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2       DOSAGE AND ADMINISTRATION

2.1 Patient Selection
Patient Selection for Single Agent Treatment
Select patients for treatment with KEYTRUDA as a single agent based on the presence of positive PD-L1 expression in:
• metastatic NSCLC [see Clinical Studies (14.2)].
• first-line treatment of metastatic or unresectable, recurrent HNSCC [see Clinical Studies (14.3)].
• metastatic urothelial carcinoma [see Clinical Studies (14.6)].
• previously treated recurrent locally advanced or metastatic esophageal cancer [see Clinical Studies (14.10)].
• recurrent or metastatic cervical cancer with disease progression on or after chemotherapy [see Clinical Studies (14.11)].
For the MSI-H/dMMR indications, select patients for treatment with KEYTRUDA as a single agent based on MSI-H/dMMR status in tumor specimens [see Clinical Studies (14.7, 14.8)].
For the TMB-H indication, select patients for treatment with KEYTRUDA as a single agent based on TMB-H status in tumor specimens [see Clinical Studies (14.16)].
Because the effect of prior chemotherapy on test results for tumor mutation burden (TMB-H), MSI-H, or dMMR in patients with high-grade gliomas is unclear, it is recommended to test for these markers in the primary tumor specimens obtained prior to initiation of temozolomide chemotherapy in patients with high- grade gliomas.

Patient Selection for Combination Therapy
For use of KEYTRUDA in combination with chemotherapy and trastuzumab, select patients based on the presence of positive PD-L1 expression (CPS ≥1) in locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma [see Clinical Studies (14.9)].
For use of KEYTRUDA in combination with chemotherapy, with or without bevacizumab, select patients based on the presence of positive PD-L1 expression in persistent, recurrent, or metastatic cervical cancer [see Clinical Studies (14.11)].

For use of KEYTRUDA in combination with chemotherapy, select patients based on the presence of positive PD-L1 expression in locally recurrent unresectable or metastatic TNBC [see Clinical Studies (14.18)].

2.2 Recommended Dosage for Melanoma
The recommended dose of KEYTRUDA in patients with unresectable or metastatic melanoma is 200 mg or 2 mg/kg, according to treating physician's discretion, administered as an intravenous infusion over
30 minutes every 3 weeks until disease progression or unacceptable toxicity.

The recommended dose of KEYTRUDA for the treatment of pediatric patients (12 years and older) with unresectable or metastatic melanoma is 2 mg/kg (up to a maximum of 200 mg) administered as an intravenous infusion over 30 minutes every 3 weeks until disease recurrence or unacceptable toxicity.

The recommended dose of KEYTRUDA for the adjuvant treatment of adult patients with melanoma is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease recurrence,
unacceptable toxicity, or for up to 12 months.

The recommended dose of KEYTRUDA for the adjuvant treatment of pediatric patients (12 years and older) with melanoma is 2 mg/kg (up to a maximum of 200 mg) administered as an intravenous infusion over 30 minutes every 3 weeks until disease recurrence, unacceptable toxicity, or up to 12 months.

2.3 Recommended Dosage for NSCLC
For first-line treatment:
The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months.
When administering KEYTRUDA in combination with chemotherapy, administer KEYTRUDA 
prior to chemotherapy when given on the same day. Refer to the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA, for recommended dosing information, as appropriate.

For second-line or greater treatment:
The recommended dose of KEYTRUDA is 200 mg or 2 mg/kg, according to treating physician's discretion, administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months.

For adjuvant treatment:
The recommended dose of KEYTRUDA for the adjuvant treatment of adult patients with NSCLC is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease recurrence, unacceptable toxicity, or for up to 12 months.

For neoadjuvant/adjuvant treatment:
The recommended dose of KEYTRUDA for the neoadjuvant treatment of adult patients with resectable NSCLC is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks in combination with chemotherapy for 12 weeks (4 doses of 200 mg every 3 weeks) or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as a single agent after surgery for 39 weeks (13 doses of 200 mg every 3 weeks) or until disease recurrence or unacceptable toxicity.

2.4 Recommended Dosage for HNSCC
The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months.
When administering KEYTRUDA in combination with chemotherapy, administer KEYTRUDA prior to chemotherapy when given on the same day. Refer to the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate.

2.5 Recommended Dosage for cHL
The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months.

The recommended dose of KEYTRUDA in pediatric patients is 2 mg/kg (up to a maximum of 200 mg), administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months.

2.6 Recommended Dosage for PMBCL
The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months.

The recommended dose of KEYTRUDA in pediatric patients is 2 mg/kg (up to a maximum of 200 mg), administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months.

2.7 Recommended Dosage for Urothelial Cancer
The recommended dose of KEYTRUDA in patients with locally advanced or metastatic urothelial carcinoma is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months.

The recommended dose of KEYTRUDA in patients with high-risk BCG-unresponsive non-muscle invasive bladder cancer is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until persistent or recurrent high-risk NMIBC, disease progression or unacceptable toxicity, or up to 24 months.

2.8 Recommended Dosage for MSI-H or dMMR Cancer
The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months.

The recommended dose of KEYTRUDA in children is 2 mg/kg (up to a maximum of 200 mg), administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months.

2.9 Recommended Dosage for MSI-H or dMMR colorectal cancer (CRC)
The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months.

2.10 Recommended Dosage for Gastric Cancer
The recommended dose of KEYTRUDA in adult is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months.

When administering KEYTRUDA in combination with trastuzumab and chemotherapy, administer KEYTRUDA prior to trastuzumab and chemotherapy when given on the same day. Refer to the prescribing information for the agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate.

When administering KEYTRUDA in combination with chemotherapy, administer KEYTRUDA prior to chemotherapy when given on the same day. Refer to the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate.

2.11     Recommended Dosage for Esophageal Cancer
The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months.
When administering KEYTRUDA in combination with chemotherapy, administer KEYTRUDA prior to chemotherapy when given on the same day. Refer to the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA, for recommended dosing information, as appropriate.

2.12 Recommended Dosage for Cervical Cancer
The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or for KEYTRUDA up to 24 months.

For combination therapy, administer KEYTRUDA prior to chemotherapy with or without bevacizumab when given on the same day. Refer to the Prescribing Information for the agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate.

2.13 Recommended Dosage for Biliary Tract Cancer
The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months.

When administering KEYTRUDA in combination with chemotherapy, administer KEYTRUDA prior to chemotherapy when given on the same day. Refer to the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate.

2.14 Recommended Dosage for MCC
The recommended dose of KEYTRUDA in adults is 200 mg or 2 mg/kg, according to treating physician's discretion, administered as an intravenous infusion over
30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months.

The recommended dose of KEYTRUDA in pediatric patients is 2 mg/kg (up to a maximum of 200 mg), administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months.

2.15 Recommended Dosage for RCC
The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 
30 minutes every 3 weeks in combination with 5 mg axitinib orally twice daily or in combination with lenvatinib 20 mg orally once daily until disease progression, unacceptable toxicity, or for KEYTRUDA, up to 24 months. When axitinib is used in combination with KEYTRUDA, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer. Refer to the Prescribing Information for the agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate.


The recommended dose of KEYTRUDA for the adjuvant treatment of adult patients with RCC is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease recurrence,
unacceptable toxicity, or for up to 12 months.

2.16 Recommended Dosage for Endometrial Carcinoma
The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks in combination with lenvatinib 20 mg orally once daily until disease progression, unacceptable toxicity, or for KEYTRUDA, up to 24 months. Refer to the Prescribing Information for the agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate.


2.17 Recommended Dosage for TMB-H Cancer
The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months.

The recommended dose of KEYTRUDA in pediatric is 2 mg/kg (up to a maximum of 200 mg), administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months.

2.18 Recommended Dosage for cSCC
The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months.

2.19 Recommended Dosage for TNBC
The recommended dose of KEYTRUDA in adult patients with high-risk early-stage TNBC for neoadjuvant treatment is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks in combination with chemotherapy for 24 weeks (8 doses of 200mg every 3 weeks) or until disease progression or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as a single agent for up to 27 weeks (9 doses of 200 mg every 3 weeks) or until disease recurrence or unacceptable toxicity.

Administer KEYTRUDA prior to chemotherapy when given on the same day. Refer to the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA, for recommended dosing information, as appropriate. Patients who experience disease progression or unacceptable toxicity related to KEYTRUDA with neoadjuvant treatment in combination with chemotherapy should not receive adjuvant single agent KEYTRUDA.

The recommended dose of KEYTRUDA in patients with locally recurrent unresectable or metastatic TNBC is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks in combination to chemotherapy until disease progression, unacceptable toxicity, or up to 24 months.

Administer KEYTRUDA prior to chemotherapy when given on the same day. Refer to the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA, for recommended dosing information, as appropriate.

2.20 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 1
Table 1 : Recommended Dosage Modifications for Adverse Reactions

Adverse Reaction                               Severity*                                Dosage Modification Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] Grade 2                                      Withhold†
Pneumonitis
Grade 3 or 4                                 Permanently discontinue
Grade 2 or 3                                 Withhold†
Colitis
Grade 4                                      Permanently discontinue
AST or ALT increases to more than 3 and up to 8 times ULN or                                           Withhold†
Hepatitis with no tumor involvement of the liver                             Total bilirubin increases to more than 1.5 and up to 3 times ULN
For liver enzyme elevations in           AST or ALT increases to more than patients treated with combination        8 times ULN therapy with axitinib, see Table 2.      or                                           Permanently discontinue Total bilirubin increases to more than
3 times ULN

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                                           Withhold†
Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to
Hepatitis with tumor involvement of      more than 8 and up to 10 times ULN the liver‡
ALT or AST increases to more than
10 times ULN or                                           Permanently discontinue
Total bilirubin increases to more than
3 times ULN

Withhold until clinically stable or permanently
Endocrinopathies                         Grade 3 or 4 discontinue depending on severity

Grade 2 or 3 increased blood creatinine      Withhold†
Nephritis with Renal Dysfunction
Grade 4 increased blood creatinine           Permanently discontinue
Suspected SJS, TEN, or DRESS                 Withhold†
Exfoliative Dermatologic Conditions
Confirmed SJS, TEN, or DRESS                 Permanently discontinue
Myocarditis                              Grade 2, 3, or 4                             Permanently discontinue Grade 2                                      Withhold†
Neurological Toxicities                  Grade 3 or 4                                 Permanently discontinue 
Hematologic toxicity in patients with
Grade 4                                        Withhold until resolution to Grades 0 or 1 cHL or PMBCL
Other Adverse Reactions
Infusion-related reactions                Grade 1 or 2                                   Interrupt or slow the rate of infusion [see Warnings and Precautions
Grade 3 or 4                                   Permanently discontinue (5.2)]
* 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.
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 
Table 2 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 2: Recommended Specific Dosage Modifications for Adverse Reactions for KEYTRUDA in Combination with Axitinib

Treatment              Adverse Reaction                          Severity                        Dosage Modification ALT or AST increases to at least
Withhold both KEYTRUDA
3 times but less than 10 times ULN and axitinib until resolution to without concurrent total bilirubin at
Grades 0 or 1†
KEYTRUDA in                                           least 2 times ULN combination with       Liver enzyme elevations*       ALT or AST increases to more than axitinib                                              3 times ULN with concurrent total Permanently discontinue both bilirubin at least 2 times ULN
KEYTRUDA and axitinib or
ALT or AST ≥10 times ULN
*  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.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal 

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 1. Refer to lenvatinib prescribing information for additional dose modification information.

2.21 Preparation and Administration

Preparation for Intravenous Infusion
•       Visually inspect the solution for particulate matter and discoloration prior to administration. The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible particles are observed.
•       Dilute KEYTRUDA 100 mg/4 mL (concentrated solution) prior to intravenous administration.
•       Withdraw the required volume from the vial(s) of KEYTRUDA and transfer into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake. The final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL.
•       Discard any unused portion left in the vial.

Storage of Diluted Solution
The product does not contain a preservative.
From a microbiological point of view, the product, once diluted, should be used immediately. If not used immediately, store the diluted solution from the KEYTRUDA 100 mg/4 mL vial either: • At room temperature for no more than 6 hours from the time of dilution. This includes room temperature storage of the diluted solution, and the duration of infusion.
• Under refrigeration at 2°C to 8°C for no more than 96 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration. Do not shake.
Discard after 6 hours at room temperature or after 96 hours under refrigeration.

Do not freeze.

Administration
• Administer diluted solution intravenously over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter.
• Do not co-administer other drugs through the same infusion line.