The recommended dose is 160 mg regorafenib (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 a low-fat breakfast that contains less than 30% fat [see Clinical Pharmacology (12.3)]. Examples of a low-fat breakfast include 2 slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly, and 8 ounces of skim milk (319 calories and 8.2 g fat); or 1 cup of cereal, 8 ounces of skim milk, 1 slice of toast with jam, apple juice, and 1 cup of coffee or tea (520 calories and 2 g fat). 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

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.

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

5.1 Hepatotoxicity

Severe drug induced liver injury with fatal outcome occurred in 0.3% of 1200 Stivarga-treated patients across all clinical trials. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration. In Study 1, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver. In Study 2, fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm [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.

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)].

5.2 Hemorrhage

Stivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% and 11% in Stivarga-treated patients compared to 8% and 3% in placebo-treated patients in Studies 1 and 2. Fatal hemorrhage occurred in 4 of 632 (0.6%) of Stivarga-treated patients in Studies 1 and 2 and involved 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)].

5.3 Dermatological Toxicity

Stivarga caused increased incidences of adverse reactions involving the skin and subcutaneous tissues (72% versus 24% in Study 1 and 78% versus 24% in Study 2), including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia (PPE), and severe rash requiring dose modification.

The overall incidence of HFSR was higher in Stivarga-treated patients, (45% versus 7% in Study 1 and 67% versus 12% in Study 2), than in the placebo-treated patients. Most cases of HFSR in Stivarga-treated patients appeared during the first cycle of treatment (69% and 71% of patients who developed HFSR in Study 1 and Study 2, respectively). The incidence of Grade 3 HFSR (17% versus 0% in Study 1 and 22% versus 0% in Study 2), Grade 3 rash (6% versus <1% in Study 1 and 7% versus 0% in Study 2), serious adverse reactions of erythema multiforme (0.2% vs. 0% in Study 1) and Stevens Johnson Syndrome (0.2% vs. 0% in Study 1) was higher in Stivarga-treated patients [see Adverse Reactions ( 6.1 )] .

Toxic epidermal necrolysis occurred in 0.17% of 1200 Stivarga-treated patients across all clinical trials.

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.

5.4 Hypertension

Stivarga caused an increased incidence of hypertension (30% versus 8% in Study 1 and 59% versus 27% in Study 2) [see Adverse Reactions ( 6.1 )] . Hypertensive crisis occurred in 0.25% of 1200 Stivarga-treated patients across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (72% in Study 1 and Study 2).

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)] .

5.5 Cardiac Ischemia and Infarction

Stivarga increased the incidence of myocardial ischemia and infarction in Study 1 (1.2% versus 0.4%) [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)

Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one of 1200 Stivarga-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue Stivarga in patients who develop RPLS.

5.7 Gastrointestinal Perforation or Fistula

Gastrointestinal perforation or fistula occurred in 0.6% of 1200 patients treated with Stivarga across all clinical trials; this included four fatal events. In Study 2, 2.1 % (4/188) of Stivarga-treated patients who were treated during the blinded or open-label portion of the study developed gastrointestinal fistula or perforation; of these, two cases of gastrointestinal perforation were fatal. 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)].

ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

* Hepatotoxicity [See Warnings and Precautions (5.1)]
* Hemorrhage [See Warnings and Precautions ( 5.2 )]
* Dermatological Toxicity [See Warnings and Precautions ( 5.3 )]
* Hypertension [See Warnings and Precautions (5.4)]
* Cardiac Ischemia and Infarction [See Warnings and Precautions ( 5.5 )]
* Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [See Warnings and Precautions ( 5.6 )]
* Gastrointestinal Perforation or Fistula [See Warnings and Precautions ( 5.7 )]

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 most frequently observed adverse drug reactions (>=20%) in patients receiving Stivarga are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea.

The most serious adverse drug reactions in patients receiving Stivarga are hepatotoxicity, hemorrhage, and gastrointestinal perforation.

6.1 Clinical Trials Experience

Colorectal Cancer

The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 1) in which 500 patients (median age 61 years; 61% men) with previously treated metastatic colorectal cancer 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 7.3 (range 0.3, 47.0) weeks 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. Drug-related adverse reactions that resulted in treatment discontinuation were reported 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 compares the incidence of adverse reactions (>=10%) in patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 1).

Table 1 Adverse drug reactions (≥10%) reported in patients treated with Stivarga in Study 1 and reported more commonly than in patients receiving placebo
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 29 28	15 3 2	46 21 15	9 2 0
Metabolism and nutrition disorders Decreased appetite and food intake	47	5	28	4
Skin and subcutaneous tissue disorders HFSR/PPE Rash	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	31	9	17	6
Vascular disorders Hypertension Hemorrhage	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

Laboratory Abnormalities

Laboratory abnormalities observed in Study 1 are shown in Table 2.

Table 2 Laboratory test abnormalities reported in Study 1
Laboratory Parameter	Stivarga (N=500 )			Placebo (N=253 )
	Grade			Grade
	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	34	3	0
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	60	<1	0	34	<1	0
Investigations
Increased INR	24	4	N/A	17	2	N/A
Increased Lipase	46	9	2	19	3	2
Increased Amylase	26	2	<1	17	2	<1

Gastrointestinal Stromal Tumors

The safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 2) in which 132 patients (median age 60 years; 64% men) with previously treated GIST received Stivarga as a single agent at 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 22.9 (range 0.1, 50.9) weeks for patients receiving Stivarga. Dose interruptions for adverse events were required in 58% of patients receiving Stivarga and 50% of patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 2.3% of Stivarga-treated patients compared to 1.5% of patients who received placebo.

Table 3 compares the incidence of adverse reactions (>=10%) in GIST patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 2).

Table 3 Adverse reactions (≥10%) reported in patients treated with Stivarga in Study 2 and reported more commonly than in patients receiving placebo
Adverse Reactions	Stivarga (N=132)		Placebo (N=66)
	Grade		Grade
	All %	>= 3 %	All %	>= 3 %
Skin and subcutaneous tissue disorders HFSR/PPE Rash Alopecia	67 30 24	22 7 2	15 3 2	2 0 0
General disorders and administration site conditions Asthenia/Fatigue Fever	52 21	4 0	39 11	2 2
Vascular disorders Hypertension Hemorrhage	59 11	28 4	27 3	5 0
Gastrointestinal disorders Diarrhea Mucositis Nausea Vomiting	47 40 20 17	8 2 2 <1	9 8 12 8	0 2 2 0
Respiratory, thoracic and mediastinal disorders Dysphonia	39	0	9	0
Infections and infestations Infection	32	5	5	0
Metabolism and nutrition disorders Decreased appetite and food intake Hypothyroidism	31 18	<1 0	21 6	3 0
Nervous system disorders Headache	16	0	9	0
Investigations Weight loss	14	0	8	0
Musculoskeletal and connective tissue disorders Musculoskeletal stiffness	14	0	3	0

Laboratory abnormalities observed in Study 2 are shown in Table 4.

Table 4 Laboratory test abnormalities reported in Study 2
Laboratory Parameter	Stivarga (N=132 )			Placebo (N=66 )
	Grade			Grade
	All %	3 %	4 %	All %	3 %	4 %
Blood and lymphatic system disorders Thrombocytopenia Neutropenia Lymphopenia	13 16 30	1 2 8	0 0 0	2 12 24	0 3 3	2 0 0
Metabolism and nutrition disorders Hypocalcemia Hypokalemia Hypophosphatemia	17 21 55	2 3 20	0 0 2	5 3 3	0 0 2	0 0 0
Hepatobiliary disorders Hyperbilirubinemia Increased AST Increased ALT	33 58 39	3 3 4	1 1 1	12 47 39	2 3 2	0 0 0
Renal and urinary disorders Proteinuria	33	3	-	30	3	-
Investigations Increased Lipase	14	0	1	5	0	0

DRUG INTERACTIONS

7.1 Effect of Strong CYP3A4 Inducers on Regorafenib

Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Stivarga decreased the mean exposure of regorafenib, increased the mean exposure of the active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite M-2. Avoid concomitant use of Stivarga with strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort) [see Clinical Pharmacology ( 12.3 )].

7.2 Effect of Strong CYP3A4 Inhibitors on Regorafenib

Co-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of Stivarga increased the mean exposure of regorafenib and decreased the mean exposure of the active metabolites M-2 and M-5. Avoid concomitant use of Stivarga with strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazadone, posaconazole, telithromycin, and voriconazole) [see Clinical Pharmacology (12.3)].

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 its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Stivarga in pregnant women. 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.

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. In a repeat dose study with daily administration of regorafenib to pregnant rats during organogenesis, findings included delayed ossification in fetuses at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) with 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.

8.3 Nursing Mothers

It is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib and its metabolites are excreted in milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Stivarga, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and efficacy of Stivarga in pediatric patients less than 18 years of age have not been established.

In 28-day repeat dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings were observed 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 632 Stivarga-treated patients enrolled in Studies 1 and 2, 37% were 65 years of age or older and over, while 8% were 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients.

8.6 Hepatic Impairment

No clinically important differences in the mean exposure of regorafenib or the active metabolites M-2 and M-5 were observed in patients with hepatocellular carcinoma and mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic function [see Clinical Pharmacology ( 12.3 )]. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. 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 (Child-Pugh Class C), as it has not been studied in this population.

8.7 Renal Impairment

No clinically relevant differences in the mean exposure of regorafenib and the active metabolites M-2 and M-5 were observed in patients with mild renal impairment (CLcr 60-89 mL/min) compared to patients with normal renal function following regorafenib 160 mg daily for 21 days [see Clinical Pharmacology ( 12.3 )]. No dose adjustment is recommended for patients with mild renal impairment. Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min). Stivarga has not been studied in patients with severe renal impairment or end-stage renal disease.

8.8 Females and Males of Reproductive Potential

Use effective contraception during treatment and up to 2 months after completion of therapy.

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 )].

OVERDOSAGE

The highest dose of Stivarga studied clinically is 220 mg per day. In the event of suspected overdose, interrupt Stivarga, institute supportive care, and observe until clinical stabilization.

DESCRIPTION

Stivarga (regorafenib) has 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 C21H15ClF4N4O3 * H2O 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.

CLINICAL PHARMACOLOGY

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, and maintenance of the tumor microenvironment. 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, BRAFV600E , SAPK2, PTK5, and Abl 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 as well as anti-metastatic activity in several mouse xenograft models including some for human colorectal carcinoma.

12.3 Pharmacokinetics

Following a single 160 mg dose of Stivarga in patients with advanced solid tumors, regorafenib reaches a geometric mean peak plasma level (Cmax) of 2.5 ug/mL at a median time of 4 hours and a geometric mean area under the plasma concentration vs. time curve (AUC) of 70.4 ug *h/mL. The AUC of regorafenib at steady-state increases less than dose proportionally at doses greater than 60 mg. At steady-state, regorafenib reaches a geometric mean Cmax of 3.9 ug/mL and a geometric mean AUC of 58.3 ug *h/mL. The coefficient of variation of AUC and Cmax is between 35% and 44%.

The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.

In a food-effect study, 24 healthy men received a single 160 mg dose of Stivarga on three separate occasions: under a fasted state, with a high-fat meal and with a low-fat meal. A high-fat meal (945 calories and 54.6 g fat) increased the mean AUC of regorafenib by 48% and decreased the mean AUC of the M-2 and M-5 metabolites by 20% and 51%, respectively, as compared to the fasted state. A low-fat meal (319 calories and 8.2 g fat) increased the mean AUC of regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively as compared to fasted conditions. Stivarga was administered with a low-fat meal in Studies 1 and 2 [see Dosage and Administration (2.1), Clinical Studies (14)].

Distribution

Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval. Regorafenib is highly bound (99.5%) to human plasma proteins.

Metabolism

Regorafenib is metabolized by CYP3A4 and UGT1A9. The main circulating metabolites of regorafenib measured at steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), both of them having similar in vitro pharmacological activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly protein bound (99.8% and 99.95%, respectively).

Elimination

Following a single 160 mg oral dose of Stivarga, the geometric mean (range) elimination half-lives for regorafenib and the M-2 metabolite in plasma are 28 hours (14 to 58 hours) and 25 hours (14 to 32 hours), respectively. M-5 has a longer mean (range) elimination half-life of 51 hours (32 to 70 hours).

Approximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19% of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution at a dose of 120 mg.

Age, Gender, and Weight

Based on the population pharmacokinetic analysis, there is no clinically relevant effect of age, gender or weight on the pharmacokinetics of regorafenib.

Hepatic Impairment

The pharmacokinetics of regorafenib, M-2, and M-5 was evaluated in 14 patients with hepatocellular carcinoma (HCC) and mild hepatic impairment (Child-Pugh A); 4 patients with HCC and moderate hepatic impairment (Child-Pugh B); and 10 patients with solid tumors and normal hepatic function after the administration of a single 100 mg dose of Stivarga. No clinically important differences in the mean exposure of regorafenib, M-2, or M-5 were observed in patients with mild or moderate hepatic impairment compared to the patients with normal hepatic function. The pharmacokinetics of regorafenib has not been studied in patients with severe hepatic impairment (Child-Pugh C).

Renal Impairment

The pharmacokinetics of regorafenib, M-2, and M-5 was evaluated in 10 patients with mild renal impairment (CLcr 60-89 mL/min) and 18 patients with normal renal function following the administration of Stivarga at a dose of 160 mg daily for 21 days. No differences in the mean steady-state exposure of regorafenib, M-2, or M-5 were observed in patients with mild renal impairment compared to patients with normal renal function. Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min). The pharmacokinetics of regorafenib has not been studied in patients with severe renal impairment or end-stage renal disease.

Drug-Drug Interactions

Effect of Regorafenib on Cytochrome P450 Substrates: In vitro studies suggested that regorafenib is an inhibitor of CYP2C8, CYP2C9, CYP2B6, CYP3A4 and CYP2C19; M-2 metabolite is an inhibitor of CYP2C9, CYP2C8, CYP3A4 and CYP2D6, and M-5 metabolite is an inhibitor of CYP2C8. In vitro studies suggested that regorafenib is not an inducer of CYP1A2, CYP2B6, CYP2C19, and CYP3A4 enzyme activity.

Patients with advanced solid tumors received single oral doses of CYP substrates, 2 mg of midazolam (CYP3A4), 40 mg of omeprazole (CYP2C19) and 10 mg of warfarin (CYP2C9) or 4 mg of rosiglitazone (CYP2C8) one week before and two weeks after Stivarga at a dose of 160 mg once daily. No clinically relevant change was observed in the mean AUC of rosiglitazone (N=12) or the mean omeprazole (N=11) plasma concentrations measured 6 hours after dosing or the mean AUC of midazolam (N=15). The mean AUC of warfarin (N=8) increased by 25% [see Warnings and Precautions (5.2)].

Effect of CYP3A4 Strong Inducers on Regorafenib: Twenty-two healthy men received a single 160 mg dose of Stivarga alone and then 7 days after starting rifampin. Rifampin, a strong CYP3A4 inducer, was administered at a dose of 600 mg daily for 9 days. The mean AUC of regorafenib decreased by 50% and mean AUC of M-5 increased by 264%. No change in the mean AUC of M-2 was observed [see Drug Interactions (7.1)].

Effect of CYP3A4 Strong Inhibitors on Regorafenib: Eighteen healthy men received a single 160 mg dose of Stivarga alone and then 5 days after starting ketoconazole. Ketoconazole, a strong CYP3A4 inhibitor, was administered at a dose of 400 mg daily for 18 days. The mean AUC of regorafenib increased by 33% and the mean AUC of M-2 and M-5 both decreased by 93% [see Drug Interactions (7.2)].

Effect of Regorafenib on UGT1A1 Substrates: In vitro studies showed that regorafenib, M-2, and M-5 competitively inhibit UGT1A9 and UGT1A1 at therapeutically relevant concentrations. Eleven patients received irinotecan-containing combination chemotherapy with Stivarga at a dose of 160 mg. The mean AUC of irinotecan increased 28% and the mean AUC of SN-38 increased by 44% when irinotecan was administered 5 days after the last of 7 daily doses of Stivarga.

In vitro screening of transporters: In vitro data suggested that regorafenib is an inhibitor of ABCG2 (Breast Cancer Resistance Protein) and ABCB1 (P-glycoprotein).

12.6 Cardiac Electrophysiology

The effect of multiple doses of Stivarga (160 mg once daily for 21 days) on the QTc interval was evaluated in an open label, single arm study in 25 patients with advanced solid tumors. No large changes in the mean QTc interval (i.e., > 20 msec) were detected in the study.

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies examining the carcinogenic potential of regorafenib have not been conducted. Regorafenib itself did not demonstrate genotoxicity in in vitro or in vivo assays; however, a major human active metabolite of regorafenib, (M-2), was positive for clastogenicity, causing chromosome aberration in Chinese hamster V79 cells.

Dedicated studies to examine the effects of regorafenib on fertility have not been conducted; however, there were histological findings of tubular atrophy and degeneration in the testes, atrophy in the seminal vesicle, and cellular debris and oligospermia in the epididymides in male rats at doses similar to those in human at the clinical recommended dose based on AUC. In female rats, there were increased findings of necrotic corpora lutea in the ovaries at the same exposures. There were similar findings in dogs of both sexes in repeat dose studies at exposures approximately 83% of the human exposure at the recommended human dose based on AUC. These findings suggest that regorafenib may adversely affect fertility in humans.

13.2 Animal Toxicology and/or Pharmacology

In a chronic 26 week repeat dose study in rats there was a dose-dependent increase in the finding of thickening of the atrioventricular valve. At a dose that resulted in an exposure of approximately 12% of the human exposure at the recommended dose, this finding was present in half of the examined animals.

CLINICAL STUDIES

14.1 Colorectal Cancer

The clinical efficacy and safety of Stivarga were evaluated in an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial (Study 1) in 760 patients with previously treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival (OS); supportive efficacy outcome measures included progression-free survival (PFS) and objective tumor response rate.

Patients were randomized to receive 160 mg regorafenib orally once daily (N=505) plus Best Supportive Care (BSC) or placebo (N=255) plus BSC for the first 21 days of each 28-day cycle. Stivarga was administered with a low-fat breakfast that contains less than 30% fat [see Dosage and Administration (2.1), Clinical Pharmacology ( 12.3 )]. Treatment continued until disease progression or unacceptable toxicity.

In the all-randomized population, median age was 61 years, 61% were men, 78% were White, and all patients had baseline ECOG performance status of 0 or 1. The primary site of disease was colon (65%), rectum (29%), or both (6%). History of KRAS evaluation was reported for 729 (96%) patients; 430 (59%) of these patients were reported to have KRAS mutation. The median number of prior lines of therapy for metastatic disease was 3. All patients received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and with bevacizumab. All but one patient with KRAS mutation-negative tumors received panitumumab or cetuximab.

The addition of Stivarga to BSC resulted in a statistically significant improvement in survival compared to placebo plus BSC (see Table 5 and Figure 1).

Table 5 Efficacy Results from Study 1
	Stivarga (N=505)	Placebo (N=255)
Overall Survival
Number of deaths, N (%)	275 (55%)	157 (62%)
Median Overall Survival (months)	6.4	5.0
95% CI	(5.8, 7.3)	(4.4, 5.8)
HR (95% CI)	0.77 (0.64, 0.94)
Stratified Log-Rank Test P-value ,	0.0102
Progression-free Survival
Number of Death or Progression, N (%)	417 (83%)	231 (91%)
Median Progression-free Survival (months)	2.0	1.7
95% CI	(1.9, 2.3)	(1.7, 1.8)
HR (95% CI)	0.49 (0.42, 0.58)
Stratified Log-Rank Test P-value	<0.0001
Overall Response Rate
Overall response, N (%)	5 (1%)	1 (0.4%)
95% CI	0.3%, 2.3%	0%, 2.2%

14.2 Gastrointestinal Stromal Tumors

The efficacy and safety of Stivarga were evaluated in an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial (Study 2) in 199 patients with unresectable, locally advanced or metastatic gastrointestinal stromal tumor (GIST), who had been previously treated with imatinib mesylate and sunitinib malate. Randomization was stratified by line of therapy (third vs. four or more) and geographic region (Asia vs. rest of the world).

The major efficacy outcome measure of Study 2 was progression-free survival (PFS) based on disease assessment by independent radiological review using modified RECIST 1.1 criteria, in which lymph nodes and bone lesions were not target lesions and progressively growing new tumor nodule within a pre-existing tumor mass was progression. The key secondary outcome measure was overall survival.

Patients were randomized to receive 160 mg regorafenib orally once daily (N=133) plus best supportive care (BSC) or placebo (N=66) plus BSC for the first 21 days of each 28-day cycle. Treatment continued until disease progression or unacceptable toxicity. In Study 2, the median age of patients was 60 years, 64% were men, 68% were White, and all patients had baseline ECOG performance status of 0 (55%) or 1 (45%). At the time of disease progression as assessed by central review, the study blind was broken and all patients were offered the opportunity to take Stivarga at the investigator's discretion. Fifty-six (85%) patients randomized to placebo and 41 (31%) patients randomized to Stivarga received open-label Stivarga.

A statistically significant improvement in PFS was demonstrated among patients treated with Stivarga compared to placebo (see Table 6 and Figure 2). There was no statistically significant difference in overall survival at the time of the planned interim analysis based on 29% of the total events for the final analysis.

HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Table 6 Efficacy Results for Study 2
	Stivarga (N=133)	Placebo (N=66)
Progression-free Survival
Number of Death or Progression, N (%)	82 (62%)	63 (96%)
Median Progression-free Survival (months)	4.8	0.9
95% CI	(3.9, 5.7)	(0.9, 1.1)
HR (95% CI)	0.27 (0.19, 0.39)
Stratified Log-Rank Test P-value	<0.0001
Overall Survival
Number of Deaths, N (%)	29 (22%)	17 (26%)
Median Overall Survival (months)	NR	NR
HR (95% CI)	0.77 (0.42, 1.41)
Stratified Log-Rank Test P-value ,	0.2

Stivarga tablets are supplied in packages containing three bottles, with each bottle containing 28 tablets, for a total of 84 tablets per package (NDC 50419-171-03).

16.2 Storage and Handling

Store Stivarga at 25degC (77degF); excursions are permitted from 15 to 30degC (59 to 86degF) [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 28 days after opening the bottle.Dispose of unused tablets in accordance with local requirements.

PATIENT COUNSELING INFORMATION

Patient Package Insert

Read this Patient Information before you start taking Stivarga and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

Liver problems. Stivarga can cause liver problems which can be serious and sometimes lead to death. Your healthcare provider will do blood tests to check your liver function before you start taking Stivarga and during your treatment with Stivarga to check for liver problems. Tell your healthcare provider right away if you get any of these symptoms of liver problems during treatment:

colon or rectal cancer that has spread to other parts of the body and for which they have received previous treatment with certain chemotherapy medicines

a rare stomach, bowel, or esophagus cancer called GIST (gastrointestinal stromal tumors) that cannot be treated with surgery or that has spread to other parts of the body and for which they have received previous treatment with certain medicines

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Stivarga may affect the way other medicines work, and other medicines may affect how Stivarga works.

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Stivarga. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Stivarga for a condition for which it was not prescribed. Do not give Stivarga to other people even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about Stivarga. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Stivarga this is written for health professionals.

Inactive ingredients: cellulose microcrystalline, croscarmellose sodium, magnesium stearate, povidone and colloidal silicon dioxide.

Film coat: ferric oxide red, ferric oxide yellow, lecithin (soy), polyethylene glycol 3350, polyvinyl alcohol, talc and titanium dioxide.

This Patient Information has been approved by the U.S. Food and Drug Administration.

WARNING: HEPATOTOXICITY

INDICATIONS AND USAGE

1.1 Colorectal Cancer

1.2 Gastrointestinal Stromal Tumors

DOSAGE AND ADMINISTRATION

2.1 Recommended Dose