6 ADVERSE REACTIONS

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)]

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 placeboa
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).
: bThe term rash represents reports of events of drug eruption, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and pruritic rash.

cFatal 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
Proteinuriac	84	2	0	61	1	0
Investigations
Increased INRd	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.

cBased on urine protein-creatinine ratio data.

dInternational normalized ratio: No Grade 4 denoted in NCI CTCAE, v3.0.

Gastrointestinal Stromal Tumors

The safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (GRID) 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 5.7 months (range 1 day, 11.7 months) 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. 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 provides the incidence of adverse reactions (≥10%) in patients in GRID.

Table 3: Adverse reactions reported in ≥10% patients treated with STIVARGA in GRID and reported more commonly than in patients receiving placeboa
Adverse Reactions	STIVARGA (N=132)		Placebo (N=66)
	Grade		Grade
	All %	≥ 3 %	All %	≥ 3 %
Skin and subcutaneous tissue disorders HFSR/PPE Rash b Alopecia	67 30 24	22 7 2	12 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 Pain Diarrhea Mucositis Nausea Vomiting	60 47 40 20 17	8 8 2 2 <1	55 9 8 12 8	14 0 2 2 0
Respiratory, thoracic and mediastinal disorders Dysphonia	39	0	9	0
Infections and infestations Infection c	32	5	5	0
Metabolism and nutrition disorders Decreased appetite and food intake Hypothyroidism d	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 Muscle spasms	14	0	3	0

a Adverse reactions graded according to NCI CTCAE v4.0.

: bThe term rash represents reports of events of rash, erythematous rash, macular rash, maculo-papular rash, papular rash and pruritic rash.
: cFatal outcomes observed.

dHypothyroidism incidence based on subset of patients with normal TSH and no thyroid supplementation at baseline.

Table 4 provides laboratory abnormalities observed in GRID.

Table 4: Laboratory test abnormalities reported in GRID
Laboratory Parameter	STIVARGA (N=132a)			Placebo (N=66 a)
	Grade b			Grade b
	All %	3 %	4 %	All %	3 %	4 %
Blood and lymphatic system disorders Thrombocytopenia Neutropenia Lymphopenia	13 16 30	1 2 8	0 1 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 c	59	3	- d	53	3	- d
Investigations Increased Lipase	14	0	1	5	0	0

: a Percent based on number of patients with post-baseline samples which may be less than 132 (regorafenib) or 66 (placebo).

b NCI CTCAE v4.0.

c Based on urine protein-creatinine ratio data.

d No Grade 4 denoted in NCI CTCAE v4.0.

Hepatocellular Carcinoma

The 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 4 week 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% were exposed to STIVARGA for greater than or equal to 6 months and 14% were exposed to STIVARGA for greater than or equal to 12 months. Dose interruptions for adverse events were required in 58.3% of patients receiving STIVARGA and 48% of patients had their dose reduced. The most common adverse reactions requiring dose modification (interruption or dose reduction) were HFSR/PPES (20.6%), blood bilirubin increase (5.9%), fatigue (5.1%) and diarrhea (5.3%). Adverse reactions that resulted in treatment discontinuation were reported in 10.4% of STIVARGA-treated patients compared to 3.6% of patients who received placebo; the most common adverse reactions requiring discontinuation of STIVARGA were HFSR/PPES (1.9%) and AST increased (1.6%).

Table 5 provides the incidence of adverse reactions (≥10%) in patients in RESORCE.

Table 5: Adverse reactions reported in ≥10% of patients treated with STIVARGA in RESORCE and reported more commonly than in patients receiving placeboa
Adverse Reactions	STIVARGA (N=374)		Placebo (N=193)
	Grade		Grade
	All %	≥ 3 %	All %	≥ 3 %
Skin and subcutaneous tissue disorders HFSR/PPE	51	12	7	<1
General disorders and administration site conditions Pain Asthenia/Fatigue Fever	55 42 20	9 10 0	44 33 7	8 5 0
Vascular disorders Hypertension Hemorrhage b	31 18	15 5	6 16	5 8
Gastrointestinal disorders Diarrhea Nausea Vomiting Mucositis	41 17 13 13	3 <1 <1 1	15 13 7 2	0 0 <1 ≤1
Respiratory, thoracic and mediastinal disorders Dysphonia	18	0	2	0
Infections and infestations Infection b	31	8	18	6
Metabolism and nutrition disorders Decreased appetite and food intake	31	3	15	2
Investigations Weight loss	13	2	4	0
Musculoskeletal and connective tissue disorders Muscle spasms	10	0	2	0

a Adverse reactions graded according to NCI CTCAE v4.0.

: bFatal 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.

Table 6: Laboratory test abnormalities reported in RESORCE
Laboratory Parameter	STIVARGA (N=374a)			Placebo (N=193 a)
	Grade b			Grade b
	All %	3 %	4 %	All %	3 %	4 %
Blood and lymphatic system disorders Thrombocytopenia Neutropenia Lymphopenia	63 14 68	5 3 16	<1 0 2	50 15 59	0 <1 11	0 <1 <1
Metabolism and nutrition disorders Hypocalcemia Hypokalemia Hypophosphatemia	23 31 70	<1 4 32	0 <1 2	10 9 31	0 2 7	0 0 0
Hepatobiliary disorders Hyperbilirubinemia Increased AST Increased ALT	78 93 70	13 16 6	3 2 <1	55 84 59	11 17 5	5 3 0
Renal and urinary disorders Proteinuria c	51	17	- d	37	3	- d
Investigations Increased INR Increased Lipase Increased Amylase	44 41 23	<1 11 3	- d 3 <1	35 27 19	2 8 2	- d 1 <1

: a Percent based on number of patients with post-baseline samples which may be less than 374 (regorafenib) or 193 (placebo).

b NCI CTCAE v4.0.

c Based on dipstick data.

d No Grade 4 denoted in NCI CTCAE v4.0.

6.2 Postmarketing Experience

The following adverse reaction has been identified during postapproval use of STIVARGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

•: hypersensitivity reaction
•: nephrotic syndrome
•: cardiac failure
•: arterial (including aortic) aneurysms, dissections, and rupture