6 ADVERSE REACTIONS

The following clinically significant adverse reactions are discussed elsewhere in the labeling [see Warnings and Precautions (5)]:

•: Hypertension [see Warnings and Precautions (5.1)]
•: Arterial thromboembolic events [see Warnings and Precautions (5.2)]
•: Venous thromboembolic events [see Warnings and Precautions (5.3)]
•: Hemorrhage [see Warnings and Precautions (5.4)]
•: Cardiac failure [see Warnings and Precautions (5.5)]
•: Gastrointestinal perforation and fistula formation [see Warnings and Precautions (5.6)]
•: Thyroid dysfunction [see Warnings and Precautions (5.7)]
•: Reversible posterior leukoencephalopathy syndrome [see Warnings and Precautions (5.9)]
•: Proteinuria [see Warnings and Precautions (5.10)]
•: Hepatotoxicity [see Warnings and Precautions (5.11)]
•: Hepatic impairment [see Warnings and Precautions (5.12)]

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 rates observed in clinical practice.

The safety of INLYTA has been evaluated in combination with avelumab in JAVELIN Renal 101 and pembrolizumab in KEYNOTE-426 for the first-line treatment of patients with advanced RCC [see Clinical Studies (14.1)]. The data described [see Adverse Reactions (6.1)] reflect exposure to INLYTA in combination with avelumab in 434 patients and pembrolizumab in 429 patients [see Clinical Studies (14.1)].

The safety of INLYTA has been evaluated in 715 patients in second-line monotherapy studies, which included 537 patients with advanced RCC. The data described [see Adverse Reactions (6.1)] reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib [see Clinical Studies (14.2)].

First-Line Advanced RCC

INLYTA in Combination with Avelumab

The safety of INLYTA in combination with avelumab was evaluated in JAVELIN Renal 101. Patients with autoimmune disease other than type I diabetes mellitus, vitiligo, psoriasis, or thyroid disorders not requiring immunosuppressive treatment were excluded. Patients received INLYTA 5 mg twice daily (N=434) in combination with avelumab 10 mg/kg every 2 weeks administered or sunitinib 50 mg once daily for 4 weeks followed by 2 weeks off (N=439).

In the INLYTA plus avelumab arm, 70% were exposed to avelumab for ≥6 months and 29% were exposed for ≥1 year in JAVELIN Renal 101 [see Clinical Studies (14.1)].

The median age of patients treated with INLYTA in combination with avelumab was 62 years (range: 29 to 83), 38% of patients were 65 years or older, 71% were male, 75% were White, and the Eastern Cooperative Oncology Group (ECOG) performance score was 0 (64%) or 1 (36%).

Fatal adverse reactions occurred in 1.8% of patients receiving INLYTA in combination with avelumab. These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing pancreatitis (0.2%).

Serious adverse reactions occurred in 35% of patients receiving INLYTA in combination with avelumab. Serious adverse reactions in ≥1% of patients included diarrhea (2.5%), dyspnea (1.8%), hepatotoxicity (1.8%), venous thromboembolic disease (1.6%), acute kidney injury (1.4%), and pneumonia (1.2%).

Permanent discontinuation due to an adverse reaction of either INLYTA or avelumab occurred in 22% of patients: 19% avelumab only, 13% INLYTA only, and 8% both drugs. The most common adverse reactions (>1%) resulting in permanent discontinuation of avelumab or the combination were hepatotoxicity (6%) and infusion-related reaction (1.8%).

Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of avelumab infusions due to infusion-related reactions, occurred in 76% of patients receiving INLYTA in combination with avelumab. This includes interruption of avelumab in 50% of patients. INLYTA was interrupted in 66% and dose reduced in 19% of patients. The most common adverse reaction (>10%) resulting in interruption of avelumab was diarrhea (10%). The most common adverse reactions resulting in either interruption or dose reduction of INLYTA were diarrhea (19%), hypertension (18%), palmar-plantar erythrodysesthesia (18%), and hepatotoxicity (10%).

The most common adverse reactions (≥20%) in patients receiving INLYTA in combination with avelumab were diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache.

Forty-eight (11%) of patients treated with INLYTA in combination with avelumab received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction [see Warnings and Precautions (5.12)].

Table 4 summarizes adverse reactions that occurred in ≥20% of INLYTA in combination with avelumab-treated patients.

Table 4: Adverse Reactions (≥20%) of Patients Receiving INLYTA in Combination with Avelumab (JAVELIN Renal 101 Trial)*
Adverse Reactions	INLYTA plus Avelumab (N=434)		Sunitinib (N=439)
	All Grades %	Grade 3–4 %	All Grades %	Grade 3–4 %
Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.03 (NCI CTCAE v4).
* The trial was not designed to demonstrate a statistically significant difference in the incidence of adverse reactions between avelumab in combination with INLYTA and sunitinib. † Diarrhea is a composite term that includes diarrhea, autoimmune colitis, and colitis ‡ Mucositis is a composite term that includes mucosal inflammation and stomatitis § Hepatotoxicity is a composite term that includes ALT increased, AST increased, autoimmune hepatitis, bilirubin conjugated, bilirubin conjugated increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver disorder, liver injury, and transaminases increased ¶ Abdominal pain is a composite term that includes abdominal pain, flank pain, abdominal pain upper, and abdominal pain lower # Fatigue is a composite term that includes fatigue and asthenia Þ Hypertension is a composite term that includes hypertension and hypertensive crisis ß Musculoskeletal pain is a composite term that includes musculoskeletal pain, musculoskeletal chest pain, myalgia, back pain, bone pain, musculoskeletal discomfort, neck pain, spinal pain, and pain in extremity à Rash is a composite term that includes rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, rash erythematous, rash papular, and rash pustular è Dyspnea is a composite term that includes dyspnea, dyspnea exertional and dyspnea at rest
Gastrointestinal Disorders
Diarrhea†	62	8	48	2.7
Nausea	34	1.4	39	1.6
Mucositis‡	34	2.8	35	2.1
Hepatotoxicity§	24	9	18	3.6
Abdominal pain¶	22	1.4	19	2.1
General Disorders and Administration Site Conditions
Fatigue#	53	6	54	6
Vascular Disorders
HypertensionÞ	50	26	36	17
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painß	40	3.2	33	2.7
Skin and Subcutaneous Tissue Disorders
Palmar-plantar erythrodysesthesia	33	6	34	4
Rashà	25	0.9	16	0.5
Respiratory, Thoracic and Mediastinal Disorders
Dysphonia	31	0.5	3.2	0
Dyspneaè	23	3.0	16	1.8
Cough	23	0.2	19	0
Metabolism and Nutrition Disorders
Decreased appetite	26	2.1	29	0.9
Endocrine Disorders
Hypothyroidism	25	0.2	14	0.2
Nervous System Disorders
Headache	21	0.2	16	0.2

Other clinically important adverse reactions that occurred in less than 20% of patients in JAVELIN Renal 101 included arthralgia, weight decreased, and chills.

Patients received pre-medication with an anti-histamine and acetaminophen prior to each infusion. Infusion-related reactions occurred in 12% (Grade 3: 1.6%; no Grade 4) of patients treated with INLYTA in combination with avelumab.

Table 5 summarizes selected laboratory abnormalities that occurred in ≥20% of INLYTA in combination with avelumab-treated patients.

Table 5: Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients Receiving INLYTA in Combination with Avelumab (JAVELIN Renal 101 Trial)*
Laboratory Abnormality	INLYTA plus Avelumab		Sunitinib†
	Any Grade %	Grade 3–4 %	Any Grade %	Grade 3–4 %
* The trial was not designed to demonstrate a statistically significant difference in the incidence of laboratory abnormalities between INLYTA in combination with avelumab and sunitinib. † Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: INLYTA in combination with avelumab group (range: 413 to 428 patients) and sunitinib group (range: 405 to 433 patients).
Chemistry
Blood triglycerides increased	71	13	48	5
Blood creatinine increased	62	2.3	68	1.4
Blood cholesterol increased	57	1.9	22	0.7
Alanine aminotransferase increased (ALT)	50	9	46	3.2
Aspartate aminotransferase increased (AST)	47	7	57	3.2
Blood sodium decreased	38	9	37	10
Lipase increased	37	14	25	7
Blood potassium increased	35	3.0	28	3.9
Blood bilirubin increased	21	1.4	23	1.4
Hematology
Platelet count decreased	27	0.7	80	1.5
Hemoglobin decreased	21	2.1	65	8

INLYTA in Combination with Pembrolizumab

The safety of INLYTA in combination with pembrolizumab was investigated in KEYNOTE-426 [see Clinical Studies (14.1)]. Patients with medical conditions that required systemic corticosteroids or other immunosuppressive medications or had a history of severe autoimmune disease other than type 1 diabetes, vitiligo, Sjogren's syndrome, and hypothyroidism stable on hormone replacement were ineligible. Patients received INLYTA 5 mg orally twice daily and pembrolizumab 200 mg intravenously every 3 weeks, or sunitinib 50 mg once daily for 4 weeks and then off treatment for 2 weeks. The median duration of exposure to the combination therapy of INLYTA and pembrolizumab was 10.4 months (range: 1 day to 21.2 months).

The study population characteristics were: median age of 62 years (range: 30 to 89), 40% age 65 or older; 71% male; 80% White; and 80% Karnofsky Performance Status (KPS) of 90–100 and 20% KPS of 70–80.

Fatal adverse reactions occurred in 3.3% of patients receiving INLYTA in combination with pembrolizumab. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism and 1 case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier's gangrene, plasma cell myeloma, pleural effusion, pneumonitis, and respiratory failure.

Serious adverse reactions occurred in 40% of patients receiving INLYTA in combination with pembrolizumab. Serious adverse reactions in ≥1% of patients receiving INLYTA in combination with pembrolizumab included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%).

Permanent discontinuation due to an adverse reaction of either INLYTA or pembrolizumab occurred in 31% of patients; 13% pembrolizumab only, 13% INLYTA only, and 8% both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of INLYTA, pembrolizumab, or the combination was hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%).

Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of pembrolizumab infusions due to infusion-related reactions, occurred in 76% of patients receiving pembrolizumab in combination with INLYTA. This includes interruption of pembrolizumab in 50% of patients. INLYTA was interrupted in 64% of patients and dose reduced in 22% of patients. The most common adverse reactions (>10%) resulting in either interruption or reduction of INLYTA were hepatotoxicity (21%), diarrhea (19%), and hypertension (18%) and the most common adverse reactions (>10%) resulting in interruption of pembrolizumab were hepatotoxicity (14%) and diarrhea (11%).

The most common adverse reactions (≥20%) in patients receiving INLYTA and pembrolizumab were diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.

Twenty-seven percent (27%) of patients treated with INLYTA in combination with pembrolizumab received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction.

Tables 6 and 7 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with INLYTA and pembrolizumab in KEYNOTE-426.

Table 6: Adverse Reactions Occurring in ≥20% of Patients Treated with INLYTA and Pembrolizumab (KEYNOTE-426 Trial)
Adverse Reactions	INLYTA plus Pembrolizumab N=429		Sunitinib N=425
	All Grades* %	Grades 3–4 %	All Grades %	Grades 3–4 %
* Graded per NCI CTCAE v4.03 † Includes diarrhea, colitis, enterocolitis, gastroenteritis, enteritis, enterocolitis hemorrhagic ‡ Includes hypertension, blood pressure increased, hypertensive crisis, labile hypertension § Includes ALT increased, AST increased, autoimmune hepatitis, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased ¶ Includes rash, butterfly rash, dermatitis, dermatitis acneform, dermatitis atopic, dermatitis, bullous, dermatitis contact, exfoliative rash, genital rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, seborrheic dermatitis, skin discoloration, skin exfoliation, perineal rash
Gastrointestinal Disorders
Diarrhea†	56	11	45	5
Nausea	28	0.9	32	0.9
Constipation	21	0	15	0.2
General
Fatigue/Asthenia	52	5	51	10
Vascular
Hypertension‡	48	24	48	20
Hepatobiliary
Hepatotoxicity§	39	20	25	4.9
Endocrine
Hypothyroidism	35	0.2	32	0.2
Metabolism and Nutrition
Decreased appetite	30	2.8	29	0.7
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia syndrome	28	5	40	3.8
Stomatitis/Mucosal inflammation	27	1.6	41	4
Rash¶	25	1.4	21	0.7
Respiratory, Thoracic, and Mediastinal
Dysphonia	25	0.2	3.3	0
Cough	21	0.2	14	0.5

Table 7: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving INLYTA With Pembrolizumab in KEYNOTE-426
Laboratory Test*	INLYTA plus Pembrolizumab		Sunitinib
	All Grades† %	Grade 3–4 %	All Grades %	Grade 3–4 %
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: pembrolizumab/axitinib (range: 342 to 425 patients) and sunitinib (range: 345 to 422 patients). † Graded per NCI CTCAE v4.03 ‡ Corrected for albumin § Two patients with a Grade 3 elevated activated partial thromboplastin time prolonged (aPTT) were also reported as having an adverse reaction of hepatotoxicity.
Chemistry
Hyperglycemia	62	9	54	3.2
Increased ALT	60	20	44	5
Increased AST	57	13	56	5
Increased creatinine	43	4.3	40	2.4
Hyponatremia	35	8	29	8
Hyperkalemia	34	6	22	1.7
Hypoalbuminemia	32	0.5	34	1.7
Hypercalcemia	27	0.7	15	1.9
Hypophosphatemia	26	6	49	17
Increased alkaline phosphatase	26	1.7	30	2.7
Hypocalcemia‡	22	0.2	29	0.7
Blood bilirubin increased	22	2.1	21	1.9
Activated partial thromboplastin time prolonged§	22	1.2	14	0
Hematology
Lymphopenia	33	11	46	8
Anemia	29	2.1	65	8
Thrombocytopenia	27	1.4	78	14

Second-Line Advanced RCC

The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib.

The most common (≥20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. Table 8 presents adverse reactions reported in ≥10% patients who received INLYTA or sorafenib.

Table 8: Adverse Reactions Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib
Adverse Reaction*	INLYTA		Sorafenib
	(N=359)		(N=355)
	All Grades†	Grade 3/4	All Grades†	Grade 3/4
	%	%	%	%
* Percentages are treatment-emergent, all-causality events † National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0
Diarrhea	55	11	53	7
Hypertension	40	16	29	11
Fatigue	39	11	32	5
Decreased appetite	34	5	29	4
Nausea	32	3	22	1
Dysphonia	31	0	14	0
Palmar-plantar erythrodysesthesia syndrome	27	5	51	16
Weight decreased	25	2	21	1
Vomiting	24	3	17	1
Asthenia	21	5	14	3
Constipation	20	1	20	1
Hypothyroidism	19	<1	8	0
Cough	15	1	17	1
Mucosal inflammation	15	1	12	1
Arthralgia	15	2	11	1
Stomatitis	15	1	12	<1
Dyspnea	15	3	12	3
Abdominal pain	14	2	11	1
Headache	14	1	11	0
Pain in extremity	13	1	14	1
Rash	13	<1	32	4
Proteinuria	11	3	7	2
Dysgeusia	11	0	8	0
Dry skin	10	0	11	0
Dyspepsia	10	0	2	0
Pruritus	7	0	12	0
Alopecia	4	0	32	0
Erythema	2	0	10	<1

Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (1%).

Table 9 presents the most common laboratory abnormalities reported in ≥10% patients who received INLYTA or sorafenib.

Table 9: Laboratory Abnormalities Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib
Laboratory Abnormality	N	INLYTA		N	Sorafenib
		All Grades*	Grade 3/4		All Grades*	Grade 3/4
		%	%		%	%
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase
* National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0
Hematology
Hemoglobin decreased	320	35	<1	316	52	4
Lymphocytes (absolute) decreased	317	33	3	309	36	4
Platelets decreased	312	15	<1	310	14	0
White blood cells decreased	320	11	0	315	16	<1
Chemistry
Creatinine increased	336	55	0	318	41	<1
Bicarbonate decreased	314	44	<1	291	43	0
Hypocalcemia	336	39	1	319	59	2
ALP increased	336	30	1	319	34	1
Hyperglycemia	336	28	2	319	23	2
Lipase increased	338	27	5	319	46	15
Amylase increased	338	25	2	319	33	2
ALT increased	331	22	<1	313	22	2
AST increased	331	20	<1	311	25	1
Hypernatremia	338	17	1	319	13	1
Hypoalbuminemia	337	15	<1	319	18	1
Hyperkalemia	333	15	3	314	10	3
Hypoglycemia	336	11	<1	319	8	<1
Hyponatremia	338	13	4	319	11	2
Hypophosphatemia	336	13	2	318	49	16

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib) and hypercalcemia (6% for INLYTA versus 2% for sorafenib).

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of INLYTA. 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.

Vascular disorders: arterial (including aortic), aneurysms, dissections, and rupture.