Inlyta Tablet, Film Coated
FDA Label NDC 0069-0145

INLYTA in combination with avelumab is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

INLYTA in combination with pembrolizumab is indicated for the first-line treatment of patients with advanced renal cell carcinoma.

INLYTA as a single agent is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.

First-Line Advanced RCC

The recommended dose of INLYTA is 5 mg orally taken twice daily (12 hours apart) with or without food in combination with avelumab 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. When INLYTA is used in combination with avelumab, dose escalation of INLYTA above the initial 5 mg dose may be considered at intervals of two weeks or longer. Review the Full Prescribing Information for recommended avelumab dosing information.

The recommended dose of INLYTA is 5 mg orally twice daily (12 hours apart) with or without food in combination with pembrolizumab 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity. When INLYTA is used in combination with pembrolizumab, dose escalation of INLYTA above the initial 5 mg dose may be considered at intervals of six weeks or longer. Review the Full Prescribing Information for recommended pembrolizumab dosing information.

Second-Line Advanced RCC

When INLYTA is used as a single agent, the recommended starting oral dose is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food.

Important Administration Instructions

Advise patients to swallow INLYTA whole with a full glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. Advise the patient to take the next prescribed dose at the usual time.

Strong CYP3A4/5 Inhibitors

The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3 – 5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Hepatic Impairment

No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Warnings and Precautions (5.12), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

Hepatotoxicity

In patients being treated with INLYTA in combination with avelumab:

• If ALT or AST ≥3 times ULN but <5 times ULN or total bilirubin ≥1.5 times ULN but <3 times ULN, withhold both INLYTA and avelumab until these adverse reactions recover to Grades 0–1. If persistent (greater than 5 days), consider corticosteroid therapy [initial dose of 0.5 to 1 mg/kg/day] prednisone or equivalent followed by a taper. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery. If rechallenging with INLYTA, consider dose reduction as per recommended dose modification guidelines.
• If ALT or AST ≥5 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN or total bilirubin ≥3 times ULN, permanently discontinue both INLYTA and avelumab and consider corticosteroid therapy [initial dose 1 to 2 mg/kg/day prednisone or equivalent followed by a taper].

Review the Full Prescribing Information for additional dose modifications for avelumab.

In patients being treated with INLYTA in combination with pembrolizumab:

• If ALT or AST ≥3 times ULN but <10 times ULN without concurrent total bilirubin ≥2 times ULN, withhold both INLYTA and pembrolizumab until these adverse reactions recover to Grades 0–1. Consider corticosteroid therapy. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery. If rechallenging with INLYTA, consider dose reduction as per recommended dose modification guidelines.
• If ALT or AST ≥10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN, permanently discontinue both INLYTA and pembrolizumab and consider corticosteroid therapy.

Review the Full Prescribing Information for additional dose modifications for pembrolizumab.

INLYTA as a Single Agent

In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm. When used as a single agent, monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA.

INLYTA in Combination with Avelumab or with Pembrolizumab

INLYTA in combination with avelumab or with pembrolizumab can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 ALT and AST elevation. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy.

With the combination of INLYTA and avelumab, Grades 3 and 4 increased ALT and increased AST were reported in 9% and 7% of patients, respectively. In patients with ALT ≥3 times ULN (Grades 2–4, n=82), ALT resolved to Grades 0–1 in 92%. Among the 73 patients who were rechallenged with either avelumab (59%) or axitinib (85%) monotherapy or with both (55%), 66% had no recurrence of ALT ≥3 times ULN.

With the combination of INLYTA and pembrolizumab, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. The median time to onset of increased ALT was 2.3 months (range: 7 days to 19.8 months). Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times ULN (Grades 2–4, n=116), ALT resolved to Grades 0–1 in 94%. Among the 92 patients who were rechallenged with either pembrolizumab (3%) or axitinib (31%) administered as a single agent or with both (50%), 55% had no recurrence of ALT >3 times ULN.

Withhold INLYTA and avelumab for moderate (Grade 2) hepatotoxicity and permanently discontinue the combination for severe or life-threatening (Grade 3 or 4) hepatotoxicity. Administer corticosteroids as needed [see avelumab full prescribing information].

For elevated liver enzymes, interrupt INLYTA and pembrolizumab and consider administering corticosteroids as needed [see pembrolizumab full prescribing information].

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%) and 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 1 summarizes adverse reactions that occurred in ≥20% of INLYTA in combination with avelumab-treated patients.

Table 1: Adverse Reactions (≥20%) of Patients Receiving INLYTA in Combination with Avelumab (JAVELIN Renal 101 Trial)

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.

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).
Gastrointestinal Disorders
Diarrhea Diarrhea is a composite term that includes diarrhea, autoimmune colitis, and colitis	62	8	48	2.7
Nausea	34	1.4	39	1.6
Mucositis Mucositis is a composite term that includes mucosal inflammation and stomatitis	34	2.8	35	2.1
Hepatotoxicity 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	24	9	18	3.6
Abdominal pain Abdominal pain is a composite term that includes abdominal pain, flank pain, abdominal pain upper, and abdominal pain lower	22	1.4	19	2.1
General Disorders and Administration Site Conditions
Fatigue Fatigue is a composite term that includes fatigue and asthenia	53	6	54	6
Vascular Disorders
Hypertension Hypertension is a composite term that includes hypertension and hypertensive crisis	50	26	36	17
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain 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	40	3.2	33	2.7
Skin and Subcutaneous Tissue Disorders
Palmar-plantar erythrodysesthesia	33	6	34	4
Rash Rash is a composite term that includes rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, rash erythematous, rash papular, and rash pustular	25	0.9	16	0.5
Respiratory, Thoracic and Mediastinal Disorders
Dysphonia	31	0.5	3.2	0
Dyspnea Dyspnea is a composite term that includes dyspnea, dyspnea exertional and dyspnea at rest	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 2 summarizes selected laboratory abnormalities that occurred in ≥20% of INLYTA in combination with avelumab-treated patients.

Table 2: Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients Receiving INLYTA in Combination with Avelumab (JAVELIN Renal 101 Trial)

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.

Laboratory Abnormality	INLYTA plus Avelumab		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).
	Any Grade %	Grade 3–4 %	Any Grade %	Grade 3–4 %
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 axitinib. 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, hypothyroidism, decreased appetite, hepatotoxicity, 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 3 and 4 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 3: 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 Graded per NCI CTCAE v4.03 %	Grades 3–4 %	All Grades %	Grades 3–4 %
Gastrointestinal Disorders
Diarrhea Includes diarrhea, colitis, enterocolitis, gastroenteritis, enteritis, enterocolitis hemorrhagic	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 Includes hypertension, blood pressure increased, hypertensive crisis, labile hypertension	48	24	48	20
Hepatobiliary
Hepatotoxicity 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	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 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	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 4: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving INLYTA With Pembrolizumab in KEYNOTE-426

Laboratory Test 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).	INLYTA plus Pembrolizumab		Sunitinib
	All Grades Graded per NCI CTCAE v4.03 %	Grade 3–4 %	All Grades %	Grade 3–4 %
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 Corrected for albumin	22	0.2	29	0.7
Blood bilirubin increased	22	2.1	21	1.9
Activated partial thromboplastin time prolonged Two patients with a Grade 3 elevated activated partial thromboplastin time prolonged (aPTT) were also reported as having an adverse reaction of hepatotoxicity.	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 5 presents adverse reactions reported in ≥10% patients who received INLYTA or sorafenib.

Table 5: Adverse Reactions Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib

Adverse Reaction Percentages are treatment-emergent, all-causality events	INLYTA		Sorafenib
	(N=359)		(N=355)
	All Grades National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0	Grade 3/4	All Grades	Grade 3/4
	%	%	%	%
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 6 presents the most common laboratory abnormalities reported in ≥10% patients who received INLYTA or sorafenib.

Table 6: Laboratory Abnormalities Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib

Laboratory Abnormality	N	INLYTA		N	Sorafenib
		All Grades National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0	Grade 3/4		All Grades	Grade 3/4
		%	%		%	%
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase
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).

Risk Summary

Based on findings in animal studies and its mechanism of action, INLYTA can cause fetal harm when administered to a pregnant woman. There are no available human data to inform the drug-associated risk. In developmental toxicity studies, axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose (see Data). Advise females of reproductive potential of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the United States (U.S.) general population of major birth defects is 2%–4% and of miscarriage is 15%–20% of clinically recognized pregnancies.

When INLYTA is used in combination with avelumab or pembrolizumab, refer to the full prescribing information of avelumab or pembrolizumab for pregnancy information.

Data

Animal Data

Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (≥15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at ≥0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose).

Risk Summary

There are no data on the presence of axitinib in human milk, or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child from INLYTA, advise lactating women not to breastfeed during treatment and for 2 weeks after the final dose.

When INLYTA is used in combination with avelumab or pembrolizumab, refer to the full prescribing information of avelumab or pembrolizumab for lactation information.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating treatment with INLYTA.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with INLYTA and for 1 week after the last dose.

Males

Based on findings in animal studies, advise males with female partners of reproductive potential to use effective contraception during treatment and for 1 week after the last dose.

Infertility

Females and Males

Based on findings in animals, INLYTA may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].

Juvenile Animal Toxicity Data

Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at ≥15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at ≥5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.

Absorption and Distribution

Following single oral 5-mg dose administration, the median Tmax ranged from 2.5 to 4.1 hours. Based on the plasma half-life, steady state is expected within 2 to 3 days of dosing. Dosing of axitinib at 5 mg twice daily resulted in approximately 1.4-fold accumulation compared to administration of a single dose. At steady state, axitinib exhibits approximately linear pharmacokinetics within the 1-mg to 20-mg dose range. The mean absolute bioavailability of axitinib after an oral 5 mg dose is 58%.

Compared to overnight fasting, administration of INLYTA with a moderate fat meal resulted in 10% lower AUC and a high fat, high-calorie meal resulted in 19% higher AUC. INLYTA can be administered with or without food [see Dosage and Administration (2.1)].

Axitinib is highly bound (>99%) to human plasma proteins with preferential binding to albumin and moderate binding to α1-acid glycoprotein. In patients with advanced RCC (n=20), at the 5 mg twice daily dose in the fed state, the geometric mean (CV%) C_max and AUC_0–24 were 27.8 (79%) ng/mL and 265 (77%) ng.h/mL, respectively. The geometric mean (CV%) clearance and apparent volume of distribution were 38 (80%) L/h and 160 (105%) L, respectively.

Metabolism and Elimination

The plasma half-life of INLYTA ranges from 2.5 to 6.1 hours. Axitinib is metabolized primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Following oral administration of a 5-mg radioactive dose of axitinib, approximately 41% of the radioactivity was recovered in feces and approximately 23% was recovered in urine. Unchanged axitinib, accounting for 12% of the dose, was the major component identified in feces. Unchanged axitinib was not detected in urine; the carboxylic acid and sulfoxide metabolites accounted for the majority of radioactivity in urine. In plasma, the N-glucuronide metabolite represented the predominant radioactive component (50% of circulating radioactivity) and unchanged axitinib and the sulfoxide metabolite each accounted for approximately 20% of the circulating radioactivity.

The sulfoxide and N-glucuronide metabolites show approximately ≥400-fold less in vitro potency against VEGFR-2 compared to axitinib.

Drug-Drug Interactions

Effects of Other Drugs on INLYTA

Axitinib is metabolized primarily in the liver by CYP3A4/5. Additionally, the aqueous solubility of axitinib is pH dependent, with higher pH resulting in lower solubility. The effects of a strong CYP3A4/5 inhibitor, a strong CYP3A4/5 inducer, and an antacid on the pharmacokinetics of axitinib are presented in Figure 1 [see Dosage and Administration (2.2) and Drug Interactions (7.1, 7.2)].

Figure 1. Impact of Co-administered Drugs and Hepatic Impairment on Axitinib Pharmacokinetics



Figure 1 (Inlyta 02)

Effects of INLYTA on Other Drugs

In vitro studies demonstrated that axitinib has the potential to inhibit CYP1A2 and CYP2C8. However, co-administration of axitinib with paclitaxel, a CYP2C8 substrate, did not increase plasma concentrations of paclitaxel in patients.

In vitro studies indicated that axitinib does not inhibit CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or UGT1A1 at therapeutic plasma concentrations. In vitro studies in human hepatocytes indicated that axitinib does not induce CYP1A1, CYP1A2, or CYP3A4/5.

Axitinib is an inhibitor of the efflux transporter P-glycoprotein (P-gp) in vitro. However, INLYTA is not expected to inhibit P-gp at therapeutic plasma concentrations.

Specific Populations

Patients with Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of axitinib are presented in Figure 1 [see Dosage and Administration (2.2), Warnings and Precautions (5.12), Use in Specific Populations (8.6)].

Patients with Renal Impairment

Population pharmacokinetic analysis (based on pre-existing renal function) was carried out in 590 healthy volunteers and patients, including five with severe renal impairment (15 mL/min ≤CLcr <29 mL/min), 64 with moderate renal impairment (30 mL/min ≤CLcr <59 mL/min), and 139 with mild renal impairment (60 mL/min ≤CLcr <89 mL/min). Mild to severe renal impairment did not have meaningful effects on the pharmacokinetics of axitinib. Data from only one patient with end-stage renal disease are available [see Use in Specific Populations (8.7)].

Other Intrinsic Factors

Population pharmacokinetic analyses indicate that there are no clinically relevant effects of age, gender, race, body weight, body surface area, UGT1A1 genotype, or CYP2C19 genotype on the clearance of axitinib.

INLYTA in Combination with Avelumab

When INLYTA 5 mg was administered in combination with avelumab 10 mg/kg, the respective exposures of INLYTA and avelumab were comparable to the single agents. There was no evidence to suggest a clinically relevant change of avelumab clearance over time in patients with advanced RCC.

INLYTA in Combination with Pembrolizumab

When INLYTA 5 mg was administered in combination with pembrolizumab 200 mg, the respective exposures of INLYTA and pembrolizumab were comparable to the single agents.

INLYTA in Combination with Avelumab

The efficacy and safety of INLYTA in combination with avelumab was demonstrated in the JAVELIN Renal 101 trial (NCT02684006), a randomized, multicenter, open-label, study of INLYTA in combination with avelumab in 886 patients with untreated advanced RCC regardless of tumor PD-L1 expression [intent-to-treat (ITT) population]. Patients with autoimmune disease or conditions requiring systemic immunosuppression were excluded.

Randomization was stratified according to Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (0 vs. 1) and region (United States vs. Canada/Western Europe vs. the rest of the world). Patients were randomized (1:1) to one of the following treatment arms:

• INLYTA 5 mg twice daily orally was given in combination with avelumab 10 mg/kg intravenous infusion every 2 weeks (N=442). Patients who tolerated INLYTA 5 mg twice daily without Grade 2 or greater INLYTA-related adverse events for 2 consecutive weeks could increase to 7 mg and then subsequently to 10 mg twice daily. INLYTA could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity.
• Sunitinib 50 mg once daily orally for 4 weeks followed by 2 weeks off (N=444) until radiographic or clinical progression or unacceptable toxicity.

Treatment with INLYTA and avelumab continued until RECIST v1.1-defined progression of disease by Blinded Independent Central Review (BICR) assessment or unacceptable toxicity. Administration of INLYTA and avelumab was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at 6 weeks, then every 6 weeks thereafter up to 18 months after randomization, and every 12 weeks thereafter until documented confirmed disease progression by BICR.

Baseline characteristics were a median age of 61 years (range: 27 to 88), 38% of patients were 65 years or older, 75% were male, 75% were White, and the ECOG PS was 0 (63%) or 1 (37%), respectively. Patient distribution by International Metastatic Renal Cell Carcinoma Database (IMDC) risk groups was 21% favorable, 62% intermediate, and 16% poor.

The major efficacy outcome measures were progression-free survival (PFS), as assessed by an BICR using RECIST v1.1 and overall survival (OS) in patients with PD-L1-positive tumors using a clinical trial assay (PD-L1 expression level ≥1%). Since PFS was statistically significant in patients with PD-L1-positive tumors [HR 0.61 (95% CI: 0.48, 0.79)], it was then tested in the ITT population and a statistically significant improvement in PFS in the ITT population was also demonstrated.

With a median overall survival follow-up of 19 months, overall survival data were immature with 27% deaths in the ITT population.

Efficacy results are presented in Table 7 and Figure 2.

Table 7: Efficacy Results from JAVELIN Renal 101 Trial-ITT

Efficacy Endpoints (Based on BICR Assessment)	INLYTA plus avelumab (N=422)	Sunitinib (N=444)
BICR: Blinded Independent Central Review; CI: Confidence interval; NE: Not estimable.
Progression-Free Survival (PFS)
Events (%)	180 (41)	216 (49)
Median in Months (95% CI)	13.8 (11.1, NE)	8.4 (6.9, 11.1)
Hazard ratio (95% CI)	0.69 (0.56, 0.84)
2-sided p-value p-value based on stratified log-rank.	0.0002
Confirmed Objective Response Rate (ORR)
Objective Response Rate n (%)	227 (51.4)	114 (25.7)
(95% CI)	(46.6, 56.1)	(21.7, 30.0)
Complete Response (CR) n (%)	15 (3.4)	8 (1.8)
Partial Response (PR) n (%)	212 (48)	106 (24)

Figure 2. K-M Estimates for PFS Based on BICR Assessment - ITT



Figure 2 (Inlyta 03)

INLYTA in Combination with Pembrolizumab

The efficacy of INLYTA in combination with pembrolizumab was investigated in KEYNOTE-426 (NCT02853331), a randomized, multicenter, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were ineligible. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk categories (favorable versus intermediate versus poor) and geographic region (North America versus Western Europe versus "Rest of the World").

Patients were randomized (1:1) to one of the following treatment arms:

• INLYTA 5 mg orally, twice daily in combination with pembrolizumab 200 mg intravenously every 3 weeks up to 24 months. Patients who tolerated INLYTA 5 mg twice daily for 2 consecutive cycles (6 weeks) could increase to 7 mg and then subsequently to 10 mg twice daily. INLYTA could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity.
• Sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks.

Treatment with INLYTA and pembrolizumab continued until RECIST v1.1-defined progression of disease or unacceptable toxicity. Administration of INLYTA and pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at Week 12, then every 6 weeks thereafter until Week 54, and then every 12 weeks thereafter.

The study population characteristics were: median age of 62 years (range: 26 to 90); 38% age 65 or older; 73% male; 79% White and 16% Asian; 19% and 80% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; and patient distribution by IMDC risk categories was 31% favorable, 56% intermediate and 13% poor.

The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures included ORR, as assessed by BICR. A statistically significant improvement in OS was demonstrated at the pre-specified interim analysis in patients randomized to INLYTA in combination with pembrolizumab compared with sunitinib. The trial also demonstrated statistically significant improvements in PFS and ORR. Table 8 and Figure 3 summarize the efficacy results for KEYNOTE-426. The median follow-up time was 12.8 months (range 0.1 to 22.0 months). Consistent results were observed across pre-specified subgroups, IMDC risk categories and PD-L1 tumor expression status.

Table 8: Efficacy Results in KEYNOTE-426

Endpoint	INLYTA and Pembrolizumab N=432	Sunitinib N=429
CI: confidence interval; NR: not reached; ORR: objective response rate; OS: overall survival; PFS: progression-free survival.
OS
Number of patients with event (%)	59 (14%)	97 (23%)
Median in months (95% CI)	NR (NR, NR)	NR (NR, NR)
Hazard ratio Based on the stratified Cox proportional hazard model (95% CI)	0.53 (0.38, 0.74)
p-Value Based on stratified log-rank test	<0.0001 p-Value (one-sided) is compared with the allocated alpha of 0.0001 for this interim analysis (with 39% of the planned number of events for final analysis).
12-month OS rate	90% (86, 92)	78% (74, 82)
PFS
Number of patients with event (%)	183 (42%)	213 (50%)
Median in months (95% CI)	15.1 (12.6, 17.7)	11.0 (8.7, 12.5)
Hazard ratio (95% CI)	0.69 (0.56, 0.84)
p-Value	0.0001 p-Value (one-sided) is compared with the allocated alpha of 0.0013 for this interim analysis (with 81% of the planned number of events for final analysis).
ORR
Overall confirmed response rate (95% CI)	59% (54, 64)	36% (31, 40)
Complete response rate	6%	2%
Partial response rate	53%	34%
p-Value Based on Miettinen and Nurminen method stratified by IMDC risk group and geographic region	<0.0001

Figure 3. Kaplan-Meier Curve for Overall Survival in KEYNOTE-426



Figure 3 (Inlyta 04)

Hypertension

Advise patients that hypertension may develop during INLYTA treatment and that blood pressure should be monitored regularly during treatment [see Warnings and Precautions (5.1)].

Arterial/Venous Thromboembolic Events

Advise patients that arterial and venous thromboembolic events have been observed during INLYTA treatment and to inform their doctor if they experience symptoms suggestive of thromboembolic events [see Warnings and Precautions (5.2, 5.3)].

Hemorrhage

Advise patients that INLYTA may increase the risk of bleeding and to promptly inform their doctor of any bleeding episodes [see Warnings and Precautions (5.4)].

Cardiac Failure

Advise patients that cardiac failure may develop during INLYTA treatment and that signs or symptoms of cardiac failure should be regularly monitored for during treatment [see Warnings and Precautions (5.5)].

Gastrointestinal Disorders

Advise patients that gastrointestinal disorders such as diarrhea, nausea, vomiting, and constipation may develop during INLYTA treatment and to seek immediate medical attention if they experience persistent or severe abdominal pain because cases of gastrointestinal perforation and fistula have been reported in patients taking INLYTA [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)].

Abnormal Thyroid Function

Advise patients that abnormal thyroid function may develop during INLYTA treatment and to inform their doctor if symptoms of abnormal thyroid function occur [see Warnings and Precautions (5.7)].

Risk of Impaired Wound Healing

Advise patients that INLYTA may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions (5.8)].

Reversible Posterior Leukoencephalopathy Syndrome

Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances) [see Warnings and Precautions (5.9)].

Major Adverse Cardiovascular Events

Advise patients receiving INLYTA in combination with avelumab to contact their healthcare provider immediately for signs or symptoms of cardiovascular events including but not limited to new or worsening chest discomfort, dyspnea, or peripheral edema [see Warnings and Precautions (5.13)].

Embryo-Fetal Toxicity

Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with INLYTA and for 1 week after the last dose.

Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 1 week following the last dose [see Warnings and Precautions (5.14) and Use in Specific Populations (8.3)].

When INLYTA is used in combination with avelumab or pembrolizumab, refer to the full prescribing information of avelumab or pembrolizumab for pregnancy and contraception information.

Lactation

Advise patients not to breastfeed while taking INLYTA and for 2 weeks after receiving the last dose [see Use in Specific Populations (8.2)].

When INLYTA is used in combination with avelumab or pembrolizumab, refer to the full prescribing information of avelumab or pembrolizumab for lactation information.

Infertility

Advise males and females of reproductive potential that INLYTA may impair fertility [see Use in Specific Populations (8.3)].

Concomitant Medications

Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements.

This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.



Logo (Inlyta 06)

LAB-0561-6.0

Dose increase or reduction is recommended based on individual safety and tolerability.

Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions Grade >2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria.

Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions (5)]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily.

• 1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with "Pfizer" on one side and "1 XNB" on the other side.
• 5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with "Pfizer" on one side and "5 XNB" on the other side.

None.

In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard anti-hypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions (6.1)].

Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving anti-hypertensive medications should be monitored for hypotension [see Dosage and Administration (2.2)].

In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions (6.1)].

In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident.

Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months.

In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism.

Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months.

In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib.

INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

In a controlled clinical study with INLYTA for the treatment of patients with RCC, cardiac failure was reported in 6/359 patients (2%) receiving INLYTA and 3/355 patients (1%) receiving sorafenib. Grade 3/4 cardiac failure was observed in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Fatal cardiac failure was reported in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA.

In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%).

Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA.

In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib [see Adverse Reactions (6.1)].

Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state.

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, INLYTA has the potential to adversely affect wound healing.

Withhold INLYTA for at least 2 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of INLYTA after resolution of wound healing complications has not been established.

In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions (6.1)]. There were two additional reports of RPLS in other clinical trials with INLYTA.

RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known.

In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib [see Adverse Reactions (6.1)].

Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.

The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

INLYTA in combination with avelumab can cause severe and fatal cardiovascular events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue INLYTA and avelumab for Grade 3–4 cardiovascular events.

MACE occurred in 7% of patients with advanced RCC treated with INLYTA in combination with avelumab compared to 3.4% treated with sunitinib in a randomized trial, JAVELIN Renal 101. These events included death due to cardiac events (1.4%), Grade 3–4 myocardial infarction (2.8%), and Grade 3–4 congestive heart failure (1.8%). Median time to onset of MACE was 4.2 months (range: 2 days to 24.5 months).

Based on its mechanism of action and findings from animal studies, INLYTA can cause fetal harm when administered to a pregnant woman. There are no available human data to inform the drug-associated risk. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception during treatment with INLYTA and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with INLYTA and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

When INLYTA is used in combination with avelumab or pembrolizumab, refer to the full prescribing information of avelumab or pembrolizumab for pregnancy and contraception information.

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

• Hypertension and hypertensive crisis [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)]

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)].

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.

Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be co-administered, the INLYTA dose should be reduced [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, and St. John's wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible.

Based on findings in animal studies, INLYTA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. When INLYTA is used in combination with avelumab or pembrolizumab, refer to the full prescribing information of avelumab or pembrolizumab for contraception information.

The safety and efficacy of INLYTA in pediatric patients have not been studied.

In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were ≥65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were ≥65 years of age and younger.

Of the 434 patients randomized to INLYTA 5 mg twice daily administered in combination with avelumab 10 mg/kg in the JAVELIN Renal 101 trial, 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety or efficacy was reported between elderly patients and younger patients.

Of the 432 patients randomized to INLYTA 5 mg twice daily administered in combination with pembrolizumab 200 mg in the KEYNOTE-426 trial, 40% were 65 years or older. No overall difference in safety or efficacy was reported between elderly patients and younger patients.

No dosage adjustment is required in elderly patients [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B).

No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B) [see Dosage and Administration (2.2), Warnings and Precautions (5.12), Clinical Pharmacology (12.3)].

INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C).

No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min ≤creatinine clearance [CLcr] <89 mL/min) [see Clinical Pharmacology (12.3)]. No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min).

There is no specific treatment for INLYTA overdose.

In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1).

In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis.

In cases of suspected overdose, INLYTA should be withheld and supportive care instituted.

INLYTA (axitinib) is a kinase inhibitor. Axitinib has the chemical name N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide. The molecular formula is C22H18N4OS and the molecular weight is 386.47 Daltons. The chemical structure is:

Chemical Structure (Inlyta 01)

Axitinib is a white to light-yellow powder with a pKa of 4.8. The solubility of axitinib in aqueous media over the range pH 1.1 to pH 7.8 is in excess of 0.2 µg/mL. The partition coefficient (n-octanol/water) is 3.5.

INLYTA is supplied as red, film-coated tablets containing either 1 mg or 5 mg of axitinib together with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, and Opadry^® II red 32K15441 as inactive ingredients. The Opadry II red 32K15441 film coating contains lactose monohydrate, HPMC 2910/Hypromellose 15cP, titanium dioxide, triacetin (glycerol triacetate), and red iron oxide.

Axitinib has been shown to inhibit receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. VEGF-mediated endothelial cell proliferation and survival were inhibited by axitinib in vitro and in mouse models. Axitinib was shown to inhibit tumor growth and phosphorylation of VEGFR-2 in tumor xenograft mouse models.

The effect of a single oral dose of INLYTA (5 mg) in the absence and presence of 400 mg ketoconazole on the QTc interval was evaluated in a randomized, single-blinded, two-way crossover study in 35 healthy subjects. No large changes in mean QTc interval (i.e., >20 ms) from placebo were detected up to 3 hours post-dose. However, small increases in mean QTc interval (i.e., <10 ms) cannot be ruled out.

The population pharmacokinetic analysis pooled data from 17 trials in healthy subjects and patients with cancer. A two-compartment disposition model with first-order absorption and lag-time adequately describes the axitinib concentration-time profile.

Carcinogenicity studies have not been conducted with axitinib.

Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay.

INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at ≥15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and ≥1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at ≥5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively).

In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (≥15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose).

The safety and efficacy of INLYTA were evaluated in a randomized, open-label, multicenter Phase 3 study. Patients (N=723) with advanced RCC whose disease had progressed on or after treatment with 1 prior systemic therapy, including sunitinib-, bevacizumab-, temsirolimus-, or cytokine-containing regimens were randomized (1:1) to receive INLYTA (N=361) or sorafenib (N=362). Progression-free survival (PFS) was assessed by a blinded independent central review committee. Other endpoints included objective response rate (ORR) and overall survival (OS).

Of the patients enrolled in this study, 389 patients (54%) had received 1 prior sunitinib-based therapy, 251 patients (35%) had received 1 prior cytokine-based therapy (interleukin-2 or interferon-alfa), 59 patients (8%) had received 1 prior bevacizumab-based therapy, and 24 patients (3%) had received 1 prior temsirolimus-based therapy. The baseline demographic and disease characteristics were similar between the INLYTA and sorafenib groups with regard to age (median 61 years), gender (72% male), race (75% white, 21% Asian), Eastern Cooperative Oncology Group (ECOG) performance status (55% 0, 45% 1), and histology (99% clear cell).

There was a statistically significant advantage for INLYTA over sorafenib for the endpoint of PFS (see Table 9 and Figure 4). There was no statistically significant difference between the arms in OS.

Figure 4. Kaplan-Meier Curve for Progression-Free Survival by Independent Assessment (Intent-to-Treat Population)

Figure 4 (Inlyta 05)

INLYTA tablets are supplied as follows:

• 1 mg tablets are red film-coated, oval tablets debossed with "Pfizer" on one side and "1 XNB" on the other; available in bottles of 180: NDC 0069-0145-01.
• 5 mg tablets are red film-coated, triangular tablets debossed with "Pfizer" on one side and "5 XNB" on the other; available in bottles of 60: NDC 0069-0151-11.
• Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Pfizer

NDC 0069-0145-01

Inlyta^®
(axitinib) tablets

1 mg

180 Tablets

Rx only

Principal Display Panel (1 mg Tablet Bottle Label)

Pfizer

NDC 0069-0151-11

Inlyta^®
(axitinib) tablets

5 mg

60 Tablets

Rx only

Principal Display Panel (5 mg Tablet Bottle Label)