Stivarga

Regorafenib · Tablet, Film Coated · Oral

Boxed warning. WARNING: HEPATOTOXICITY
• Severe and sometimes fatal hepatotoxicity has occurred in clinical trials [see Warnings and Precautions ( 5.1 )] .
• Monitor hepatic function prior to and during treatment [see Warnings and Precautions ( 5.1 )].
• Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence [see Dosage and Administration ( 2.2 )] . WARNING: HEPATOTOXICITY See full prescribing information for complete boxed warning.
• Severe and sometimes fatal hepatotoxicity has occurred in clinical trials. ( 5.1 )
• Monitor hepatic function prior to and during treatment. ( 5.1 )
• Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence. ( 2.2 )

Uses

1 INDICATIONS AND USAGE STIVARGA is a kinase inhibitor indicated for the treatment of adult patients with:
• Metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy. ( 1.1 )
• Locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. ( 1.2 )
• Hepatocellular carcinoma (HCC) who have been previously treated with sorafenib ( 1.3 ) 1.1 Colorectal Cancer STIVARGA is indicated for the treatment of adult patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy. 1.2 Gastrointestinal Stromal Tumors STIVARGA is indicated for the treatment of adult patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. 1.3 Hepatocellular Carcinoma STIVARGA is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

Dosage and administration

• Recommended dose: 160 mg orally, once daily for the first 21 days of each 28-day cycle. ( 2.1 )
• Take STIVARGA after a low-fat meal. ( 2.1 , 12.3 ) 2.1 Recommended Dose The recommended dose is 160 mg STIVARGA (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-day cycle. Continue treatment until disease progression or unacceptable toxicity. Take STIVARGA at the same time each day. Swallow tablet whole with water after a low-fat meal that contains less than 600 calories and less than 30% fat [see Clinical Pharmacology ( 12.3 )] . Do not take two doses of STIVARGA on the same day to make up for a missed dose from the previous day. 2.2 Dose Modifications If dose modifications are required, reduce the dose in 40 mg (one tablet) increments; the lowest recommended daily dose of STIVARGA is 80 mg daily. Interrupt STIVARGA for the following:
• Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia syndrome (PPES)] that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 HFSR
• Symptomatic Grade 2 hypertension
• Any Grade 3 or 4 adverse reaction
• Worsening infection of any grade Reduce the dose of STIVARGA to 120 mg:
• For the first occurrence of Grade 2 HFSR of any duration
• After recovery of any Grade 3 or 4 adverse reaction except infection
• For Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation, only resume if the potential benefit outweighs the risk of hepatotoxicity Reduce the dose of STIVARGA to 80 mg:
• For re-occurrence of Grade 2 HFSR at the 120 mg dose
• After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity or infection) Discontinue STIVARGA permanently for the following:
• Failure to tolerate 80 mg dose
• Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN)
• Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more than 2 times ULN
• Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction to 120 mg
• For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks

Dosage forms and strengths

3 DOSAGE FORMS AND STRENGTHS STIVARGA is a 40 mg, light pink, oval-shaped, film-coated tablet, debossed with 'BAYER' on one side and '40' on the other side. Tablets: 40 mg ( 3 )

Contraindications

None. None.

Warnings and precautions

• 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%).

Side effects

The 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 )] The most common adverse reactions (≥20%) 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 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in practice. The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to STIVARGA in more than 4800 patients 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 4518 patients 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 4518 patients, 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 observed adverse 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. Colorectal Cancer The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (CORRECT) in which 500 patients (median age 61 years; 61% men) with previously-treated metastatic colorectal cancer (CRC) received STIVARGA as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The median duration of therapy was 1.7 months (range 2 days, 10.8 months) for patients receiving STIVARGA. Due to adverse reactions, 61% of the patients receiving STIVARGA required a dose interruption and 38% of the patients had their dose reduced. Adverse reactions that resulted in treatment discontinuation occurred in 8.2% of STIVARGA-treated patients compared to 1.2% of patients who received placebo. Hand-foot skin reaction (HFSR) and rash were the most common reasons for permanent discontinuation 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 and reported more commonly than in patients receiving placebo a Adverse Reactions STIVARGA (N=500) Placebo (N=253) Grade Grade All % ≥ 3 % All % ≥ 3 % General disorders and administration site conditions Asthenia/fatigue Pain Fever 64 59 28 15 9 2 46 48 15 9 7 0 Metabolism and nutrition disorders Decreased appetite and food intake 47 5 28 4 Skin and subcutaneous tissue disorders HFSR/PPES Rash b 45 26 17 6 7 4 0 <1 Gastrointestinal disorders Diarrhea Mucositis 43 33 8 4 17 5 2 0 Investigations Weight loss 32 <1 10 0 Infections and infestations Infection c 31 9 17 6 Vascular disorders Hypertension Hemorrhage c 30 21 8 2 8 8 <1 <1 Respiratory, thoracic and mediastinal disorders Dysphonia 30 0 6 0 Nervous system disorders Headache 10 <1 7 0 a Adverse reactions graded according to National Cancer Institute Common Toxicity for Adverse Events version 3.0 (NCI CTCAE v3.0). b 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. c Fatal outcomes observed. Table 2 provides laboratory abnormalities observed in CORRECT. Table 2: Laboratory test abnormalities reported in CORRECT Laboratory Parameter STIVARGA (N=500 a ) Placebo (N=253 a ) Grade b Grade b All % 3 % 4 % All % 3 % 4 % Blood and lymphatic system disorders Anemia 79 5 1 66 3 0 Thrombocytopenia 41 2 <1 17 <1 0 Neutropenia 3 1 0 0 0 0 Lymphopenia 54 9 0 35 4 <1 Metabolism and nutrition disorders Hypocalcemia 59 1 <1 18 1 0 Hypokalemia 26 4 0 8 <1 0 Hyponatremia 30 7 1 22 4 0 Hypophosphatemia 57 31 1 11 4 0 Hepatobiliary disorders Hyperbilirubinemia 45 10 3 17 5 3 Increased AST 65 5 1 46 4 1 Increased ALT 45 5 1 30 3 <1 Renal and urinary disorders Proteinuria c 84 2 0 61 1 0 Investigations Increased INR d 24 4 N/A 17 2 N/A Increased Lipase 46 9 2 19 3 2 Increased Amylase 26 2 <1 17 2 <1 a % based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo). b NCI CTCAE v3.0. c Based on urine protein-creatinine ratio data. d International normalized ratio: No Grade 4 denoted in NCI CTCAE, v3.0.

Drug interactions

• Strong CYP3A4 inducers: Avoid strong CYP3A4 inducers. ( 7.1 )
• Strong CYP3A4 inhibitors: Avoid strong CYP3A4 inhibitors. ( 7.2 )
• BCRP substrates: Monitor patients closely for symptoms of increased exposure to BCRP substrates. ( 7.3 ) 7.1 Effect of Strong CYP3A4 Inducers on Regorafenib Co-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 concentrations of the active metabolite M-2 [see Clinical Pharmacology ( 12.3 )] , and may lead to decreased efficacy. Avoid concomitant use of STIVARGA with strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort). 7.2 Effect of Strong CYP3A4 Inhibitors on Regorafenib Co-administration of a strong CYP3A4 inhibitor with STIVARGA increased the plasma concentrations of regorafenib and decreased the plasma concentrations of the active metabolites M-2 and M-5 [see Clinical Pharmacology ( 12.3 )] , and may lead 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) Substrates Co-administration of STIVARGA with a BCRP substrate increased the plasma concentrations of the BCRP substrate [see Clinical Pharmacology ( 12.3 )] . Monitor patients closely for signs and symptoms of exposure related toxicity to the BCRP substrate (e.g. methotrexate, fluvastatin, atorvastatin). Consult the concomitant BCRP substrate product information when considering administration of such products together with STIVARGA.

Use in specific populations

Nursing Mothers: Discontinue drug or nursing, taking into consideration the importance of the drug to the mother. ( 8.3 ) 8.1 Pregnancy Risk Summary Based on animal studies and its mechanism of action, STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Administration of 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 [see Data ] . Advise pregnant women of the potential hazard to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 % and 15 to 20%, respectively. Data Animal Data In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC). In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain barrier in fetuses compared to dams. Daily administration of regorafenib to pregnant rats during organogenesis resulted in fetal findings of delayed ossification at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) and dose-dependent increases in skeletal malformations including cleft palate and enlarged fontanelle at doses ≥ 1 mg/kg (approximately 10% of the clinical exposure based on AUC). At doses ≥ 1.6 mg/kg (approximately 11% of the recommended human dose based on body surface area), there were dose-dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis. In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC), administration of regorafenib resulted in dose-dependent increases in the incidence of additional cardiovascular malformations and skeletal anomalies, as well as significant adverse effects on the urinary system including missing kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were male decreased with increasing dose in two rabbit embryo-fetal toxicity studies. 8.2 Lactation Risk Summary There are no data on the presence of regorafenib or its metabolites in human milk, the effects of regorafenib on the breastfed infant, or on milk production. In rats, regorafenib and its metabolites are excreted in milk. Because of the potential for serious adverse reactions in breastfed infants from STIVARGA, do not breastfeed during treatment with STIVARGA and for 2 weeks after the final dose. 8.3 Females and Males of Reproductive Potential Contraception Females Use effective contraception during treatment and for 2 months after completion of therapy. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 2 months following the final dose of STIVARGA [see Nonclinical Toxicology ( 13.1 )] . Infertility There are no data on the effect of STIVARGA on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility [see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use The safety and efficacy of STIVARGA in pediatric patients less than 18 years of age have not been established. Animal Data In 28-day repeat-dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings occurred at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the recommended dose). In 13-week repeat-dose studies in dogs there were similar findings of dentin alteration at doses as low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose). Administration of regorafenib in these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate. 8.5 Geriatric Use Of the 1142 STIVARGA-treated patients enrolled in randomized, placebo-controlled trials, 40% were 65 years of age and over, while 10% were 75 and over. No overall differences in efficacy were observed between these patients and younger patients. There was an increased incidence of Grade 3 hypertension (18% versus 9%) in the placebo-controlled trials among STIVARGA-treated patients 65 years of age and older as compared to younger patients. In addition, one Grade 4 hypertension event has been reported in the 65 years and older age group and none in the younger age group. 8.6 Hepatic Impairment No dose adjustment is recommended in patients with mild (total bilirubin ≤ULN and AST >ULN, or total bilirubin >ULN to ≤1.5 times ULN) or moderate (total bilirubin >1.5 to ≤3 times ULN and any AST) hepatic impairment, [see Clinical Pharmacology ( 12.3 )] . Closely monitor patients with hepatic impairment for adverse reactions [see Warnings and Precautions ( 5.1 )] . STIVARGA is not recommended for use in patients with severe hepatic impairment (total bilirubin >3x ULN) as STIVARGA has not been studied in this population. 8.7 Renal Impairment No dose adjustment is recommended for patients with renal impairment.

Pregnancy

8.1 Pregnancy Risk Summary Based on animal studies and its mechanism of action, STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Administration of 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 [see Data ] . Advise pregnant women of the potential hazard to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 % and 15 to 20%, respectively. Data Animal Data In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC). In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain barrier in fetuses compared to dams. Daily administration of regorafenib to pregnant rats during organogenesis resulted in fetal findings of delayed ossification at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) and dose-dependent increases in skeletal malformations including cleft palate and enlarged fontanelle at doses ≥ 1 mg/kg (approximately 10% of the clinical exposure based on AUC). At doses ≥ 1.6 mg/kg (approximately 11% of the recommended human dose based on body surface area), there were dose-dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis. In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC), administration of regorafenib resulted in dose-dependent increases in the incidence of additional cardiovascular malformations and skeletal anomalies, as well as significant adverse effects on the urinary system including missing kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were male decreased with increasing dose in two rabbit embryo-fetal toxicity studies.

Pediatric use

8.4 Pediatric Use The safety and efficacy of STIVARGA in pediatric patients less than 18 years of age have not been established. Animal Data In 28-day repeat-dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings occurred at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the recommended dose). In 13-week repeat-dose studies in dogs there were similar findings of dentin alteration at doses as low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose). Administration of regorafenib in these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate.

Geriatric use

8.5 Geriatric Use Of the 1142 STIVARGA-treated patients enrolled in randomized, placebo-controlled trials, 40% were 65 years of age and over, while 10% were 75 and over. No overall differences in efficacy were observed between these patients and younger patients. There was an increased incidence of Grade 3 hypertension (18% versus 9%) in the placebo-controlled trials among STIVARGA-treated patients 65 years of age and older as compared to younger patients. In addition, one Grade 4 hypertension event has been reported in the 65 years and older age group and none in the younger age group.

Overdosage

The highest dose of STIVARGA studied clinically is 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue. There is no known antidote for STIVARGA overdose. In the event of suspected overdose, interrupt STIVARGA, institute supportive care, and observe until clinical stabilization.

Description

(regorafenib) is a multikinase inhibitor with the chemical name 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate. Regorafenib has the following structural formula: Regorafenib is a monohydrate and it has a molecular formula C 21 H 15 ClF 4 N 4 O 3
• H 2 O and a molecular weight of 500.83. Regorafenib is practically insoluble in water, slightly soluble in acetonitrile, methanol, ethanol, and ethyl acetate and sparingly soluble in acetone. STIVARGA tablets for oral administration are formulated as light pink, oval-shaped tablets debossed with "BAYER" on one side and "40" on the other. Each tablet contains 40 mg of regorafenib in the anhydrous state, which corresponds to 41.49 mg of regorafenib monohydrate, and the following inactive ingredients: cellulose microcrystalline, croscarmellose sodium, magnesium stearate, povidone, and colloidal silicon dioxide. The film-coating contains the following inactive ingredients: ferric oxide red, ferric oxide yellow, lecithin (soy), polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide. Description: Chemical Structure

Mechanism of action

12.1 Mechanism of Action Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, metastasis and tumor immunity. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, Abl and CSF1R at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model and inhibition of tumor growth in several mouse xenograft models including some for human colorectal carcinoma, gastrointestinal stromal and hepatocellular carcinoma. Regorafenib also demonstrated anti-metastatic activity in a mouse xenograft model and two mouse orthotopic models of human colorectal carcinoma.

How supplied

How Supplied STIVARGA (regorafenib) is supplied as 40 mg tablets that are light pink, oval-shaped, film-coated tablets, debossed with 'BAYER' on one side and '40' on the other side in the following:
• Packages containing three bottles, with each bottle containing 28 tablets, for a total of 84 tablets per package (NDC 50419-171-03).
• Packages containing four bottles, with each bottle containing 21 tablets, for a total of 84 tablets per package (NDC 50419-171-06). Storage and Handling Store STIVARGA at 25°C (77°F); excursions are permitted from 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Store tablets in the original bottle and do not remove the desiccant. Keep the bottle tightly closed after first opening. Discard any unused tablets 7 weeks after opening the bottle. Dispose of unused tablets in accordance with local requirements.

Patient information

Advise the patient to read the FDA-approved patient labeling (Patient Information). Hepatotoxicity Advise patients that they will need to undergo monitoring for liver damage and to report immediately any signs or symptoms of severe liver damage to their healthcare provider. Advise patients to contact their healthcare provider immediately if they experience a severe and/or persistent headache, visual disturbances, seizures, noticeable decrease in energy, drowsiness, trembling, confusion, memory loss or disorientation [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.6 )]. Infections Advise patients to contact their healthcare provider if they experience signs and symptoms of infection [see Warnings and Precautions (5.2 )]. Hemorrhage Advise patients to contact their healthcare provider for unusual bleeding, bruising, or symptoms of bleeding, such as lightheadedness [see Warnings and Precautions ( 5.3 )] . Gastrointestinal Perforation or Fistula Advise patients to contact a healthcare provider immediately if they experience severe pains in their abdomen, persistent swelling of the abdomen, high fever, chills, nausea, vomiting, or dehydration [see Warnings and Precautions (5.4)] . Dermatologic Toxicity Advise patients to contact their healthcare provider if they experience skin changes including HFSR, rash, pain, blisters, bleeding, or swelling [see Warnings and Precautions ( 5.5 )]. Hypertension Advise patients they will need to undergo blood pressure monitoring and to contact their healthcare provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms [see Warnings and Precautions ( 5.6 )]. Cardiac Ischemia and Infarction Advise patients to seek immediate emergency help if they experience chest pain, shortness of breath, feel dizzy, or feel like passing out [see Warnings and Precautions ( 5.7 )] . Reversible Posterior leukoencephalopathy syndrome Advise patients to contact their healthcare provider if they experience signs and symptoms of RPLS [see Warnings and Precautions ( 5.8 )] . Risk of Impaired Wound Healing Advise patients that STIVARGA may impair wound healing. Advise patients that temporary interruption of STIVARGA is recommended prior to any elective surgery [see Warnings and Precautions ( 5.9 )]. Embryo-Fetal Toxicity Advise patients that regorafenib can cause fetal harm. Advise a pregnant woman of the potential risk to a fetus [see Warnings and Precautions ( 5.10 ), Use in Specific Populations ( 8.1 , 8.3 )]. Females and Males of Reproductive Potential
• Advise women of reproductive potential of the need for effective contraception during STIVARGA treatment and for 2 months after completion of treatment. Instruct women of reproductive potential to immediately contact her healthcare provider if pregnancy is suspected or confirmed during or within 2 months of completing treatment with STIVARGA [see Warnings and Precautions ( 5.10 ) and Use in Specific Populations ( 8.1 , 8.3 )] .
• Advise men of reproductive potential of the need for effective contraception during STIVARGA treatment and for 2 months after completion of treatment [see Use in Specific Populations ( 8.3 )] . Lactation Advise nursing mothers that it is not known whether regorafenib is present in breast milk and discuss whether to discontinue nursing or to discontinue regorafenib [see Use in Specific Populations ( 8.2 )] . Administration
• Advise patients to swallow the STIVARGA tablet whole with water at the same time each day following a low-fat meal. Inform patients that the low-fat meal should contain less than 600 calories and less than 30% fat [see Dosage and Administration ( 2.1 )] .
• Advise patients to store medicine in the original container. Do not place medication in daily or weekly pill boxes. Discard any remaining tablets 7 weeks after opening the bottle. Tightly close bottle after each opening and keep the desiccant in the bottle [see How Supplied ( 16 )] . Dosing Instructions Advise patients to take STIVARGA after a low fat meal. Advise patients to take any missed dose on the same day, as soon as they remember, and that they must not take two doses on the same day to make up for a dose missed on the previous day [see Dose and Administration ( 2.1 )]. Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981 USA

Label text from the FDA structured product label by Bayer HealthCare Pharmaceuticals Inc. (revised Feb 9, 2026). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Regorafenib in 1 product

Stivarga NDC products (1)

NDC	Strength & form	Labeler	Type
50419-171	Regorafenib 40 mg/1 Tablet, Film Coated	Bayer HealthCare Pharmaceuticals Inc.	NDA

Frequently asked questions

What is Stivarga used for?

What are the side effects of Stivarga?

Who makes Stivarga?

Stivarga is listed by 1 labeler in the FDA NDC directory, including Bayer HealthCare Pharmaceuticals Inc..