HIGHLIGHTS OF PRESCRIBING INFORMATION
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` These highlights do not include all the information needed to use
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` INLYTA safely and effectively. See full prescribing information for
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` INLYTA.
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`INLYTA® (axitinib) tablets, for oral administration
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`Initial U.S. Approval: 2012
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`---------------------------RECENT MAJOR CHANGES --------------------------­
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`Indications and Usage, First-line advanced RCC (1.1)
`6/2020
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`Dosage and Administration, Recommended Dosing (2.1)
`6/2020
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`Dosage and Administration, Dose Modification Guidelines (2.2)
`6/2020
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`Warnings and Precautions, Risk of Impaired Wound Healing (5.8)
`1/2020
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`Warnings and Precautions, Hepatotoxicity (5.11)
`6/2020
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`Warnings and Precautions, Major Adverse Cardiovascular Events (MACE)
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`6/2020
`(5.13)
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`--------------------------- INDICATIONS AND USAGE---------------------------­
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`INLYTA is a kinase inhibitor indicated:
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`in combination with avelumab, for the first-line treatment of patients
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`with advanced renal cell carcinoma (RCC). (1.1)
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`in combination with pembrolizumab, for the first-line treatment of
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`patients with advanced RCC. (1.1)
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`as a single agent, for the treatment of advanced renal cell carcinoma
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`(RCC) after failure of one prior systemic therapy. (1.2)
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`-----------------------DOSAGE AND ADMINISTRATION ----------------------­
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`INLYTA 5 mg orally twice daily with avelumab 800 mg every 2 weeks.
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`(2.1)
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`INLYTA 5 mg orally twice daily with pembrolizumab 200 mg every
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`3 weeks or 400 mg every 6 weeks. (2.1)
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`INLYTA as a single agent the starting dose is 5 mg orally twice daily.
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`(2.1)
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`Dose adjustments can be made based on individual safety and
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`tolerability. (2.2)
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`Administer INLYTA dose approximately 12 hours apart with or without
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`food. (2.1)
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`INLYTA should be swallowed whole with a glass of water. (2.1)
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`If a strong CYP3A4/5 inhibitor is required, decrease the INLYTA dose
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`by approximately half. (2.2)
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`For patients with moderate hepatic impairment, decrease the starting
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`dose by approximately half. (2.2)
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`--------------------- DOSAGE FORMS AND STRENGTHS---------------------­
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`1 mg and 5 mg tablets (3)
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`------------------------------ CONTRAINDICATIONS -----------------------------­
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`None. (4)
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`----------------------- WARNINGS AND PRECAUTIONS-----------------------­
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`Hypertension and Hypertensive Crisis: Hypertension including
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`hypertensive crisis has been observed. Blood pressure should be
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`well-controlled prior to initiating INLYTA. Monitor for hypertension
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`and treat as needed. For persistent hypertension despite use of
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`anti-hypertensive medications, reduce the INLYTA dose. (5.1)
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`Arterial and Venous Thromboembolic Events: Arterial and venous
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`thrombotic events have been observed and can be fatal. Use with caution
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`in patients who are at increased risk for these events. (5.2, 5.3)
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`Hemorrhage: Hemorrhagic events, including fatal events, have been
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`reported. INLYTA has not been studied in patients with evidence of
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`untreated brain metastasis or recent active gastrointestinal bleeding and
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`should not be used in those patients. (5.4)
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`Cardiac Failure: Cardiac failure has been observed and can be fatal.
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`Monitor for signs or symptoms of cardiac failure throughout treatment
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`with INLYTA. (5.5)
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`Reference ID: 4619585
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`Gastrointestinal Perforation and Fistula Formation: Gastrointestinal
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`perforation and fistula, including death, have occurred. Use with caution
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`in patients at risk for gastrointestinal perforation or fistula. (5.6)
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`Hypothyroidism: Hypothyroidism requiring thyroid hormone
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`replacement has been reported. Monitor thyroid function before
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`initiation of, and periodically throughout, treatment with INLYTA. (5.7)
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`Risk of Impaired Wound Healing: Withhold INLYTA for at least 2 days
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`prior to elective surgery. Do not administer for at least 2 weeks
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`following major surgery and until adequate wound healing. The safety of
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`resumption of INLYTA after resolution of wound healing complications
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`has not been established. (5.8)
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`Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS
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`has been observed. Permanently discontinue INLYTA if signs or
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`symptoms of RPLS occur. (5.9)
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`Proteinuria: Monitor for proteinuria before initiation of, and periodically
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`throughout, treatment with INLYTA. For moderate to severe proteinuria,
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`reduce the dose or temporarily interrupt treatment with INLYTA. (5.10)
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`Hepatotoxicity: Liver enzyme elevation has occurred during treatment
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`with INLYTA as a single agent. Monitor ALT, AST and bilirubin before
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`initiation of, and periodically throughout, treatment with INLYTA.
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`When used in combination with avelumab or pembrolizumab, higher
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`frequencies of Grade 3 and 4 ALT and AST elevation may occur.
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`Consider more frequent monitoring of liver enzymes. Consider
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`withholding INLYTA and/or avelumab or pembrolizumab, initiating
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`corticosteroid therapy, and/or permanently discontinuing the
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`combination for severe or life-threatening hepatotoxicity. (5.11)
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`Use in Patients with Hepatic Impairment: Decrease the starting dose of
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`INLYTA if used in patients with moderate hepatic impairment.
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`INLYTA has not been studied in patients with severe hepatic
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`impairment. (2.2, 5.12)
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`• Major adverse cardiovascular events (INLYTA in combination with
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`avelumab): Optimize management of cardiovascular risk factors.
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`Discontinue INLYTA in combination with avelumab for Grade 3-4
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`events. (5.13)
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`Embryo-Fetal Toxicity: INLYTA can cause fetal harm. Advise patients
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`of the potential risk to the fetus and to use effective contraception. (5.14,
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`8.1, 8.3)
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`------------------------------ ADVERSE REACTIONS -----------------------------­
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`Most common adverse reactions (≥20%) are:
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`INLYTA in combination with avelumab: diarrhea, fatigue, hypertension,
`musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia,
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`dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough,
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`dyspnea, abdominal pain, and headache. (6.1)
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`INLYTA in combination with pembrolizumab: diarrhea, fatigue/asthenia,
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`hypertension, hypothyroidism, decreased appetite, hepatotoxicity,
`palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation,
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`dysphonia, rash, cough, and constipation. (6.1)
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`INLYTA as a single agent: diarrhea, hypertension, fatigue, decreased appetite,
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`nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome,
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`weight decreased, vomiting, asthenia, and constipation. (6.1)
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`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
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`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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`------------------------------ DRUG INTERACTIONS------------------------------­
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`Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the INLYTA
`•
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`dose. (2.2, 7.1)
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`Avoid strong CYP3A4/5 inducers. (7.2)
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`----------------------- USE IN SPECIFIC POPULATIONS ----------------------­
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`Lactation: Advise not to breastfeed. (8.2)
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`See 17 for PATIENT COUNSELING INFORMATION and
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`FDA-approved patient labeling.
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`Revised: 6/2020
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`

`

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` CYP3A4/5 Inhibitors
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`
` 7.1
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` 7.2
` CYP3A4/5 Inducers
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` 8 USE IN SPECIFIC POPULATIONS
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` Pregnancy
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` 8.1
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` 8.2
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` Lactation
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` 8.3
` Females and Males of Reproductive Potential
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` Pediatric Use
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` 8.4
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` 8.5
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` Geriatric Use
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` 8.6
` Hepatic Impairment
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` Renal Impairment
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` 8.7
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` 10 OVERDOSAGE
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` 11 DESCRIPTION
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` 12 CLINICAL PHARMACOLOGY
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` 12.1 Mechanism of Action
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` 12.2
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` Pharmacodynamics
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` 12.3
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` Pharmacokinetics
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` 13 NONCLINICAL TOXICOLOGY
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` Carcinogenesis, Mutagenesis, Impairment of Fertility
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` 13.1
` 14 CLINICAL STUDIES
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` First-Line Advanced RCC
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` 14.1
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` 14.2
` Second-Line Advanced RCC
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` 16 HOW SUPPLIED/STORAGE AND HANDLING
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` 17 PATIENT COUNSELING INFORMATION
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`*Sections or subsections omitted from the Full Prescribing Information are not
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`listed.
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` FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 1
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` INDICATIONS AND USAGE
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`
` First-Line Advanced Renal Cell Carcinoma
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`
` 1.1
` Second-Line Advanced Renal Cell Carcinoma
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` 1.2
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` 2 DOSAGE AND ADMINISTRATION
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` 2.1
` Recommended Dosing
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` 2.2
` Dose Modification Guidelines
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` 3 DOSAGE FORMS AND STRENGTHS
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` 4 CONTRAINDICATIONS
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` 5 WARNINGS AND PRECAUTIONS
` Hypertension and Hypertensive Crisis
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` 5.1
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` 5.2
` Arterial Thromboembolic Events
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` Venous Thromboembolic Events
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` 5.3
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` 5.4
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` Hemorrhage
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` 5.5
` Cardiac Failure
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` Gastrointestinal Perforation and Fistula Formation
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` 5.6
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` Thyroid Dysfunction
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` 5.7
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` Risk of Impaired Wound Healing
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` 5.8
` Reversible Posterior Leukoencephalopathy Syndrome
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` 5.9
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` 5.10
` Proteinuria
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` 5.11 Hepatotoxicity
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` 5.12 Use in Patients with Hepatic Impairment
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` 5.13 Major Adverse Cardiovascular Events (MACE)
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` 5.14
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` Embryo-Fetal Toxicity
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` 6 ADVERSE REACTIONS
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` 6.1
` Clinical Trials Experience
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` 6.2
` Postmarketing Experience
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` 7 DRUG INTERACTIONS
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`Reference ID: 4619585
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`

`

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`INDICATIONS AND USAGE
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`First-Line Advanced Renal Cell Carcinoma
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` Second-Line Advanced Renal Cell Carcinoma
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` FULL PRESCRIBING INFORMATION
`
`
`1
`
`
`1.1
`
` 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.
`
` 1.2
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`
`
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`INLYTA as a single agent is indicated for the treatment of advanced renal cell carcinoma (RCC) after
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`failure of one prior systemic therapy.
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`
`2
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`2.1
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`First-Line Advanced RCC
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`The recommended dose of INLYTA is 5 mg orally taken twice daily (12 hours apart) with or without food
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`in combination with avelumab 800 mg administered as an intravenous infusion over 60 minutes every
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`2 weeks until disease progression or unacceptable toxicity. When INLYTA is used in combination with
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`avelumab, dose escalation of INLYTA above the initial 5 mg dose may be considered at intervals of two
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`weeks or longer. Review the Full Prescribing Information for recommended avelumab dosing information.
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`The recommended dose of INLYTA is 5 mg orally twice daily (12 hours apart) with or without food in
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`combination with pembrolizumab 200 mg every 3 weeks or 400 mg every 6 weeks administered as an
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`intravenous infusion over 30 minutes until disease progression or unacceptable toxicity. When INLYTA is
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`used in combination with pembrolizumab, dose escalation of INLYTA above the initial 5 mg dose may be
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`considered at intervals of six weeks or longer. Review the Full Prescribing Information for recommended
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`pembrolizumab dosing information.
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`Second-Line Advanced RCC
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`When INLYTA is used as a single agent, the recommended starting oral dose is 5 mg twice daily.
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`Administer INLYTA doses approximately 12 hours apart with or without food.
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`Important Administration Instructions
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`Advise patients to swallow INLYTA whole with a full glass of water. If the patient vomits or misses a
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`dose, an additional dose should not be taken. Advise the patient to take the next prescribed dose at the
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`usual time.
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`DOSAGE AND ADMINISTRATION
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`Recommended Dosing
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`Reference ID: 4619585
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`

`

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` Dose Modification Guidelines
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` 2.2
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`Dose increase or reduction is recommended based on individual safety and tolerability.
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`Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no
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`adverse reactions Grade >2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]),
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`are normotensive, and are not receiving anti-hypertension medication, may have their dose increased.
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`When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to
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`7 mg twice daily, and further to 10 mg twice daily using the same criteria.
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`Over the course of treatment, management of some adverse drug reactions may require temporary
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`interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and
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`Precautions (5)]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg
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`twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily.
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`Strong CYP3A4/5 Inhibitors
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`The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole,
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`clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and
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`voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition
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`potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving
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`strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of
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`INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib
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`area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The
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`subsequent doses can be increased or decreased based on individual safety and tolerability. If
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`co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after
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`3 – 5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor [see Drug
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`Interactions (7.1) and Clinical Pharmacology (12.3)].
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`Hepatic Impairment
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`No starting dose adjustment is required when administering INLYTA to patients with mild hepatic
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`impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should
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`be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh
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`class B). The subsequent doses can be increased or decreased based on individual safety and tolerability.
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`INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see
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`Warnings and Precautions (5.12), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
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`Hepatotoxicity
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`In patients being treated with INLYTA in combination with avelumab:
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`If ALT or AST ≥3 times ULN but <5 times ULN or total bilirubin ≥1.5 times ULN but <3 times
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`•
`ULN, withhold both INLYTA and avelumab until these adverse reactions recover to Grades 0-1. If
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`persistent (greater than 5 days), consider corticosteroid therapy [initial dose of 0.5 to 1 mg/kg/day]
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` prednisone or equivalent followed by a taper. Consider rechallenge with a single drug or sequential
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`rechallenge with both drugs after recovery. If rechallenging with INLYTA, consider dose
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`reduction as per recommended dose modification guidelines.
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`Reference ID: 4619585
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`
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`

`

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` 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
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`corticosteroid therapy [initial dose 1 to 2 mg/kg/day prednisone or equivalent followed by a taper].
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`•
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`Review the Full Prescribing Information for additional dose modifications for avelumab.
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` In patients being treated with INLYTA in combination with pembrolizumab:
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`If ALT or AST ≥3 times ULN but <10 times ULN without concurrent total bilirubin ≥2 times
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`•
`ULN, withhold both INLYTA and pembrolizumab until these adverse reactions recover to Grades
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`0-1. Consider corticosteroid therapy. Consider rechallenge with a single drug or sequential
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`rechallenge with both drugs after recovery. If rechallenging with INLYTA, consider dose
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`reduction as per recommended dose modification guidelines.
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`If ALT or AST ≥10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN,
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`permanently discontinue both INLYTA and pembrolizumab and consider corticosteroid therapy.
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`DOSAGE FORMS AND STRENGTHS
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`Review the Full Prescribing Information for additional dose modifications for pembrolizumab.
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`
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`3
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`• 1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and
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`“1 XNB” on the other side.
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`• 5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side
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`and “5 XNB” on the other side.
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`CONTRAINDICATIONS
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`WARNINGS AND PRECAUTIONS
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`4
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`None.
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`5
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`5.1 Hypertension and Hypertensive Crisis
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`In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was
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`reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib.
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`Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients
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`(11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA
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`and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood
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`pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of
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`INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting
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`INLYTA. Hypertension was managed with standard anti-hypertensive therapy. Discontinuation of
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`INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of
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`the patients receiving sorafenib [see Adverse Reactions (6.1)].
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`Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for
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`hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent
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`hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue
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`INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of
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`INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA
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`Reference ID: 4619585
`
`
`
`

`

`Arterial Thromboembolic Events
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`
`
`
`
`
` Venous Thromboembolic Events
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`
`
`
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`is interrupted, patients receiving anti-hypertensive medications should be monitored for hypotension [see
`
`Dosage and Administration (2.2)].
`
`
`5.2
`
`
`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.
`
`
`
` 5.3
`
`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.
`
` 5.4 Hemorrhage
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4619585
`
`
`
`

`

`
`
`
`
` Cardiac Failure
`
`
`Thyroid Dysfunction
`
`
`
`
`Risk of Impaired Wound Healing
`
` 5.5
`
`
`
`
`
`
`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.
`
`
`
`
`5.6 Gastrointestinal Perforation and Fistula Formation
`
`
`
`
`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.
`
`
`5.7
`
`
`
`
`
`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.
`
`
`5.8
`
`
`
`
`
`
`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.
`
`
`5.9
`
`
`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.
`
`
`
`Reversible Posterior Leukoencephalopathy Syndrome
`
`
`
`
`Reference ID: 4619585
`
`
`
`

`

`
`
`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.
`
`
`
`5.10 Proteinuria
`
`
`
`
`
`
`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.
`
`
`
`5.11 Hepatotoxicity
`
`
`
`
`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].
`
`
`
`
`
`Reference ID: 4619585
`
`
`
`

`

`
`
`
`
`
`
`
`For elevated liver enzymes, interrupt INLYTA and pembrolizumab and consider administering
`
`
`
`corticosteroids as needed [see pembrolizumab full prescribing information].
`
`
`
` 5.12 Use in Patients with Hepatic Impairment
`
`
`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)].
`
`
`
`
`5.13 Major Adverse Cardiovascular Events (MACE)
`
`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).
`
`
`
`5.14 Embryo-Fetal Toxicity
`
`
`
`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.
`
`
`
`6
`
`
`The following clinically significant adverse reactions are discussed elsewhere in the labeling [see
`
`
`
`
`
`
`Warnings and Precautions (5)]:
`
`
`
`ADVERSE REACTIONS
`
`
`• 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)]
`
`
`
`
`
`
`
`
`Reference ID: 4619585
`
`

`

` • 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)]
`
`