HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`INLYTA safely and effectively. See full prescribing information for
`INLYTA.
`
`INLYTA® (axitinib) tablets, for oral administration
`Initial U.S. Approval: 2012
`
` --------------------------- RECENT MAJOR CHANGES ---------------------------
`Dosage and Administration, Recommended Dosing (2.1)
`9/2022
`Dosage and Administration, Dose Modification Guidelines (2.2)
`9/2022
`Warnings and Precautions, Hypertension (5.1)
`9/2022
`Warnings and Precautions, Arterial Thromboembolic Events (5.2)
`9/2022
`Warnings and Precautions, Venous Thromboembolic Events (5.3)
`9/2022
`Warnings and Precautions, Hemorrhage (5.4)
`9/2022
`Warnings and Precautions, Cardiac Failure (5.5)
`9/2022
`Warnings and Precautions, Impaired Wound Healing (5.8)
`9/2022
`Warnings and Precautions, Reversible Posterior Leukoencephalopathy
`Syndrome (5.9)
`Warnings and Precautions, Proteinuria (5.10)
`Warnings and Precautions, Hepatotoxicity (5.11)
`Warnings and Precautions, Major Adverse Cardiovascular
`Events (5.13)
`
` --------------------------- INDICATIONS AND USAGE ----------------------------
`INLYTA is a kinase inhibitor indicated:
`in combination with avelumab, for the first-line treatment of patients
`•
`with advanced renal cell carcinoma (RCC). (1.1)
`in combination with pembrolizumab, for the first-line treatment of
`patients with advanced RCC. (1.1)
`as a single agent, for the treatment of advanced renal cell carcinoma
`(RCC) after failure of one prior systemic therapy. (1.2)
`
`9/2022
`9/2022
`9/2022
`
`9/2022
`
`•
`
`•
`
`
` ----------------------- DOSAGE AND ADMINISTRATION -----------------------
`INLYTA 5 mg orally twice daily with avelumab 800 mg every
`•
`2 weeks. (2.1)
`INLYTA 5 mg orally twice daily with pembrolizumab 200 mg every
`3 weeks or 400 mg every 6 weeks. (2.1)
`INLYTA as a single agent the starting dose is 5 mg orally twice
`daily. (2.1)
`Dose adjustments can be made based on individual safety and
`tolerability. (2.2)
`Administer INLYTA dose approximately 12 hours apart with or without
`food. (2.1)
`INLYTA should be swallowed whole with a glass of water. (2.1)
`See Full Prescribing Information for dosage modifications for adverse
`reactions. (2 2)
`If a strong CYP3A4/5 inhibitor is required, decrease the INLYTA dose
`by approximately half. (2.2)
`For patients with moderate hepatic impairment, decrease the starting
`dose by approximately half. (2.2)
`
` --------------------- DOSAGE FORMS AND STRENGTHS ----------------------
`1 mg and 5 mg tablets (3)
`
` ------------------------------ CONTRAINDICATIONS ------------------------------
`None. (4)
`
` ----------------------- WARNINGS AND PRECAUTIONS ------------------------
`Hypertension: Hypertension including hypertensive crisis has been
`•
`observed. Blood pressure should be well-controlled prior to initiating
`INLYTA. Monitor for hypertension and treat as needed. Withhold and
`then dose reduce INLYTA or permanently discontinue based on severity
`of hypertension. (5.1)
`Arterial and Venous Thromboembolic Events: Arterial and venous
`thrombotic events have been observed and can be fatal. Use with caution
`in patients who are at increased risk for these events. Permanently
`discontinue INLYTA if an arterial thromboembolic event occurs during
`treatment. Withhold INLYTA and then resume at same dose or
`permanently discontinue based on severity of VTE. (5.2, 5.3)
`Hemorrhage: Hemorrhagic events, including fatal events, have been
`reported. INLYTA has not been studied in patients with evidence of
`untreated brain metastasis or recent active gastrointestinal bleeding and
`should not be used in those patients. Withhold and then dose reduce
`
`•
`
`•
`
`•
`
`•
`
`•
`•
`
`•
`
`•
`
`•
`
`•
`
`INLYTA or discontinue based on severity and persistence of
`hemorrhage. (5.4)
`Cardiac Failure: Cardiac failure has been observed and can be fatal.
`Monitor for signs or symptoms of cardiac failure throughout treatment
`with INLYTA. Management of cardiac failure may require dose
`reduction, dose interruption or permanent discontinuation of INLYTA.
`(5.5)
`Gastrointestinal Perforation and Fistula Formation: Gastrointestinal
`perforation and fistula, including death, have occurred. Use with caution
`in patients at risk for gastrointestinal perforation or fistula. (5.6)
`Hypothyroidism: Hypothyroidism requiring thyroid hormone
`replacement has been reported. Monitor thyroid function before
`initiation of, and periodically throughout, treatment with INLYTA. (5.7)
`Impaired 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. Resume INLYTA at a
`reduced dose or discontinue based on severity and persistence of the
`impaired wound healing. The safety of resumption of INLYTA after
`resolution of wound healing complications has not been established.
`(5.8)
`Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS
`has been observed. Permanently discontinue INLYTA if signs or
`symptoms of RPLS occur. (5.9)
`Proteinuria: Monitor for proteinuria before initiation of, and periodically
`throughout, treatment with INLYTA. For moderate to severe proteinuria,
`withhold and then dose reduce INLYTA. (5.10)
`Hepatotoxicity: Liver enzyme elevation has occurred during treatment
`with INLYTA as a single agent. Monitor ALT, AST and bilirubin before
`initiation of, and periodically throughout, treatment with INLYTA.
`When used in combination with avelumab or pembrolizumab, higher
`frequencies of Grade 3 and 4 ALT and AST elevation may occur.
`Consider more frequent monitoring of liver enzymes. Withhold
`INLYTA and avelumab or pembrolizumab, initiate corticosteroid
`therapy as needed, and/or permanently discontinue the combination for
`severe or life-threatening hepatotoxicity. (5.11)
`Use in Patients with Hepatic Impairment: Decrease the starting dose of
`INLYTA if used in patients with moderate hepatic impairment.
`INLYTA has not been studied in patients with severe hepatic
`impairment. (2.2, 5.12)
`• Major adverse cardiovascular events (INLYTA in combination with
`avelumab): Optimize management of cardiovascular risk factors.
`Permanently discontinue INLYTA in combination with avelumab for
`Grade 3-4 events. (5.13)
`Embryo-Fetal Toxicity: INLYTA can cause fetal harm. Advise patients
`of the potential risk to the fetus and to use effective contraception. (5.14,
`8.1, 8.3)
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`
` ------------------------------ ADVERSE REACTIONS ------------------------------
`Most common adverse reactions (≥20%) are:
`
`INLYTA in combination with avelumab: diarrhea, fatigue, hypertension,
`musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia,
`dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough,
`dyspnea, abdominal pain, and headache. (6.1)
`
`INLYTA in combination with pembrolizumab: diarrhea, fatigue/asthenia,
`hypertension, hepatotoxicity, hypothyroidism, decreased appetite,
`palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation,
`dysphonia, rash, cough, and constipation. (6.1)
`
`INLYTA as a single agent: diarrhea, hypertension, fatigue, decreased appetite,
`nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome,
`weight decreased, vomiting, asthenia, and constipation. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
` ------------------------------ DRUG INTERACTIONS-------------------------------
`Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the INLYTA
`•
`dose. (2.2, 7.1)
`Avoid strong CYP3A4/5 inducers. (7.2)
`
`•
`
` ----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`Lactation: Advise not to breastfeed. (8.2)
`
`Reference ID: 5053445
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling.
`
`
`Revised: 9/2022
`
`
`Reference ID: 5053445
`
`2
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`7 DRUG INTERACTIONS
`7.1
`CYP3A4/5 Inhibitors
`7.2
`CYP3A4/5 Inducers
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
`8.3
`Females and Males of Reproductive Potential
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Hepatic Impairment
`8.7
`Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1
`First-Line Advanced RCC
`14.2
`Second-Line Advanced RCC
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the Full Prescribing Information are not
`listed.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 1
`
`
`
`INDICATIONS AND USAGE
`1.1
`First-Line Advanced Renal Cell Carcinoma
`1.2
`Second-Line Advanced Renal Cell Carcinoma
`2 DOSAGE AND ADMINISTRATION
`2.1
`Recommended Dosing
`2.2
`Dose Modification Guidelines
`2.3
`Dosage Modification for Drug Interactions
`2.4
`Dosage Modification for Hepatic Impairment
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Hypertension
`5.2
`Arterial Thromboembolic Events
`5.3
`Venous Thromboembolic Events
`5.4
`Hemorrhage
`5.5
`Cardiac Failure
`5.6
`Gastrointestinal Perforation and Fistula Formation
`5.7
`Thyroid Dysfunction
`5.8
`Impaired Wound Healing
`5.9
`Reversible Posterior Leukoencephalopathy Syndrome
`5.10
`Proteinuria
`5.11 Hepatotoxicity
`5.12 Use in Patients with Hepatic Impairment
`5.13 Major Adverse Cardiovascular Events (MACE)
`5.14
`Embryo-Fetal Toxicity
`6 ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`
`
`Reference ID: 5053445
`
`3
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
` 2
`
`
`
`DOSAGE AND ADMINISTRATION
`
`Recommended Dosing
`
`
`2.1
`
`First-Line Advanced RCC
`
`INLYTA in Combination with Avelumab
`
`The recommended starting dosage 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.
`
`INLYTA in Combination with Pembrolizumab
`
`The recommended starting dosage 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.
`
`
`
`
`Reference ID: 5053445
`
`4
`
` 1
`
`
`
`INDICATIONS AND USAGE
`
`First-Line Advanced Renal Cell Carcinoma
`
`Second-Line Advanced Renal Cell Carcinoma
`
`
`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 RCC.
`
`1.2
`
`INLYTA as a single agent is indicated for the treatment of advanced RCC after failure of one prior
`systemic therapy.
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`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.
`
`2.2
`
`Dose increase or reduction is recommended based on individual safety and tolerability.
`
`Recommended INLYTA dosage increases and reductions are provided in Table 1.
`
`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.
`
`Table 1:Recommended Dosage Increases and Reductions for INLYTA
`Dose Modification
`Dose Regimen
`Recommended starting dosage
`5 mg twice daily
`Dosage increase
`First dose increase
`Second dose increase
`Dosage reductiona
`First dose reductionb
`Second dose reduction
`a: for management of adverse drug reactions
`b: from 5 mg twice daily
`
`Dose Modification Guidelines
`
`7 mg twice daily
`10 mg twice daily
`
`3 mg twice daily
`2 mg twice daily
`
`
`Recommended dosage modifications for adverse reactions for INLYTA are provided in Table 2.
`
`Table 2:Recommended Dosage Modification for INLYTA for Adverse Reactions
`Adverse Reaction
`Severity
`Dosage Modifications for INLYTA
`Hypertension [see Warnings and
`SBP > 150 mmHg or DBP > 100
`• Reduce dose by one level.
`Precautions (5.1)]
`mmHg despite antihypertensive
`
`treatment
`
`SBP > 160 mmHg or DBP > 105
`mmHg
`
`Grade 4 or hypertensive crisis
`
`Hemorrhage [see Warnings and
`Precautions (5.4)]
`
`Grade 3 or 4
`
`
`
`Reference ID: 5053445
`
`5
`
`• Withhold until BP < 150/100
`mmHg.
`• Resume at a reduced dose.
`• Permanently discontinue.
`
`• Withhold until resolution to Grade
`0 or 1 or baseline.
`• Either resume at a reduced dose or
`discontinue depending on the
`severity and persistence of adverse
`reaction.
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`Adverse Reaction
`Cardiac failure [see Warnings and
`Precautions (5.5)]
`
`Impaired wound healing
`[see Warnings and Precautions
`(5.8)]
`
`Severity
`Asymptomatic cardiomyopathy
`(left ventricular ejection fraction
`greater than 20% but less than 50%
`below baseline or below the lower
`limit of normal if baseline was not
`obtained)
`Clinically manifested congestive
`heart failure
`Any Grade
`
`Reversible Posterior
`Leukoencephalopathy Syndrome
`[see Warnings and
`Precautions (5.9)]
`Proteinuria [see Warnings and
`Precautions (5.10)]
`
`Other Adverse Reactions
`
`Any Grade
`
`2 or more grams proteinuria per 24
`hours
`
`Grade 3
`Grade 4
`
`Dosage Modifications for INLYTA
`• Withhold until resolution to Grade
`0 or 1 or baseline.
`• Resume at a reduced dose.
`
`
`• Permanently discontinue.
`
`• The safety of resumption of
`INLYTA after resolution of wound
`healing has not been established.
`• Either resume at a reduced dose or
`discontinue depending on the
`severity and persistence of the
`adverse reaction.
`• Permanently discontinue.
`
`• Withhold until resolution to less
`than 2 grams per 24 hours.
`• Resume at a reduced dose.
`• Reduce dosage by one level.
`• Withhold until resolution to Grade
`2.
`• Resume at a reduced dose.
`
`
`Table 3 represents additional recommended dosage modifications for adverse reactions when INLYTA is
`administered in combination with avelumab or pembrolizumab.
`
`See the Full Prescribing Information for additional dosage information for avelumab or pembrolizumab
`including dose modifications for immune-mediated adverse reactions.
`
`
`
`
`Reference ID: 5053445
`
`6
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

` Table 3: Recommended Dosage Modification for Adverse Reactions for INLYTA in Combination
`with Avelumab or Pembrolizumab
`Treatment
`Adverse
`Severity*
`Reaction
`
`
`
`
`
`
`
`
`
`
`
`
`INLYTA in
`combination with
`avelumab OR
`pembrolizumab
`
`
`Liver enzyme
`elevationsb
`
`ALT or AST at least
`3 times ULN but less than
`10 times ULN without
`concurrent total bilirubin
`at least 2 times ULN
`
`ALT or AST increases to
`more than 3 times ULN
`with concurrent total
`bilirubin at least 2 times
`ULN or ALT or AST at
`least 10 times ULN
`Grade 1-2
`
`Grade 3
`
`Dosage Modifications for
`INLYTA
`• Withhold both INLYTA and
`avelumab or pembrolizumab
`until resolution to
`Grades 0-1
`• Consider rechallenge with
`INLYTA and/or avelumab
`or pembrolizumaba
`• Permanently discontinue
`both INLYTA and avelumab
`or pembrolizumab
`
`•
`
`•
`
`Initiate symptomatic
`medications.
`Interrupt INLYTA and
`initiate symptomatic
`medications. If diarrhea is
`controlled, INLYTA may be
`resumed at either the same
`dose or reduced by 1 dose
`level.
`• Withhold INLYTA until
`resolution to Grade <2, then
`restart INLYTA dose
`reduced by 1 dose level
`• Permanently discontinue
`
`Diarrhea
`
`Grade 4
`
`Grade 3 or 4
`
`Dosage Modification for Drug Interactions
`
`Major Adverse
`INLYTA in
`Cardiovascular
`combination with
`Events (MACE)
`avelumab
`* Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
`a If rechallenging with INLYTA, consider dosage reduction per Table 1. Consider rechallenge with a single drug or sequential
`rechallenge with both drugs after recovery.
` b Consider corticosteroid therapy
`ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal
`
`2.3
`
`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
`
`
`
`Reference ID: 5053445
`
`7
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`Dosage Modification for Hepatic Impairment
`
`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)].
`
`2.4
`
`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)].
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`• 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.
`
` 3
`
`
`
`CONTRAINDICATIONS
`
` 4
`
`
`
`
`None.
`
` 5
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
`5.1 Hypertension
`
`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)].
`
`Ensure that blood pressure is well-controlled prior to initiating INLYTA. Monitor patients for
`hypertension and treat as needed with standard anti-hypertensive therapy. Withhold and then dose reduce
`INLYTA or permanently discontinue based on severity of hypertension [see Dosage and Administration
`(2.2)].
`
`
`
`
`Reference ID: 5053445
`
`8
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`Venous Thromboembolic Events
`
`Arterial Thromboembolic Events
`
`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)].
`
`INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous
`12 months. 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.
`
`Permanently discontinue INLYTA if an arterial thromboembolic event occurs during treatment.
`
`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.
`
`INLYTA has not been studied in patients who had a venous thromboembolic event within the previous
`6 months. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients
`(3%), with two deaths secondary to pulmonary embolism.
`
`Monitor for signs and symptoms of VTE and PE. Withhold INLYTA and then resume at same dose or
`permanently discontinue based on severity of VTE.
`
`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. Withhold and then dose reduce
`INLYTA or discontinue based on severity and persistence of hemorrhage.
`
`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
`
`
`
`Reference ID: 5053445
`
`9
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`Thyroid Dysfunction
`
`Impaired Wound Healing
`
`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 dose reduction, dose interruption or
`permanent discontinuation of INLYTA [see Dosage and Administration (2.2)].
`
`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. Resume INLYTA at a reduced dose or
`discontinue based on severity and persistence of the impaired wound healing. The safety of resumption of
`INLYTA after resolution of wound healing complications has not been established [see Dosage and
`Administration (2.2)].
`
`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: 5053445
`
`10
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`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. Permanently discontinue INLYTA in
`patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing
`RPLS is not known [see Dosage and Administration (2.2)].
`
`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, withhold and then dose reduce
`INLYTA [see Dosage and Administration (2.2)].
`
`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 elevations. Monitor liver enzymes before initiation
`of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as
`compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt or
`permanently discontinue INLYTA and avelumab or pembrolizumab, and administer corticosteroids as
`needed [see Dosage and Administration (2.3)].
`
`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
`(n=3) or axitinib (n=25) administered as a single agent or with both (n=45), recurrence of ALT ≥3 times
`ULN was observed in no patient receiving avelumab, 6 patients receiving INLYTA, and 15 patients
`receiving both avelumab and INLYTA. Twenty-two (88%) patients with a recurrence of ALT ≥3 ULN
`subsequently recovered to Grade 0-1 from the event. Immune-mediated hepatitis was reported in 7% of
`patients including 4.9% with Grade 3 or 4 immune-mediated hepatitis. Hepatotoxicity led to permanent
`discontinuation in 7% and immune-mediated hepatitis led to permanent discontinuation of either
`avelumab or INLYTA in 5% of patients. Thirty-four patients were treated with corticosteroids and one
`patient was treated with a non-steroidal immunosuppressant. Resolution of hepatitis occurred in 31 of the
`35 patients at the time of data cut-off.
`
`
`
`
`Reference ID: 5053445
`
`11
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`With the combination of INLYTA and pembrolizumab, Grades 3 and 4 increased ALT (20%) and
`increased AST (13%) were seen. 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 (n=3) or INLYTA (n=34)
`administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in
`1 patient receiving pembrolizumab, 16 patients receiving INLYTA, and 24 patients receiving both
`pembrolizumab and INLYTA. All patients with a recurrence of ALT ≥3 ULN subsequently recovered
`from the event.
`
`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) compar