Inlyta

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 First-Line Advanced Renal Cell Carcinoma

  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.
  )
• •in combination with pembrolizumab, for the first-line treatment of patients with advanced RCC. (
  1.1 First-Line Advanced Renal Cell Carcinoma

  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.
  )
• •as a single agent, for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. (
  1.2 Second-Line Advanced Renal Cell Carcinoma

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

• •INLYTA 5 mg orally twice daily with avelumab 800 mg every 2 weeks. (
  2.1 Recommended Dosing

  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.

  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.
  )
• •INLYTA 5 mg orally twice daily with pembrolizumab 200 mg every 3 weeks or 400 mg every 6 weeks. (
  2.1 Recommended Dosing

  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.

  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.
  )
• •INLYTA as a single agent the starting dose is 5 mg orally twice daily. (
  2.1 Recommended Dosing

  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.

  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.
  )
• •Dose adjustments can be made based on individual safety and tolerability. (
  2.2 Dose Modification Guidelines

  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	7 mg twice daily
  Second dose increase	10 mg twice daily
  Dosage reduction for management of adverse drug reactions
  First dose reductionfrom 5 mg twice daily	3 mg twice daily
  Second dose reduction	2 mg twice daily

  Recommended dosage modifications for adverse reactions for INLYTA are provided in Table 2.

  Reduce dose by one level.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.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 2: Recommended Dosage Modification for INLYTA for Adverse Reactions

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  •

  Adverse Reaction	Severity	Dosage Modifications for INLYTA
  Hypertension [see Warnings and Precautions (5.1)]	SBP >150 mmHg or DBP >100 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
  Cardiac failure [see Warnings and Precautions (5.5)]	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
  Impaired wound healing [see Warnings and Precautions (5.8)]	Any Grade
  Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.9)]	Any Grade
  Proteinuria [ see Warnings and Precautions (5.10) ]	2 or more grams proteinuria per 24 hours
  Other Adverse Reactions	Grade 3
  	Grade 4

  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.

  Withhold both INLYTA and avelumab or pembrolizumab until resolution to Grades 0–1

  Consider rechallenge with INLYTA and/or avelumab or pembrolizumabIf rechallenging with INLYTA, consider dosage reduction per Table 1. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery.Permanently discontinue both INLYTA and avelumab or pembrolizumabInitiate 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 levelPermanently discontinue

  Table 3: Recommended Dosage Modification for Adverse Reactions for INLYTA in Combination with Avelumab or Pembrolizumab

  •

  •

  •

  •

  •

  •

  •

  Treatment	Adverse Reaction	Severity Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.	Dosage Modifications for INLYTA
  ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal
  INLYTA in combination with avelumab OR pembrolizumab	Liver enzyme elevationsConsider corticosteroid therapy	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
  	Diarrhea	Grade 1–2
  		Grade 3
  		Grade 4
  INLYTA in combination with avelumab	Major Adverse Cardiovascular Events (MACE)	Grade 3 or 4
  )
• •Administer INLYTA dose approximately 12 hours apart with or without food. (
  2.1 Recommended Dosing

  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.

  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.
  )
• •INLYTA should be swallowed whole with a glass of water. (
  2.1 Recommended Dosing

  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.

  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.
  )
• •See Full Prescribing Information for dosage modifications for adverse reactions. (
  2.2 Dose Modification Guidelines

  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	7 mg twice daily
  Second dose increase	10 mg twice daily
  Dosage reduction for management of adverse drug reactions
  First dose reductionfrom 5 mg twice daily	3 mg twice daily
  Second dose reduction	2 mg twice daily

  Recommended dosage modifications for adverse reactions for INLYTA are provided in Table 2.

  Reduce dose by one level.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.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 2: Recommended Dosage Modification for INLYTA for Adverse Reactions

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  Adverse Reaction	Severity	Dosage Modifications for INLYTA
  Hypertension [see Warnings and Precautions (5.1)]	SBP >150 mmHg or DBP >100 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
  Cardiac failure [see Warnings and Precautions (5.5)]	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
  Impaired wound healing [see Warnings and Precautions (5.8)]	Any Grade
  Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.9)]	Any Grade
  Proteinuria [ see Warnings and Precautions (5.10) ]	2 or more grams proteinuria per 24 hours
  Other Adverse Reactions	Grade 3
  	Grade 4

  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.

  Withhold both INLYTA and avelumab or pembrolizumab until resolution to Grades 0–1

  Consider rechallenge with INLYTA and/or avelumab or pembrolizumabIf rechallenging with INLYTA, consider dosage reduction per Table 1. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery.Permanently discontinue both INLYTA and avelumab or pembrolizumabInitiate 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 levelPermanently discontinue

  Table 3: Recommended Dosage Modification for Adverse Reactions for INLYTA in Combination with Avelumab or Pembrolizumab

  •

  •

  •

  •

  •

  •

  •

  Treatment	Adverse Reaction	Severity Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.	Dosage Modifications for INLYTA
  ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal
  INLYTA in combination with avelumab OR pembrolizumab	Liver enzyme elevationsConsider corticosteroid therapy	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
  	Diarrhea	Grade 1–2
  		Grade 3
  		Grade 4
  INLYTA in combination with avelumab	Major Adverse Cardiovascular Events (MACE)	Grade 3 or 4
  )
• •If a strong CYP3A4/5 inhibitor is required, decrease the INLYTA dose by approximately half. (
  2.2 Dose Modification Guidelines

  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	7 mg twice daily
  Second dose increase	10 mg twice daily
  Dosage reduction for management of adverse drug reactions
  First dose reductionfrom 5 mg twice daily	3 mg twice daily
  Second dose reduction	2 mg twice daily

  Recommended dosage modifications for adverse reactions for INLYTA are provided in Table 2.

  Reduce dose by one level.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.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 2: Recommended Dosage Modification for INLYTA for Adverse Reactions

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  Adverse Reaction	Severity	Dosage Modifications for INLYTA
  Hypertension [see Warnings and Precautions (5.1)]	SBP >150 mmHg or DBP >100 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
  Cardiac failure [see Warnings and Precautions (5.5)]	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
  Impaired wound healing [see Warnings and Precautions (5.8)]	Any Grade
  Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.9)]	Any Grade
  Proteinuria [ see Warnings and Precautions (5.10) ]	2 or more grams proteinuria per 24 hours
  Other Adverse Reactions	Grade 3
  	Grade 4

  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.

  Withhold both INLYTA and avelumab or pembrolizumab until resolution to Grades 0–1

  Consider rechallenge with INLYTA and/or avelumab or pembrolizumabIf rechallenging with INLYTA, consider dosage reduction per Table 1. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery.Permanently discontinue both INLYTA and avelumab or pembrolizumabInitiate 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 levelPermanently discontinue

  Table 3: Recommended Dosage Modification for Adverse Reactions for INLYTA in Combination with Avelumab or Pembrolizumab

  •

  •

  •

  •

  •

  •

  •

  Treatment	Adverse Reaction	Severity Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.	Dosage Modifications for INLYTA
  ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal
  INLYTA in combination with avelumab OR pembrolizumab	Liver enzyme elevationsConsider corticosteroid therapy	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
  	Diarrhea	Grade 1–2
  		Grade 3
  		Grade 4
  INLYTA in combination with avelumab	Major Adverse Cardiovascular Events (MACE)	Grade 3 or 4
  )
• •For patients with moderate hepatic impairment, decrease the starting dose by approximately half. (
  2.2 Dose Modification Guidelines

  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	7 mg twice daily
  Second dose increase	10 mg twice daily
  Dosage reduction for management of adverse drug reactions
  First dose reductionfrom 5 mg twice daily	3 mg twice daily
  Second dose reduction	2 mg twice daily

  Recommended dosage modifications for adverse reactions for INLYTA are provided in Table 2.

  Reduce dose by one level.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.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 2: Recommended Dosage Modification for INLYTA for Adverse Reactions

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  Adverse Reaction	Severity	Dosage Modifications for INLYTA
  Hypertension [see Warnings and Precautions (5.1)]	SBP >150 mmHg or DBP >100 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
  Cardiac failure [see Warnings and Precautions (5.5)]	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
  Impaired wound healing [see Warnings and Precautions (5.8)]	Any Grade
  Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.9)]	Any Grade
  Proteinuria [ see Warnings and Precautions (5.10) ]	2 or more grams proteinuria per 24 hours
  Other Adverse Reactions	Grade 3
  	Grade 4

  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.

  Withhold both INLYTA and avelumab or pembrolizumab until resolution to Grades 0–1

  Consider rechallenge with INLYTA and/or avelumab or pembrolizumabIf rechallenging with INLYTA, consider dosage reduction per Table 1. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery.Permanently discontinue both INLYTA and avelumab or pembrolizumabInitiate 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 levelPermanently discontinue

  Table 3: Recommended Dosage Modification for Adverse Reactions for INLYTA in Combination with Avelumab or Pembrolizumab

  •

  •

  •

  •

  •

  •

  •

  Treatment	Adverse Reaction	Severity Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.	Dosage Modifications for INLYTA
  ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal
  INLYTA in combination with avelumab OR pembrolizumab	Liver enzyme elevationsConsider corticosteroid therapy	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
  	Diarrhea	Grade 1–2
  		Grade 3
  		Grade 4
  INLYTA in combination with avelumab	Major Adverse Cardiovascular Events (MACE)	Grade 3 or 4
  )

• •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.

Lactation: Advise not to breastfeed. (

• •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 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)]

  .
  )
• •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 Arterial Thromboembolic Events

  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 Venous Thromboembolic Events

  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.
  )
• •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 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.
  )
• •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 Cardiac Failure

  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 dose reduction, dose interruption or permanent discontinuation of INLYTA

  [see Dosage and Administration (2.2)]

  .
  )
• •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 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.
  )
• •Hypothyroidism: Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. (
  5.7 Thyroid Dysfunction

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

  [see Adverse Reactions (6.1)]

  .

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

  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)]

  .
  )
• •Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been observed. Permanently discontinue INLYTA if signs or symptoms of RPLS occur. (
  5.9 Reversible Posterior Leukoencephalopathy Syndrome

  In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib

  [see Adverse Reactions (6.1)]

  . There were two additional reports of RPLS in other clinical trials with INLYTA.

  RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. 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)]

  .
  )
• •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 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)]

  .
  )
• •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 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.

  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.
  )
• •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 Dose Modification Guidelines

  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	7 mg twice daily
  Second dose increase	10 mg twice daily
  Dosage reduction for management of adverse drug reactions
  First dose reductionfrom 5 mg twice daily	3 mg twice daily
  Second dose reduction	2 mg twice daily

  Recommended dosage modifications for adverse reactions for INLYTA are provided in Table 2.

  Reduce dose by one level.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.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 2: Recommended Dosage Modification for INLYTA for Adverse Reactions

  •

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  Adverse Reaction	Severity	Dosage Modifications for INLYTA
  Hypertension [see Warnings and Precautions (5.1)]	SBP >150 mmHg or DBP >100 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
  Cardiac failure [see Warnings and Precautions (5.5)]	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
  Impaired wound healing [see Warnings and Precautions (5.8)]	Any Grade
  Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.9)]	Any Grade
  Proteinuria [ see Warnings and Precautions (5.10) ]	2 or more grams proteinuria per 24 hours
  Other Adverse Reactions	Grade 3
  	Grade 4

  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.

  Withhold both INLYTA and avelumab or pembrolizumab until resolution to Grades 0–1

  Consider rechallenge with INLYTA and/or avelumab or pembrolizumabIf rechallenging with INLYTA, consider dosage reduction per Table 1. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery.Permanently discontinue both INLYTA and avelumab or pembrolizumabInitiate 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 levelPermanently discontinue

  Table 3: Recommended Dosage Modification for Adverse Reactions for INLYTA in Combination with Avelumab or Pembrolizumab

  •

  •

  •

  •

  •

  •

  •

  Treatment	Adverse Reaction	Severity Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.	Dosage Modifications for INLYTA
  ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal
  INLYTA in combination with avelumab OR pembrolizumab	Liver enzyme elevationsConsider corticosteroid therapy	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
  	Diarrhea	Grade 1–2
  		Grade 3
  		Grade 4
  INLYTA in combination with avelumab	Major Adverse Cardiovascular Events (MACE)	Grade 3 or 4
  ,
  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)]

  .
  )
• •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 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. Permanently 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).
  )
• •Embryo-Fetal Toxicity: INLYTA can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception. (
  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.
  ,
  8.1 Pregnancy

  Risk Summary

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

  (see Data)

  . Advise females of reproductive potential of the potential risk to a fetus.

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

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

  Data

  Animal Data

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

  Based on findings in animal studies, INLYTA can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations (8.1)].

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

  Pregnancy Testing

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

  Contraception

  Females

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

  Males

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

  Infertility

  Females and Males

  Based on findings in animals, INLYTA may impair fertility in females and males of reproductive potential

  [see Nonclinical Toxicology (13.1)]

  .
  )