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.
|Adverse Reactions||INLYTA plus Avelumab (N=434)||Sunitinib (N=439)|
|Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.03 (NCI CTCAE v4).|
|General Disorders and Administration Site Conditions|
|Musculoskeletal and Connective Tissue Disorders|
|Skin and Subcutaneous Tissue Disorders|
|Respiratory, Thoracic and Mediastinal Disorders|
|Metabolism and Nutrition Disorders|
|Nervous System Disorders|
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.
|Laboratory Abnormality||INLYTA plus Avelumab||Sunitinib†|
|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|
|Blood potassium increased||35||3.0||28||3.9|
|Blood bilirubin increased||21||1.4||23||1.4|
|Platelet count decreased||27||0.7||80||1.5|
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.
|Adverse Reactions||INLYTA plus Pembrolizumab N=429||Sunitinib N=425|
|Metabolism and Nutrition|
|Skin and Subcutaneous Tissue|
|Palmar-plantar erythrodysesthesia syndrome||28||5||40||3.8|
|Respiratory, Thoracic, and Mediastinal|
|Laboratory Test*||INLYTA plus Pembrolizumab||Sunitinib|
|Increased alkaline phosphatase||26||1.7||30||2.7|
|Blood bilirubin increased||22||2.1||21||1.9|
|Activated partial thromboplastin time prolonged§||22||1.2||14||0|
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.
|All Grades†||Grade 3/4||All Grades†||Grade 3/4|
|Palmar-plantar erythrodysesthesia syndrome||27||5||51||16|
|Pain in extremity||13||1||14||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.
|All Grades*||Grade 3/4||All Grades*||Grade 3/4|
|ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase|
|Lymphocytes (absolute) decreased||317||33||3||309||36||4|
|White blood cells decreased||320||11||0||315||16||<1|
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.