KEYTRUDA (Page 3 of 21)

2.3 Dose Modifications

No dose reduction for KEYTRUDA is recommended. In general, withhold KEYTRUDA for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue KEYTRUDA 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 steroids.

Dosage modifications for KEYTRUDA for adverse reactions that require management different from these general guidelines are summarized in Table 2.

Table 2: Recommended Dosage Modifications for Adverse Reactions
Adverse Reaction Severity * Dosage Modification
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal
*
Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0
Resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids.
If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue KEYTRUDA based on recommendations for hepatitis with no liver involvement.
Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
Pneumonitis Grade 2 Withhold
Grade 3 or 4 Permanently discontinue
Colitis Grade 2 or 3 Withhold
Grade 4 Permanently discontinue
Hepatitis with no tumor involvement of the liver AST or ALT increases to more than 3 and up to 8 times ULNorTotal bilirubin increases to more than 1.5 and up to 3 times ULN Withhold
For liver enzyme elevations in patients treated with combination therapy with axitinib, see Table 3. AST or ALT increases to more than 8 times ULN orTotal bilirubin increases to more than 3 times ULN Permanently discontinue
Hepatitis with tumor involvement of the liver Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN Withhold
ALT or AST increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue
Endocrinopathies Grade 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity
Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold
Grade 4 increased blood creatinine Permanently discontinue
Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold
Confirmed SJS, TEN, or DRESS Permanently discontinue
Myocarditis Grade 2, 3, or 4 Permanently discontinue
Neurological Toxicities Grade 2 Withhold
Grade 3 or 4 Permanently discontinue
Hematologic toxicity in patients with cHL or PMBCL Grade 4 Withhold until resolution to Grades 0 or 1
Other Adverse Reactions
Infusion-related reactions [see Warnings and Precautions (5.2)] Grade 1 or 2 Interrupt or slow the rate of infusion
Grade 3 or 4 Permanently discontinue

The following table represents dosage modifications that are different from those described above for KEYTRUDA or in the Full Prescribing Information for the drug administered in combination.

Table 3: Recommended Specific Dosage Modifications for Adverse Reactions for KEYTRUDA in Combination with Axitinib
Treatment Adverse Reaction Severity Dosage Modification
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal
*
Consider corticosteroid therapy
Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery. If rechallenging with axitinib, consider dose reduction as per the axitinib Prescribing Information.
KEYTRUDA in combination with axitinib Liver enzyme elevations * ALT or AST increases to at least 3 times but less than 10 times ULN without concurrent total bilirubin at least 2 times ULN Withhold both KEYTRUDA and axitinib until resolution to Grades 0 or 1
ALT or AST increases to more than 3 times ULN with concurrent total bilirubin at least 2 times ULN or ALT or AST ≥10 times ULN Permanently discontinue bothKEYTRUDA and axitinib

Recommended Dose Modifications for Adverse Reactions for KEYTRUDA in Combination with Lenvatinib

When administering KEYTRUDA in combination with lenvatinib, modify the dosage of one or both drugs. Withhold or discontinue KEYTRUDA as shown in Table 2. Refer to lenvatinib prescribing information for additional dose modification information.

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