INLYTA® Dosage and Administration

(axitinib)

2 DOSAGE AND ADMINISTRATION

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.

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 ModificationDose Regimen
*
for management of adverse drug reactions
†
from 5 mg twice daily

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*

  First dose reduction†

3 mg twice daily

  Second dose reduction

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 ReactionSeverityDosage Modifications for INLYTA

Hypertension [see Warnings and Precautions (5.1)]

SBP >150 mmHg or DBP >100 mmHg despite antihypertensive treatment

•
Reduce dose by one level.

SBP >160 mmHg or DBP >105 mmHg

•
Withhold until BP <150/100 mmHg.
•
Resume at a reduced dose.

Grade 4 or hypertensive crisis

•
Permanently discontinue.

Hemorrhage [see Warnings and Precautions (5.4)]

Grade 3 or 4

•
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.

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)

•
Withhold until resolution to Grade 0 or 1 or baseline.
•
Resume at a reduced dose.

Clinically manifested congestive heart failure

•
Permanently discontinue.

Impaired wound healing [see Warnings and Precautions (5.8)]

Any Grade

•
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.

Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.9)]

Any Grade

•
Permanently discontinue.

Proteinuria [see Warnings and Precautions (5.10)]

2 or more grams proteinuria per 24 hours

•
Withhold until resolution to less than 2 grams per 24 hours.
•
Resume at a reduced dose.

Other Adverse Reactions

Grade 3

•
Reduce dosage by one level.

Grade 4

•
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.

Table 3: Recommended Dosage Modification for Adverse Reactions for INLYTA in Combination with Avelumab or Pembrolizumab
TreatmentAdverse ReactionSeverity*Dosage Modifications for INLYTA
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal
*
Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
†
Consider corticosteroid therapy
‡
If rechallenging with INLYTA, consider dosage reduction per Table 1. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery.

INLYTA in combination with avelumab OR pembrolizumab

Liver enzyme elevations†

ALT or AST at least 3 times ULN but less than 10 times ULN without concurrent total bilirubin at least 2 times ULN

•
Withhold both INLYTA and avelumab or pembrolizumab until resolution to Grades 0–1
•
Consider rechallenge with INLYTA and/or avelumab or pembrolizumab‡

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

•
Permanently discontinue both INLYTA and avelumab or pembrolizumab

Diarrhea

Grade 1–2

•
Initiate symptomatic medications.

Grade 3

•
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.

Grade 4

•
Withhold INLYTA until resolution to Grade <2, then restart INLYTA dose reduced by 1 dose level

INLYTA in combination with avelumab

Major Adverse Cardiovascular Events (MACE)

Grade 3 or 4

•
Permanently discontinue

2.3 Dosage Modification for Drug Interactions

Strong CYP3A4/5 Inhibitors

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

2.4 Dosage Modification for Hepatic Impairment

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

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Dosage and Administration

2 DOSAGE AND ADMINISTRATION

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.

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 ModificationDose Regimen
*
for management of adverse drug reactions
†
from 5 mg twice daily

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*

  First dose reduction†

3 mg twice daily

  Second dose reduction

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 ReactionSeverityDosage Modifications for INLYTA

Hypertension [see Warnings and Precautions (5.1)]

SBP >150 mmHg or DBP >100 mmHg despite antihypertensive treatment

•
Reduce dose by one level.

SBP >160 mmHg or DBP >105 mmHg

•
Withhold until BP <150/100 mmHg.
•
Resume at a reduced dose.

Grade 4 or hypertensive crisis

•
Permanently discontinue.

Hemorrhage [see Warnings and Precautions (5.4)]

Grade 3 or 4

•
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.

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)

•
Withhold until resolution to Grade 0 or 1 or baseline.
•
Resume at a reduced dose.

Clinically manifested congestive heart failure

•
Permanently discontinue.

Impaired wound healing [see Warnings and Precautions (5.8)]

Any Grade

•
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.

Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.9)]

Any Grade

•
Permanently discontinue.

Proteinuria [see Warnings and Precautions (5.10)]

2 or more grams proteinuria per 24 hours

•
Withhold until resolution to less than 2 grams per 24 hours.
•
Resume at a reduced dose.

Other Adverse Reactions

Grade 3

•
Reduce dosage by one level.

Grade 4

•
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.

Table 3: Recommended Dosage Modification for Adverse Reactions for INLYTA in Combination with Avelumab or Pembrolizumab
TreatmentAdverse ReactionSeverity*Dosage Modifications for INLYTA
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal
*
Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
†
Consider corticosteroid therapy
‡
If rechallenging with INLYTA, consider dosage reduction per Table 1. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery.

INLYTA in combination with avelumab OR pembrolizumab

Liver enzyme elevations†

ALT or AST at least 3 times ULN but less than 10 times ULN without concurrent total bilirubin at least 2 times ULN

•
Withhold both INLYTA and avelumab or pembrolizumab until resolution to Grades 0–1
•
Consider rechallenge with INLYTA and/or avelumab or pembrolizumab‡

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

•
Permanently discontinue both INLYTA and avelumab or pembrolizumab

Diarrhea

Grade 1–2

•
Initiate symptomatic medications.

Grade 3

•
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.

Grade 4

•
Withhold INLYTA until resolution to Grade <2, then restart INLYTA dose reduced by 1 dose level

INLYTA in combination with avelumab

Major Adverse Cardiovascular Events (MACE)

Grade 3 or 4

•
Permanently discontinue

2.3 Dosage Modification for Drug Interactions

Strong CYP3A4/5 Inhibitors

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

2.4 Dosage Modification for Hepatic Impairment

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