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BAVENCIO® (avelumab) in combination with INLYTA® (axitinib) dosing

  • Premedicate patients with an antihistamine and with acetaminophen prior to the first 4 infusions of BAVENCIO
    • Premedication should be administered for subsequent BAVENCIO doses based upon clinical judgment and presence/severity of prior infusion reactions
  • When INLYTA is used in combination with BAVENCIO, 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 INLYTA prior to initiation

The recommended dose of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity

Adverse reaction management

  • Management of some adverse reactions may require temporary interruption or permanent discontinuation. See BAVENCIO Dose Modifications

Premedication

  • Premedicate patients with an antihistamine and with acetaminophen prior to the first 4 infusions of BAVENCIO
    • Premedication should be administered for subsequent BAVENCIO doses based on clinical judgment and presence/severity of prior infusion reactions

Preparation

  • Visually inspect vial for particulate matter and discoloration. BAVENCIO is a clear, colorless to slightly yellow solution. Discard vial if the solution is cloudy, discolored, or contains particulate matter
  • Withdraw the required volume of BAVENCIO from the vial(s) and inject it into a 250 mL infusion bag containing either 0.9% sodium chloride injection or 0.45% sodium chloride injection
  • Gently invert the bag to mix the diluted solution and avoid foaming or excessive shearing
  • Inspect the solution to ensure it is clear, colorless, and free of visible particles
  • Discard any partially used or empty vials

Storage of diluted BAVENCIO solution

  • Protect from light
  • Store diluted BAVENCIO solution:
    • At room temperature up to 77°F (25°C) for no more than 4 hours from the time of dilution
    • Or
    • Under refrigeration at 36°F to 46°F (2°C to 8°C) for no more than 24 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration
  • Do not freeze or shake diluted solution

Administration

  • Administer the diluted solution over 60 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micron)
  • Do not coadminister other drugs through the same intravenous line

Recommended dose modifications of BAVENCIO for adverse reactions

Severe and fatal immune-mediated adverse reactions

  • BAVENCIO is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions
  • Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions 
  • Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and at any time after starting treatment with a PD-1/PD-L1 blocking antibody 
  • While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, they can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies

Monitor and assess

  • Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies
  • Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions
  • Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment
  • In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate

General dose modifications

  • No dose reduction for BAVENCIO is recommended
  • In general, withhold BAVENCIO for severe (Grade 3) immune-mediated adverse reactions
  • Permanently discontinue BAVENCIO for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids
    • Dosage modifications for BAVENCIO for adverse reactions that require management different from these general guidelines are summarized in the table below

General corticosteroid management

  • In general, if BAVENCIO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less
    • Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month
    • Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy
    • Toxicity management guidelines for adverse reactions that do not necessarily require systemic corticosteroids (eg, endocrinopathies and dermatologic reactions) are discussed in the table below
Modify treatment based on severity
Withhold* Permanently discontinue
 For Grade 2 For Grade 3 or 4
Modify treatment based on severity

Withhold*

For Grade 2

Permanently discontinue

For Grade 3 or 4

*Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating corticosteroids.

Modify treatment based on severity  
Withhold* Permanently discontinue
For Grade 2 For Grade 3 or 4
Modify treatment based on severity
Withhold*
For Grade 2
Permanently discontinue
For Grade 3 or 4

Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating corticosteroids.

Liver enzyme elevations in patients being treated with BAVENCIO as monotherapy:

Modify treatment based on severity
  Withhold* Permanently discontinue
Hepatitis with no tumor involvement of the liver For AST or ALT increases >3 and up to 8 times ULN, or total bilirubin increases >1.5 and up to 3 times ULN For AST or ALT >8 times ULN or total bilirubin >3 times ULN
Hepatitis with tumor involvement of the liver If baseline AST or ALT is >1 and up to 3 times ULN and increases to >5 and up to 10 times ULN, or baseline AST or ALT is >3 and up to 5 times ULN and increases to >8 and up to 10 times ULN For AST or ALT increases to >10 times ULN or total bilirubin increases to >3 times ULN
Modify treatment based on severity
Withhold*

Hepatitis with no tumor involvement of the liver

For AST or ALT increases >3 and up to 8 times ULN, or total bilirubin increases >1.5 and up to 3 times ULN

Hepatitis with tumor involvement of the liver§

If baseline AST or ALT is >1 and up to 3 times ULN and increases to >5 and up to 10 times ULN, or baseline AST or ALT is >3 and up to 5 times ULN and increases to >8 and up to 10 times ULN
Permanently discontinue

Hepatitis with no tumor involvement of the liver

For AST or ALT >8 times ULN or total bilirubin >3 times ULN

Hepatitis with tumor involvement of the liver§

For AST or ALT increases to >10 times ULN or total bilirubin increases to >3 times ULN

*Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating corticosteroids.

*If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue BAVENCIO based on recommendations for hepatitis where there is no tumor involvement of the liver.

ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal

 

Liver enzyme elevations in patients being treated with BAVENCIO in combination with INLYTA:

Modify treatment based on severity

Withhold

both BAVENCIO and INLYTA until adverse reactions recover to Grades 0-1

Permanently discontinue

both BAVENCIO and INLYTA

For ALT or AST ≥3 times ULN but <10 times ULN without concurrent total bilirubin ≥2 times ULN For ALT or AST ≥10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN
Consider rechallenge with BAVENCIO or INLYTA or sequential rechallenge with both BAVENCIO and INLYTA after recovery||  
Modify treatment based on severity

Withhold

both BAVENCIO and INLYTA until adverse reactions recover to Grades 0-1

For ALT or AST ≥3 times ULN but <10 times ULN without concurrent total bilirubin ≥2 times ULN

Consider rechallenge with BAVENCIO or INLYTA or sequential rechallenge with both BAVENCIO and INLYTA after recovery||

Permanently discontinue

both BAVENCIO and INLYTA

For ALT or AST ≥10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN

Consider corticosteroid therapy

||Dose reduction according to the INLYTA Full Prescribing Information should be considered if rechallenging with INLYTA

Modify treatment based on severity
Grade 2 or higher Grade 3-4
Initiate symptomatic treatment, including hormone replacement, as clinically indicated Withhold BAVENCIO for adrenal insufficiency until clinically stable, or permanently discontinue depending on severit
Modify treatment based on severity

Grade 2 or higher

Initiate symptomatic treatment, including hormone replacement, as clinically indicated

Grade 3-4

Initiate symptomatic treatment, including hormone replacement, as clinically indicated
Modify treatment based on severity
Any Grade Grade 3-4
Initiate hormone replacement as clinically indicated Withhold BAVENCIO until clinically stable, or permanently discontinue depending on severity
Modify treatment based on severity

Grade 2 or higher

Initiate hormone replacement as clinically indicated

Grade 3-4

Withhold BAVENCIO until clinically stable, or permanently discontinue depending on severity
Modify treatment based on severity
Any grade hypothyroidism or hyperthyroidism Grade 3-4
Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism, as clinically indicated Withhold BAVENCIO until clinically stable, or permanently discontinue depending on severity
Modify treatment based on severity

Any grade hypothyroidism or hyperthyroidism

Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism, as clinically indicated

Grade 3-4

Withhold BAVENCIO until clinically stable, or permanently discontinue depending on severity
Modify treatment based on severity
Hyperglycemia
Initiate treatment with insulin as clinically indicated. Withhold BAVENCIO until clinically stable or permanently discontinue depending on severity
Modify treatment based on severity

Hyperglycemia

Initiate treatment with insulin as clinically indicated. Withhold BAVENCIO until clinically stable or permanently discontinue depending on severity
Modify treatment based on severity
Withhold# Permanently discontinue
For Grade 2 or 3 increased blood creatinine For Grade 4 increased blood creatinine
Modify treatment based on severity

Withhold#

For Grade 2 or 3 increased blood creatinine

Permanently discontinue

For Grade 4 increased blood creatinine

#Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating corticosteroids.

Modify treatment based on severity
Withhold** Permanently discontinue
Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism, as clinically indicated For confirmed SJS, TEN, or DRESS
Modify treatment based on severity

Withhold**

For suspected Stevens Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS)

Permanently discontinue

For confirmed SJS, TEN, or DRESS
  •  Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions

**Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating corticosteroids.

Modify treatment based on severity
For myocarditis, permanently discontinue BAVENCIO for Grade 2, Grade 3, or Grade 4 adverse reactions
For neurological toxicities, withhold BAVENCIO for Grade 2†† and permanently discontinue for Grade 3 or Grade 4 adverse reactions
Modify treatment based on severity

For myocarditis, permanently discontinue BAVENCIO for Grade 2, Grade 3, or Grade 4 adverse reactions

For neurological toxicities, withhold BAVENCIO for Grade 2†† and permanently discontinue for Grade 3 or Grade 4 adverse reactions

††Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating corticosteroids.

Modify treatment based on severity
Grade 1-2 Grade 3-4
Interrupt or slow the rate of infusion Stop the infusion and permanently discontinueBAVENCIO
Modify treatment based on severity

Grade 1-2

Interrupt or slow the rate of infusion

Grade 3-4

Stop the infusion and permanently discontinue BAVENCIO
Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT
Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT
Modify treatment based on severity
Grade 3-4
Discontinue BAVENCIO and INLYTA
Modify treatment based on severity

Grade 3-4

Discontinue BAVENCIO and INLYTA

 

*Observed with BAVENCIO or with other anti-PD-1/PD-L1 monoclonal antibodies.

Starting dose for most patients is 5 mg orally taken twice daily

  • Dose titration
    • Dose can be increased or decreased based on individual safety and tolerability  

  • Half-life
    • The half-life of INLYTA ranges from 2.5 to 6.1 hours
INLYTA dosing considerations
  • For patients with moderate hepatic impairment, or for patients on a strong CYP3A4/5 inhibitor, decrease the INLYTA dose by approximately half
  • Avoid strong CYP3A4/5 inhibitors. If unavoidable reduce the dose
  • Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers
  • Patients should not eat grapefruit, drink grapefruit juice, or take St John's wort while taking INLYTA
  • Stop treatment with INLYTA at least 2 days prior to elective surgery. Do not re-administer INLYTA for at least 2 weeks following major surgery and until adequate wound healing

Management of some AEs may require temporary interruption or permanent discontinuation and/or dose reduction

  • The dose of INLYTA may be increased or reduced based on individual safety or tolerability
  • Film-coated tablets in 2 different strengths (5 mg and 1 mg) allow for titration
  • Do not break apart INLYTA tablets

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Dose modification criteria

If a dose reduction from the starting dose is required:

  • Reduce dose to 3 mg twice daily
  • Reduce dose to 2 mg twice daily if additional dose reduction is required

 

Dose increase criteria: Patients tolerate INLYTA for at least 2 consecutive weeks with no AEs >Grade 2 and are normotensive without antihypertension medication

  • Dose may be increased to 7 mg twice daily if patients meet dose increase criteria at the starting dose
  • Dose may be further increased to 10 mg twice daily if patients meet the dose increase criteria at the 7-mg dose