3A4 Inducers on RegorafenibCo-administration of a strong CYP3A4 inducer with STIVARGA decreased the plasma concentrations of regorafenib,increased the plasma concentrations of the active metabolite M-5, and resulted in no change in the plasma concentrations12

of the active metabolite M-2 [see Clinical Pharmacology (12.3)], and may lead to decreased efficacy. Avoid concomitantuse of STIVARGA with strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’sWort).7.2 Effect of Strong CYP3A4 Inhibitors on RegorafenibCo-administration of a strong CYP3A4 inhibitor with STIVARGA increased the plasma concentrations of regorafenib anddecreased the plasma concentrations of the active metabolites M-2 and M-5 [see Clinical Pharmacology (12.3)], and maylead to increased toxicity. Avoid concomitant use of STIVARGA with strong CYP3A4 inhibitors (e.g. clarithromycin,grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole).7.3 Effect of Regorafenib on Breast Cancer Resistance Protein (BCRP) SubstratesCo-administration of STIVARGA with a BCRP substrate inc

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use STIVARGA safely and effectively. See full prescribing information for STIVARGA. STIVARGA (regorafenib) tablets, for oral use Initial U.S. Approval: 2012 cardiac ischemia/infarction and re