Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

KEYTRUDA (BLA-125514)

(PEMBROLIZUMAB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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03/11/2024 (SUPPL-160)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

…

Of the 121 patients treated with KEYTRUDA in combination with enfortumab vedotin, 43% (n=52) were 65-74 years and 33% (n=40) were 75 years or older. No overall differences in effectiveness were observed between patients 65 years of age or older and younger patients. There were an insufficient number of patients treated with KEYTRUDA in combination with enfortumab vedotin in clinical trials to accurately characterize safety by age.

Of the 432 patients randomized to KEYTRUDA in combination with axitinib in the KEYNOTE-426 trial, 40% were 65 years or older. No overall difference in safety or efficacy was reported between patients who were ?65 years of age and younger.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Rejection of a transplanted organ or tissue. Your healthcare provider should tell you what signs and symptoms you should report and monitor you depending on the type of organ or tissue transplant that you have had.

…

Before receiving KEYTRUDA, tell your healthcare provider about all of your medical conditions, including if you:

• have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus

• have received an organ or tissue transplant, including corneal transplant

• have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)

• have received radiation treatment to your chest area

• have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome

• are pregnant or plan to become pregnant. KEYTRUDA can harm your unborn baby.

Females who are able to become pregnant:

o Your healthcare provider will give you a pregnancy test before you start treatment with KEYTRUDA.

o You should use an effective method of birth control during treatment with KEYTRUDA and for 4 months after the last dose of KEYTRUDA.

???Talk to your healthcare provider about birth control methods that you can use during this time.

…

01/25/2024 (SUPPL-124)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Previously Treated HCC

The safety of KEYTRUDA was investigated in KEYNOTE-394, a multicenter, double-blind, randomized, placebo-controlled trial that enrolled patients with previously treated HCC. Patients were randomized (2:1) and received KEYTRUDA 200 mg (n=299) or placebo (n=153) intravenously every 3 weeks for up to 35 cycles [see Clinical Studies (14.12)].

The median duration of exposure was 3.3 months (range: 1 day to 27.3 months) in the KEYTRUDA arm and 2.2 months (range: 1 day to 15.5 months) in the placebo arm. KEYTRUDA was discontinued due to adverse reactions in 13% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was ascites (2.3%). Adverse reactions leading to interruption of KEYTRUDA occurred in 26% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (greater than or equal to 2%) were increased blood bilirubin (9%), increased AST (5%), and increased ALT (2%).

Tables 43 and 44 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-394.

Please refer to label to view Tables 43 and 44

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Addition and/or revisions underlined:

…

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

…

a kind of liver cancer called hepatocellular carcinoma (HCC). KEYTRUDA may be used when:

you have HCC after having hepatitis B, and
you have received anti-cancer treatment that did not contain a “PD-1” or “PD-L1” blocking medicine.

…

01/12/2024 (SUPPL-147)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined

Of the 564 patients with locally advanced or metastatic urothelial cancer treated with KEYTRUDA in combination with enfortumab vedotin, 44% (n=247) were 65-74 years and 26% (n=144) were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 7% in patients 75 years or older.

…

Of 292 adult patients with FIGO 2014 Stage III-IVA cervical cancer who were treated with KEYTRUDA in combination with CRT in KEYNOTE-A18, 42 (14%) were 65 years and over. No overall differences in safety or efficacy were observed between elderly and younger patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

KEYTRUDA is a prescription medicine used to treat:

…

a kind of cancer called cervical cancer.

KEYTRUDA may be used with chemotherapy and radiation therapy when your cervical cancer has spread to nearby tissue or organs or has affected your kidneys (Stage III to IVA cervical cancer based on FIGO 2014 classification).

KEYTRUDA may be used with chemotherapy medicines, with or without the medicine bevacizumab, when:

your cervical cancer does not go away (persistent), has returned, or has spread (advanced cervical cancer), and
your tumor tests positive for “PD-L1”.

KEYTRUDA may be used alone when your cervical cancer:

has returned, or has spread (advanced cervical cancer), and
you have received chemotherapy, and it did not work or is no longer working, and
your tumor tests positive for “PD-L1”.

a kind of liver cancer called hepatocellular carcinoma, after you have received the medicine sorafenib.

…

Common side effects of KEYTRUDA when given with certain chemotherapy or chemotherapy with radiation therapy medicines include: feeling tired or weak, …

12/15/2023 (SUPPL-151)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined; refer to label for numerous table(s) numbering updates)

…

Urothelial Cancer

Patients with urothelial cancer in combination with enfortumab vedotin

The safety of KEYTRUDA in combination with enfortumab vedotin was investigated in KEYNOTE-A39 in patients with locally advanced or metastatic urothelial cancer [see Clinical Studies (14.6)]. A total of 440 patients received KEYTRUDA 200 mg on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle compared to 433 patients who received gemcitabine on Days 1 and 8 and investigator’s choice of cisplatin or carboplatin on Day 1 of each 21-day cycle. Among patients who received KEYTRUDA and enfortumab vedotin, the median duration of exposure to KEYTRUDA was 8.5 months (range: 9 days to 28.5 months).

Fatal adverse reactions occurred in 3.9% of patients treated with KEYTRUDA in combination with enfortumab vedotin including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%).

Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin. Serious adverse reactions in ?2% of patients receiving KEYTRUDA in combination with enfortumab vedotin were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%).

Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (greater than or equal to 2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%).

Dose interruptions of KEYTRUDA occurred in 61% of patients. The most common adverse reactions (greater than or equal to 2%) resulting in interruption of KEYTRUDA were rash (17%), peripheral neuropathy (7%), COVID-19 (5%), diarrhea (4.3%), pneumonitis/ILD (3.6%), neutropenia (3.4%), fatigue (3%), alanine aminotransferase increased (2.7%), hyperglycemia (2.5%), pneumonia (2%), and pruritis (2%).

Tables 24 and 25 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with enfortumab vedotin in KEYNOTE-A39.

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of 3781 patients with melanoma, NSCLC, HNSCC, or urothelial carcinoma who were treated with KEYTRUDA in clinical studies, 48% were 65 years and over and 17% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.

Of 389 adult patients with cHL who were treated with KEYTRUDA in clinical studies, 46 (12%) were 65 years and over. Patients aged 65 years and over had a higher incidence of serious adverse reactions (50%) than patients aged younger than 65 years (24%). Clinical studies of KEYTRUDA in cHL did not include sufficient numbers of patients aged 65 years and over to determine whether effectiveness differs from that in younger patients.

Of 506 adult patients with Stage IB (T2a ?4 cm), II, or IIIA NSCLC following complete resection and platinum-based chemotherapy who were treated with KEYTRUDA in KEYNOTE-091, 242 (48%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.

Of 596 adult patients with TNBC who were treated with KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin in KEYNOTE-355, 137 (23%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.

Of 406 adult patients with endometrial carcinoma who were treated with KEYTRUDA in combination with lenvatinib in KEYNOTE-775, 201 (50%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Extensive changes; please refer to label for complete information)

12/15/2023 (SUPPL-152)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined; refer to label for numerous table(s) numbering updates)

…

Urothelial Cancer

Patients with urothelial cancer in combination with enfortumab vedotin

Tables 24 and 25 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with enfortumab vedotin in KEYNOTE-A39.

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of 506 adult patients with Stage IB (T2a greater than or equal to 4 cm), II, or IIIA NSCLC following complete resection and platinum-based chemotherapy who were treated with KEYTRUDA in KEYNOTE-091, 242 (48%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Extensive changes; please refer to label for complete information)

11/16/2023 (SUPPL-143)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Gastric Cancer

First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma

The safety of KEYTRUDA was evaluated in 433 patients with HER2-positive gastric or GEJ cancer enrolled in KEYNOTE-811, which included 217 patients treated with KEYTRUDA 200 mg, trastuzumab, and CAPOX (n=189) or FP (n=28) every 3 weeks, compared to 216 patients treated with placebo, trastuzumab, and CAPOX (n=187) or FP (n=29) every 3 weeks [see Clinical Studies (14.9)].

…

First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Negative Gastric or Gastroesophageal Junction Adenocarcinoma

The safety of KEYTRUDA was evaluated in 1572 patients with HER2-negative gastric or GEJ cancer enrolled in KEYNOTE-859, which included, 785 patients treated with KEYTRUDA 200 mg and FP (n=106) or CAPOX (n=674) every 3 weeks, compared to 787 patients who received placebo and FP (n=107) or CAPOX (n=679) every 3 weeks [see Clinical Studies (14.9)].

The median duration of exposure to KEYTRUDA was 6.2 months (range: 1 day to 33.7 months).

Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received KEYTRUDA including infection (2.3%) and thromboembolism (1.3%).

Permanent discontinuation of KEYTRUDA due to adverse reactions occurred in 15% of patients. Adverse reaction resulting in permanent discontinuation of KEYTRUDA in greater than or equal to 1% were infections (1.8%) and diarrhea (1.0%).

Dosage interruptions of KEYTRUDA due to an adverse reaction occurred in 65% of patients. Adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (greater than or equal to 2%) were neutropenia (21%), thrombocytopenia (13%), diarrhea (5.5%), fatigue (4.8%), infection (4.8%), anemia (4.5%), increased AST (4.3%), increased ALT (3.8%), increased blood bilirubin (3.3%), white blood cell count decreased (2.2%), nausea (2%), palmer-plantar erythrodysesthesia syndrome (2%), and vomiting (2%).

Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-859.

Please refer to label to view Table 31 and 32.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions, please refer to label for complete information.

11/07/2023 (SUPPL-148)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

BTC

The safety of KEYTRUDA in combination with gemcitabine and cisplatin, was investigated in KEYNOTE-966, a multicenter, double-blind, randomized, placebo-controlled trial in patients with locally advanced unresectable or metastatic BTC who had not received prior systemic therapy in the advanced disease setting [see Clinical Studies (14.13)]. A total of 1063 patients received either KEYTRUDA 200 mg plus gemcitabine and cisplatin chemotherapy (n=529) or placebo plus gemcitabine and cisplatin chemotherapy (n=534) every 3 weeks.

The median duration of exposure to KEYTRUDA was 6 months (range: 1 day to 28 months).

KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (greater than or equal to 1%) was pneumonitis (1.3%).

Adverse reactions leading to the interruption of KEYTRUDA occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (greater than or equal to 2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%).

In the KEYTRUDA plus chemotherapy versus placebo plus chemotherapy arms, there was a difference of greater than or equal to 5% incidence in adverse reactions between patients treated with KEYTRUDA versus placebo for pyrexia (26% vs 20%), rash (21% vs 13%), pruritus (15% vs 10%), and hypothyroidism (9% vs. 2.6%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

There was a difference of ?5% incidence in laboratory abnormalities between patients treated with KEYTRUDA plus chemotherapy versus placebo plus chemotherapy for decreased lymphocytes (69% vs 61%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

Among the 105 patients with MCC enrolled in KEYNOTE-017 and KEYNOTE-913 [see Clinical Studies (14.14)], the median duration of exposure to KEYTRUDA was 6.3 months (range 1 day to 28 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included increased lipase (17%).

RCC

In combination with axitinib in the first-line treatment of advanced RCC (KEYNOTE-426)

The safety of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 [see Clinical Studies (14.15)].

…

Adjuvant treatment of RCC

The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-564, a randomized (1:1) double-blind placebo-controlled trial in which 984 patients who had undergone nephrectomy for RCC received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=488) or placebo (n=496) for up to one year [see Clinical Studies (14.15)]. The median duration of exposure to KEYTRUDA was 11.1 months (range: 1 day to 14.3 months). Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.

…

Endometrial Carcinoma

In Combination with Lenvatinib for the Treatment of Advanced Endometrial Carcinoma That Is pMMR or Not MSI-H.

The safety of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-775, a multicenter, open-label, randomized (1:1), active-controlled trial in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings [see Clinical Studies (14.16)]. Patients with endometrial carcinoma that is pMMR or not MSI-H received KEYTRUDA 200 mg every 3 weeks in combination with lenvatinib 20mg orally once daily (n=342) or received doxorubicin or paclitaxel (n=325).

…

As a Single Agent for the Treatment of Advanced MSI-H or dMMR Endometrial Carcinoma

Among the 90 patients with MSI-H or dMMR endometrial carcinoma enrolled in KEYNOTE-158 [see Clinical Studies (14.16)] treated with KEYTRUDA as a single agent, the median duration of exposure to KEYTRUDA was 8.3 months (range: 1 day to 26.9 months). Adverse reactions occurring in patients with endometrial carcinoma were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

…

TMB-H Cancer

The safety of KEYTRUDA was investigated in 105 patients with TMB-H cancer enrolled in KEYNOTE-158 [see Clinical Studies (14.17)]. The median duration of exposure to KEYTRUDA was 4.9 months (range: 0.03 to 35.2 months). Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

…

cSCC

Among the 159 patients with advanced cSCC (recurrent or metastatic or locally advanced disease) enrolled in KEYNOTE-629 [see Clinical Studies (14.18)], the median duration of exposure to KEYTRUDA was 6.9 months (range 1 day to 28.9 months). Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (10%) and decreased sodium (10%).

TNBC

Neoadjuvant and Adjuvant Treatment of High-Risk Early-Stage TNBC

The safety of KEYTRUDA in combination with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent was investigated in KEYNOTE-522, a randomized (2:1), multicenter, double-blind, placebo-controlled trial in patients with newly diagnosed, previously untreated, high-risk early-stage TNBC.

A total of 778 patients on the KEYTRUDA arm received at least 1 dose of KEYTRUDA in combination with neoadjuvant chemotherapy followed by KEYTRUDA as adjuvant treatment after surgery, compared to 389 patients who received at least 1 dose of placebo in combination with neoadjuvant chemotherapy followed by placebo as adjuvant treatment after surgery [see Clinical Studies (14.19)].

…

Locally Recurrent Unresectable or Metastatic TNBC

The safety of KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin was investigated in KEYNOTE-355, a multicenter, double-blind, randomized (2:1), placebo-controlled trial in patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting [see Clinical Studies (14.19)]. A total of 596 patients (including 34 patients from a safety run-in) received KEYTRUDA 200 mg every 3 weeks in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin.

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of KEYTRUDA as a single agent have been established in pediatric patients with melanoma, cHL, PMBCL, MCC, MSI-H or dMMR cancer, and TMB-H cancer. Use of KEYTRUDA in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1, 14.4, 14.5, 14.7, 14.14, 14.17)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE KEYTRUDA (key-true-duh) (pembrolizumab) injection

(Extensive changes; please refer to label for complete information)

10/31/2023 (SUPPL-144)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Newly added subsection:

BTC

disease setting [see Clinical Studies (14.13)]. A total of 1063 patients received either KEYTRUDA 200 mg plus gemcitabine and cisplatin chemotherapy (n=529) or placebo plus gemcitabine and cisplatin chemotherapy (n=534) every 3 weeks.

The median duration of exposure to KEYTRUDA was 6 months (range: 1 day to 28 months). KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse

reaction resulting in permanent discontinuation of KEYTRUDA (greater than or equal to 1%) was pneumonitis (1.3%).

There was a difference of greater than or equal to 5% incidence in laboratory abnormalities between patients treated with KEYTRUDA plus chemotherapy versus placebo plus chemotherapy for decreased lymphocytes (69% vs 61%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

…

a kind of bile duct or gallbladder cancer called biliary tract cancer (BTC). KEYTRUDA may be used with chemotherapy medicines gemcitabine and cisplatin when your biliary tract cancer has spread or cannot be removed by surgery.

10/23/2023 (SUPPL-142)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

MCC

Among the 105 patients with MCC enrolled in KEYNOTE-017 and KEYNOTE-913 [see Clinical Studies (14.13)], the median duration of exposure to KEYTRUDA was 6.3 months (range 1 day to 28 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MCC were similar to those occurring in

2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included increased lipase (17%).

…

10/16/2023 (SUPPL-139)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Newly added information:

Neoadjuvant and Adjuvant Treatment of Resectable NSCLC

The safety of KEYTRUDA in combination with neoadjuvant platinum-containing chemotherapy followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent after surgery was investigated in KEYNOTE-671, a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition [see Clinical Studies (14.2)]. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible.

The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 10.9 months (range: 1 day to 18.6 months). The study population characteristics were: median age of 64 years (range: 26 to 83), 45% age 65 or older, 7% age 75 or older; 71% male; 61% White, 31% Asian, 2% Black, 4% race not reported; 9% Hispanic or Latino.

Adverse reactions occurring in patients with resectable NSCLC receiving KEYTRUDA in combination with platinum containing chemotherapy, given as neoadjuvant treatment and continued as single agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving KEYTRUDA in combination with chemotherapy.

Neoadjuvant Phase of KEYNOTE-671

A total of 396 patients received at least 1 dose of KEYTRUDA in combination with platinum-containing chemotherapy as neoadjuvant treatment and 399 patients received at least 1 dose of placebo in combination with platinum-containing chemotherapy as neoadjuvant treatment.

Serious adverse reactions occurred in 34% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (> or = to 2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%) and immune-mediated lung disease (0.3%).

Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (?1%) adverse reactions that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%%), neutropenia (1.5%), and pneumonia (1.3%).

Of the 396 KEYTRUDA-treated patients and 399 placebo-treated patients who received neoadjuvant treatment, 6% (n=25) and 4.3% (n=17), respectively, did not receive surgery due to adverse reactions. The most frequent (> or = to 1%) adverse reactions that led to cancellation of surgery in the KEYTRUDA arm was interstitial lung disease (1%).

Of the 325 KEYTRUDA-treated patients who received surgery, 3.1%; n=10) experienced delay of surgery (surgery more than 8 weeks from last neoadjuvant treatment if patient received less than 4 cycles of neoadjuvant therapy or more than 20 weeks after first dose of neoadjuvant treatment if patient received

4 cycles of neoadjuvant therapy) due to adverse reactions. Of the 317 placebo-treated patients who received surgery, 2.5% (n=8) experienced delay of surgery due to adverse reactions.

Of the 325 KEYTRUDA-treated patients who received surgery, 7% (n=22) did not receive adjuvant treatment due to adverse reactions. Of the 317 placebo-treated patients who received surgery, 3.2% (n=10) did not receive adjuvant treatment due to adverse reactions.

Adjuvant Phase of KEYNOTE-671

A total of 290 patients in the KEYTRUDA arm and 267 patients in the placebo arm received at least 1 dose of adjuvant treatment.

Of the patients who received single agent KEYTRUDA as adjuvant treatment, 14% experienced serious adverse reactions; the most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of adjuvant KEYTRUDA due to an adverse reaction occurred in 12% of patients; the most frequent (> or = to 1%) adverse reactions that led to permanent discontinuation of adjuvant KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), AST increased (1%), and musculoskeletal pain (1%).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Newly added information:

KEYTRUDA may be used in combination with chemotherapy that contains platinum and another chemotherapy medicine:

before surgery when you have early-stage NSCLC which can be removed by surgery, and then continued alone after surgery to help prevent your lung cancer from coming back.

10/12/2023 (SUPPL-138)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

MCC

2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included increased lipase (17%).

…

03/28/2023 (SUPPL-132)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Urothelial Carcinoma

(Additions and/or revisions underlined)

BCG-unresponsive High-risk NMIBC…

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

The safety of KEYTRUDA was investigated in 504 patients with MSI-H or dMMR cancer enrolled in KEYNOTE-158, KEYNOTE-164, and KEYNOTE-051 [see Clinical Studies (14.7)]. The median duration of exposure to KEYTRUDA was 6.2 months (range: 1 day to 53.5 months). Adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

In KEYNOTE-051, 173 pediatric patients (65 pediatric patients aged 6 months to younger than 12 years and 108 pediatric patients aged 12 to 17 years) with advanced melanoma, lymphoma, or PD-L1 positive solid tumors received KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 25 months). Adverse reactions that occurred at a greater than or equal to 10% higher rate in pediatric patients when compared to adults included pyrexia (33%), vomiting (29%), headache (25%), abdominal pain (23%), decreased lymphocyte count (13%), and decreased white blood cell count (11%). Laboratory abnormalities that occurred at a greater than or equal to 10% higher rate in pediatric patients when compared to adults were leukopenia (31%), neutropenia (28%), thrombocytopenia (22%), and anemia (17%).

The safety and effectiveness of KEYTRUDA in pediatric patients have not been established in the other approved indications [see Indications and Usage (1)].

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(Extensive changes; please refer to label for complete information)

01/26/2023 (SUPPL-128)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

Newly added information:

In a clinical study enrolling 580 adult patients with resected NSCLC (KEYNOTE-091) who received KEYTRUDA as a single agent for adjuvant treatment, pneumonitis occurred in 41 (7%) patients, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.

…

The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE- 091), including Grade 3 (0.2%) hyperthyroidism.

…

The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE- 091), including Grade 3 (0.3%) hypothyroidism.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

The data described in the WARNINGS AND PRECAUTIONS reflect exposure to KEYTRUDA as a single agent in 2799 patients in three randomized, open-label, active-controlled trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial (KEYNOTE-001), which enrolled 655 patients with melanoma and 550 patients with NSCLC. In addition to the 2799 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to KEYTRUDA as a single agent in a randomized, placebo-controlled trial (KEYNOTE-091), which enrolled 580 patients with resected NSCLC, a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and two randomized, open-label, active-controlled trials (KEYNOTE- 040 and KEYNOTE-048 single agent arms), which enrolled 909 patients with HNSCC; in two non- randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087) and one randomized, open-label, active-controlled trial (KEYNOTE-204), which enrolled 389 patients with cHL; in a randomized, open- label, active-controlled trial (KEYNOTE-048 combination arm), which enrolled 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE 426), which enrolled 429 patients with RCC; and in post-marketing use.

…

Adjuvant Treatment of Resected NSCLC

The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-091, a multicenter, randomized (1:1), triple-blind, placebo-controlled trial in patients with completely resected stage IB

(T2a greater than or equal to 4 cm), II, or IIIA NSCLC; adjuvant chemotherapy up to 4 cycles was optional [see Clinical Studies (14.2)]. A total of 1161 patients received KEYTRUDA 200 mg (n=580) or placebo (n=581) every 3 weeks. Patients were ineligible if they had active autoimmune disease, were on chronic immunosuppressive agents or had a history of interstitial lung disease or pneumonitis.

The median duration of exposure to KEYTRUDA was 11.7 months (range: 1 day to 18.9 months). Sixty- eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ?6 months.

The adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred.

…

8 Use in Specific Populations

8.2 Lactation

Newly added information:

Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to KEYTRUDA are unknown.

8.5 Geriatric Use

Newly added information:

Of 506 adult patients with stage IB (T2a greater than or equal to 4 cm), II, or IIIA NSCLC following complete resection and platinum-based chemotherapy who were treated with KEYTRUDA in KEYNOTE-091, 242 (48%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.

08/05/2022 (SUPPL-133)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Changes to tables 41 and 42; please refer to label

…

Endometrial Carcinoma
In Combination with Lenvatinib for the Treatment of Advanced Endometrial Carcinoma That Is pMMR or Not MSI-H.

The safety of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-775, a multicenter, open-label, randomized (1:1), active-controlled trial in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings [see Clinical Studies (14.15)]. Patients with endometrial carcinoma that is pMMR or not MSI-H received KEYTRUDA 200 mg every 3 weeks in combination with lenvatinib 20mg orally once daily (n=342) or received doxorubicin or paclitaxel (n=325).

For patients with pMMR or not MSI-H tumor status, the median duration of study treatment was 7.2 months (range 1 day to 26.8 months) and the median duration of exposure to KEYTRUDA was 6.8 months (range: 1 day to 25.8 months).

…

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Additions and/or revisions underlined:

…

• a kind of uterine cancer called advanced endometrial carcinoma.

KEYTRUDA may be used with the medicine lenvatinib:

when a laboratory test shows that your tumor is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H), and
you have received anti-cancer treatment, and it is no longer working, and
your cancer cannot be cured by surgery or radiation.

…

03/21/2022 (SUPPL-110)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Following Table 40: Selected* Laboratory Abnormalities Worsened From Baseline Occurring in greater than or equal to 20% of Patients Receiving KEYTRUDA in KEYNOTE-564; additions and/or revisions underlined:

Endometrial Carcinoma

In Combination with Lenatinib for the Treatment of Advanced Endometrial Carcinoma That is Not MSI-H or dMMR

The safety of KEYTRUDA in combination with lenvatinib was investigated …

Following Table 42: Laboratory Abnormalities Worsened from Baseline* Occurring in greater than or equal to 20% (All Grades) or greater than or equal to 3% (Grades 3-4) of Patients with Endometrial Carcinoma in KEYNOTE-775; newly added information prior to TMB-H Cancer section:

As a Single Agent for the Treatment of Advanced MSI-H or dMMR Endometrial Carcinoma

Among the 90 patients with MSI-H or dMMR endometrial carcinoma enrolled in KEYNOTE-158 [see Clinical Studies (14.150] treated with KEYTRUDA as a single agent, the median duration of exposure to KEYTRUDA was 8.3 months (range 1 day to 26.9 months). Adverse reactions occurring in patients with endometrial carcinoma were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

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Additions and/or revisions underlined:

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

a kind of uterine cancer called endometrial carcinoma

o KEYTRUDA may be used alone:

If your cancer is shown by a laboratory test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and
you have received anti-cancer treatment, and it is no longer working, and
your cancer cannot be cured by surgery or radiation (advanced endometrial carcinoma).

02/04/2022 (SUPPL-125)

Approved Drug Label (PDF)

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MEDICATION GUIDE

Additions and/or revisions underlined:

What is KEYTRUDA?

a kind of stomach cancer called gastric or gastroesophageal junction (GEJ) adenocarcinoma. KEYTRUDA may be used in combination with the medicine trastuzumab along with fluoropyrimidine and platinum chemotherapy as your first treatment when your stomach cancer: …

12/03/2021 (SUPPL-112)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Following Table 7: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in greater than or equal to 20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-002

Additions and/or revisions underlined:

Adjuvant Treatment of Resected Stage IIB or IIC Melanoma

Among the 969 patients with stage IIB or IIC melanoma enrolled in KEYNOTE-716 [see Clinical Studies (14.1)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 9.9 months (range: 0 to 15.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054 or the 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

Adjuvant Treatment of Stage III Resected Melanoma

The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-054, a randomized (1:1) double-blind trial …

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of KEYTRUDA as a single agent have been established in pediatric patients with melanoma, cHL, PMBCL, MCC, MSI-H cancer, and TMB-H cancer …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

a kind of skin cancer called melanoma. KEYTRUDA may be used:
- when your melanoma has spread or cannot be removed by surgery (advanced melanoma), or
- in adults and children 12 years of age and older with Stage IIB, Stage IIC, or Stage III melanoma, to help prevent melanoma from coming back after it and lymph nodes that contain cancer have been removed by surgery.

11/17/2021 (SUPPL-113)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Adjuvant treatment of RCC

The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-564, a randomized (1:1) double-blind placebo-controlled trial in which 984 patients who had undergone nephrectomy for RCC received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=488) or placebo (n=496) for up to one year [see Clinical Studies (14.1)]. The median duration of exposure to KEYTRUDA was 11.1 months (range: 1 day to 14.3 months). Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.

Serious adverse reactions occurred in 20% of these patients receiving KEYTRUDA. Serious adverse reactions (greater than or equal to 1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% of those treated with KEYTRUDA, including one case of pneumonia.

Discontinuation of KEYTRUDA due to an adverse reaction occurred in 21% of patients; the most common (greater than or equal to 1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%).

Dose interruptions of KEYTRUDA due to an adverse reaction occurred in 26% of patients; the most common (greater than or equal to 1%) were increased AST (2.3%), arthralgia (1.6%), hypothyroidism (1.6%), diarrhea (1.4%), increased ALT (1.4%), fatigue (1.4%), rash, decreased appetite, and vomiting (1% each). Tables 39 and 40 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-564.

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Additions and/or revisions underlined:

KEYTRUDA may be used alone if you are at intermediate-high or high risk of your kidney cancer (RCC) coming back after surgery to:
- remove all or part of your kidney, or
- remove all or part of your kidney and also surgery to remove cancer that has spread to other parts of the body (metastatic lesions).

What are the possible side effects of KEYTRUDA?

KEYTRUDA can cause serious side effects. See “What is the most important information I should know about KEYTRUDA?”

Common side effects of KEYTRUDA when used alone include: feeling tired, pain, including pain in muscles, rash, diarrhea, fever, cough, decreased appetite, itching, shortness of breath, constipation, bones or joints and stomach-area (abdominal) pain, nausea, and low levels of thyroid hormone.

10/13/2021 (SUPPL-121)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Cervical Cancer

Persistent, Recurrent, or Metastatic Cervical Cancer

The safety of KEYTRUDA in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was investigated in KEYNOTE-826, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent [see Clinical Studies (14.11)]. A total of 616 patients, regardless of tumor PD-L1 expression, received KEYTRUDA 200 mg and chemotherapy with or without bevacizumab (n=307) every 3 weeks or placebo and chemotherapy with or without bevacizumab (n=309) every 3 weeks.

The median duration of exposure to KEYTRUDA was 9.9 months (range: 1 day to 26 months).

Fatal adverse reactions occurred in 4.6% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab, including 3 cases of hemorrhage, 2 cases of sepsis, 2 cases due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection.

Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab. Serious adverse reactions in greater than or equal to 3% of patients included febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), acute kidney injury (3.3%), and sepsis (3.3%).

KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (greater than or equal to 1%) was colitis (1%).

Adverse reactions leading to interruption of KEYTRUDA occurred in 66% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (greater than or equal to 2%) were thrombocytopenia (15%), neutropenia (14%), anemia (11%), increased ALT (6%), leukopenia (5%), fatigue/asthenia (4.2%), urinary tract infection (3.6%), increased AST (3.3%), pyrexia (3.3%), diarrhea (2.6%), acute kidney injury (2.6%), increased blood creatinine (2.6%), colitis (2.3%), decreased appetite (2%), and cough (2%).

For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common (greater than or equal to 20%) adverse reactions were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea (41%), neutropenia (41%), diarrhea (39%), hypertension (35%), thrombocytopenia (35%), constipation (31%), arthralgia (31%), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%). Table 31 and Table 32 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-826.

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(Additions and/or revisions underlined)

What is KEYTRUDA?

a kind of cancer called cervical cancer that tests positive for “PD-L1.”
- KEYTRUDA may be used with chemotherapy medicines, with or without the medicine bevacizumab, when your cervical cancer does not go away (persistent), has returned, or has spread (advanced cervical cancer).
- KEYTRUDA may be used alone when your cervical cancer:
  - has returned, or has spread or cannot be removed by surgery (advanced cervical cancer), and
  - you have received chemotherapy, and it did not work or is no longer working.

10/13/2021 (SUPPL-122)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Cervical Cancer

Persistent, Recurrent, or Metastatic Cervical Cancer

The median duration of exposure to KEYTRUDA was 9.9 months (range: 1 day to 26 months).

KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (greater than or equal to 1%) was colitis (1%).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

What is KEYTRUDA?

a kind of cancer called cervical cancer that tests positive for “PD-L1.”
- KEYTRUDA may be used with chemotherapy medicines, with or without the medicine bevacizumab, when your cervical cancer does not go away (persistent), has returned, or has spread (advanced cervical cancer).
- KEYTRUDA may be used alone when your cervical cancer:
  - has returned, or has spread or cannot be removed by surgery (advanced cervical cancer), and
  - you have received chemotherapy, and it did not work or is no longer working.

08/31/2021 (SUPPL-117)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions underlined

…

Urothelial Carcinoma

Platinum Ineligible Patients with Urothelial Carcinoma

The safety of KEYTRUDA was investigated in KEYNOTE-052, a single-arm trial that enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who had one or more comorbidities. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible [see Clinical Studies (14.6)].

.…

08/31/2021 (SUPPL-118)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions underlined

…

Urothelial Carcinoma

Platinum Ineligible Patients with Urothelial Carcinoma

.…

08/10/2021 (SUPPL-102)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive additions/revisions; please refer to label)

08/03/2021 (SUPPL-104)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

(Additions and/or revisions underlined)

KEYTRUDA 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 adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur 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, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

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. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to labeling)

6.3 Postmarketing Experience

(Newly Added Subsection)

The following adverse reactions have been identified during postapproval use of KEYTRUDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepatobiliary: sclerosing cholangitis

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions underlined)

07/26/2021 (SUPPL-114)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

Additions underlined

… For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions underlined

…

TNBC

Neoadjuvant and Adjuvant Treatment of High-Risk Early-Stage TNBC

The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 13.3 months (range: 1 day to 21.9 months).

Fatal adverse reactions occurred in 0.9% of patients receiving KEYTRUDA, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction.

Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA. Serious adverse reactions in greater than or equal to 2% of patients who received KEYTRUDA included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%).

KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions (greater than or equal to 1%) resulting in permanent discontinuation of KEYTRUDA were increased ALT (2.7%), increased AST (1.5%), and rash (1%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 57% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (greater than or equal to 2%) were neutropenia (26%), thrombocytopenia (6%), increased ALT (6%), increased AST (3.7%), anemia (3.5%), rash (3.2%), febrile neutropenia (2.8%), leukopenia (2.8%), upper respiratory tract infection (2.6%), pyrexia (2.2%), and fatigue (2.1%).

Tables 37 and 38 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-522.

Please refer to label to view Tables 37and 38.

…

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Additions underlined

…

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

…

a kind of cancer called triple-negative breast cancer (TNBC).
- KEYTRUDA may be used with chemotherapy medicines as treatment before surgery and then continued alone after surgery when you:
  - have early-stage breast cancer, and
  - are at high risk of your breast cancer coming back.
    …
    What are the possible side effects of KEYTRUDA?
    KEYTRUDA can cause serious side effects. See “What is the most important information I should know about KEYTRUDA?”
    …
    Common side effects of KEYTRUDA when given with certain chemotherapy medicines include: feeling tired or weak, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, trouble breathing, fever, hair loss, inflammation of the nerves that may cause pain, weakness, and paralysis in the arms and legs, swelling of the lining of the mouth, nose, eyes, throat, intestines, or vagina, mouth sores, headache, weight loss, stomach-area (abdominal) pain, joint and muscle pain, and trouble sleeping.

…

07/26/2021 (SUPPL-89)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

Additions underlined

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions underlined

…

TNBC

Neoadjuvant and Adjuvant Treatment of High-Risk Early-Stage TNBC

The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 13.3 months (range: 1 day to 21.9 months).

Tables 37 and 38 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-522.

Please refer to label to view Tables 37and 38.

…

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Additions underlined

…

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

…

a kind of cancer called triple-negative breast cancer (TNBC).
- KEYTRUDA may be used with chemotherapy medicines as treatment before surgery and then continued alone after surgery when you:
  - have early-stage breast cancer, and
  - are at high risk of your breast cancer coming back.
    …
    What are the possible side effects of KEYTRUDA?
    KEYTRUDA can cause serious side effects. See “What is the most important information I should know about KEYTRUDA?”
    …
    Common side effects of KEYTRUDA when given with certain chemotherapy medicines include: feeling tired or weak, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, trouble breathing, fever, hair loss, inflammation of the nerves that may cause pain, weakness, and paralysis in the arms and legs, swelling of the lining of the mouth, nose, eyes, throat, intestines, or vagina, mouth sores, headache, weight loss, stomach-area (abdominal) pain, joint and muscle pain, and trouble sleeping.

…

07/21/2021 (SUPPL-105)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Following Table 34: Laboratory Abnormalities Worsened from Baseline Occurring in greater than or equal to 20% od Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426

Endometrial Carcinoma

Additions and/or revisions underlined:

The safety of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-775, a multicenter, open-label, randomized (1:1), active-controlled trial in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings [see Clinical Studies (14.15)]. Patients with endometrial carcinoma that is not MSI-H or dMMR received KEYTRUDA 200 mg every 3 weeks in combination with lenvatinib 20mg orally once daily (n=342) or received doxorubicin or paclitaxel (n=325).

For patients with not MSI-H or dMMR tumor status, the median duration of study treatment was 7.2 months (range 1 day to 26.8 months) and the median duration of exposure to KEYTRUDA was 6.8 months (range: 1 day to 25.8 months).

Fatal adverse reactions among these patients occurred in 4.7% of those treated with KEYTRUDA and lenvatinib, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction.

Serious adverse reactions occurred in 50% of these patients receiving KEYTRUDA and lenvatinib.

Serious adverse reactions (greater than or equal to 3%) were hypertension (4.4%) and urinary tract infections (3.2%).

Discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of KEYTRUDA (greater than or equal to 1%) was increased ALT (1.2%).

Dose interruptions of KEYTRUDA due to an adverse reaction occurred in 48% of these patients. The most common adverse reactions leading to interruption of KEYTRUDA (greater than or equal to 3%) were diarrhea (8%), increased ALT (4.4%), increased AST (3.8%), and hypertension (3.5%).

Tables 35 and 36 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with lenvatinib in KEYNOTE-775.

Table 35: Adverse Reactions Occurring in greater than or equal to 20% of Patients with Endometrial Carcinoma in KEYNOTE-775 (Footnotes for table have extensive changes; please refer to label for complete information).

Table 36: Laboratory Abnormalities Worsened from Baseline* Occurring in greater than or equal to 20% (All Grades) or greater than or equal to 3% (Grades 3-4) of Patients with Endometrial Carcinoma in KEYNOTE-775

8 Use in Specific Populations

8.5 Geriatric Use

Newly added information to end of subsection underlined:

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

a kind of cancer that is shown by a laboratory test to be a microsatellite instability-high (MSI-H) or a mismatch repair deficient (dMMR) solid tumor. KEYTRUDA may be used in adults and children to treat:
- cancer that has spread or cannot be removed by surgery (advanced cancer), and
- has progressed following treatment, and you have no satisfactory treatment options.
  It is not known if KEYTRUDA is safe and effective in children with MSI-H cancers of the brain or spinal cord (central nervous system cancers).

06/28/2021 (SUPPL-108)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Extensive changes; please refer to labeling)

05/05/2021 (SUPPL-97)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

Gastric Cancer

First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Positive Gastric Cancer with Trastuzumab and Chemotherapy

The safety analysis of Study KEYNOTE-811 included 217 patients with HER2-positive gastric cancer who received KEYTRUDA 200 mg, trastuzumab, and CAPOX (n=189) or FP (n=28) every 3 weeks, compared to 216 patients who received placebo, trastuzumab, and CAPOX (n=187) or FP (n=29) every 3 weeks [see Clinical Studies (14.9)].

The median duration of exposure to KEYTRUDA was 5.8 months (range: 1 day to 17.7 months).

The study population characteristics were: median age of 63 years (range: 19 to 84), 43% age 65 or older; 81% male; 58% White, 35% Asian, and 0.9% Black; 44% ECOG PS of 0 and 56% ECOG PS of 1.

KEYTRUDA and placebo were discontinued due to adverse reactions in 6% of patients in each arm. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 58% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (greater than or equal to 2%) were neutropenia (18%), thrombocytopenia (12%), diarrhea (6%), anemia (3.7%), hypokalemia (3.7%), fatigue/asthenia (3.2%), decreased appetite (3.2%), increased AST (2.8%), increased blood bilirubin (2.8%), pneumonia (2.8%), increased ALT (2.3%), and vomiting (2.3%).

In the KEYTRUDA arm versus placebo, there was a difference of greater than or equal to 5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%), and nausea (49% vs 44%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

There was a difference of greater than or equal to 5% incidence between patients treated with KEYTRUDA versus standard of care for increased ALT (34% vs 29%), and increased creatinine (20% vs 10%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

Previously Treated Gastric Cancer

Among the 259 patients with gastric cancer enrolled in KEYNOTE-059 [see Clinical Studies (14.9)], the median duration of exposure to KEYTRUDA was 2.1 months (range: 1 day to 21.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible. Adverse reactions occurring in patients with gastric cancer were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Extensive changes; please refer to label)

03/22/2021 (SUPPL-96)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

First-line Treatment of Locally Advanced Unresectable or Metastatic Esophageal Cancer/Gastroesophageal Junction

(Newly added section)

The safety of KEYTRUDA, in combination with cisplatin and FU chemotherapy was investigated in KEYNOTE-590, a multicenter, double-blind, randomized (1:1), placebo-controlled trial for the first-line treatment in patients with metastatic or locally advanced esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation [see Clinical Studies (14.11)]. A total of 740 patients received either KEYTRUDA 200 mg (n=370) or placebo (n=370) every 3 weeks for up to 35 cycles, both in combination with up to 6 cycles of cisplatin and up to 35 cycles of FU.

The median duration of exposure was 5.7 months (range: 1 day to 26 months) in the KEYTRUDA combination arm and 5.1 months (range: 3 days to 27 months) in the chemotherapy arm.

KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (?1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 67% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (?2%) were neutropenia (19%), fatigue/asthenia (8%), decreased white blood cell count (5%), pneumonia (5%), decreased appetite (4.3%), anemia (3.2%), increased blood creatinine (3.2%), stomatitis (3.2%), malaise (3.0%), thrombocytopenia (3%), pneumonitis (2.7%), diarrhea (2.4%), dysphagia (2.2%), and nausea (2.2%).

Tables 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-590.

(Newly added tables)

Previously Treated Recurrent Locally Advanced or Metastatic Esophageal Cancer

(Newly added subsection heading)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(Newly added Medication Guide; please see label)

11/10/2020 (SUPPL-48)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

(Subsection title revised)

(Extensive changes; please refer to label)

5.2 Infusion-Related Reactions

(Additions and/or revisions underlined)

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion- related reactions, stop infusion and permanently discontinue KEYTRUDA [see Dosage and Administration (2.3)].

6 Adverse Reactions

(Additions and/or revisions underlined)

The following clinically significant adverse reactions are described elsewhere in the labeling.

Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1)].
Infusion-related reactions [see Warnings and Precautions (5.2)].

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Extensive changes; please refer to label)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Immune-Mediated Adverse Reactions

Inform patients of the risk of immune-mediated adverse reactions that may be severe or fatal, may occur after discontinuation of treatment, and may require corticosteroid treatment and interruption or discontinuation of KEYTRUDA. These reactions may include:

Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)].
Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.1)].
Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding [see Warnings and Precautions (5.1)].
Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of adrenal insufficiency, hypophysitis, hypothyroidism, hyperthyroidism, or Type 1 diabetes mellitus [see Warnings and Precautions (5.1)].
Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis [see Warnings and Precautions (5.1)].
Severe skin reactions: Advise patients to contact their healthcare provider immediately for any signs or symptoms of severe skin reactions, SJS or TEN [see Warnings and Precautions (5.1)].
Other immune-mediated adverse reactions:
- Advise patients that immune-mediated adverse reactions can occur and may involve any organ system, and to contact their healthcare provider immediately for any new or worsening signs or symptoms [see Warnings and Precautions (5.1)].
- Advise patients of the risk of solid organ transplant rejection and to contact their healthcare provider immediately for signs or symptoms of organ transplant rejection [see Warnings and Precautions (5.1)].

Infusion-Related Reactions

Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion- related reactions [see Warnings and Precautions (5.2)].

Complications of Allogeneic HSCT

Advise patients of the risk of post-allogeneic hematopoietic stem cell transplantation complications [see Warnings and Precautions (5.3)].

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)].

Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)].

Lactation

Advise women not to breastfeed during treatment with KEYTRUDA and for 4 months after the final dose [see Use in Specific Populations (8.2)].

Laboratory Tests

Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Warnings and Precautions (5.1)].

10/14/2020 (SUPPL-85)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Immune-Mediated Pneumonitis

Newly added information to the bottom of the subsection:

In clinical studies enrolling 389 adult patients with cHL who received KEYTRUDA as a single agent, pneumonitis occurred in 31 (8%) patients, including Grades 3-4 pneumonitis in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months).

Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 21 (5.4%) patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

5.4 Immune-Mediated Endocrinopathies

Thyroid Disorders

Additions and/or revisions underlined:

… Hypothyroidism resolved in 48 (20%) of the 237 patients. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. The median time of onset was 1.2 months (range: 0.5 to 3.5 months).

5.9 Complications of Allogeneic HSCT

Additions and/or revisions underlined:

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody.

Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid- requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

6 Adverse Reactions

6.1 Clinical Trials Experience

Table 16: Laboratory Abnormalities Worsened from Baseline Occurring in greater than or equal to 20% of Patients Receiving KEYTRUDA in KEYNOTE-048

Previously treated recurrent or metastatic HNSCC …

Newly added information:

Relapsed or Refractory cHL

KEYNOTE-204

The safety of KEYTRUDA was evaluated in KEYNOTE-204 [see Clinical Studies (14.5)]. Adults with relapsed or refractory cHL received KEYTRUDA 200 mg intravenously every 3 weeks (n=148) or brentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeks (n=152). The trial required an ANC greater than or equal to1000/µL, platelet count greater than or equal to 75,000/µL, hepatic transaminases less than or equal to 2.5 times the upper limit of normal (ULN), bilirubin less than or equal to 1.5 times ULN, and ECOG performance status of 0 or 1. The trial excluded patients with active non-infectious pneumonitis, prior pneumonitis requiring steroids, active autoimmune disease, a medical condition requiring immunosuppression, or allogeneic HSCT within the past 5 years. The median duration of exposure to KEYTRUDA was 10 months (range: 1 day to 2.2 years), with 68% receiving at least 6 months of treatment and 48% receiving at least 1 year of treatment.

Serious adverse reactions occurred in 30% of patients who received KEYTRUDA. Serious adverse reactions in greater than or equal to 1% included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients (2%) died from causes other than disease progression: two from complications after allogeneic HSCT and one from unknown cause.

Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 14% of patients; 7% of patients discontinued treatment due to pneumonitis. Dosage interruption of KEYTRUDA due to an adverse reaction occurred in 30% of patients. Adverse reactions which required dosage interruption in greater than or equal to3% of patients were upper respiratory tract infection, pneumonitis, transaminase increase, and pneumonia.

Thirty-eight percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Table 17 summarizes adverse reactions in KEYNOTE-204.

Table 17: Adverse Reactions (greater than or equal to 10%) in Patients with cHL Who Received KEYTRUDA in KEYNOTE-204 Newly added table for Study 204 to compare against Brentixuimab Vedotin; please refer to label for complete information.

Additions and/or revisions underlined:

Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included herpes virus infection (9%), pneumonia (8%), oropharyngeal pain (8%), hyperthyroidism (5%), hypersensitivity (4.1%), infusion reactions (3.4%), altered mental state (2.7%), and in 1.4% each, uveitis, myocarditis, thyroiditis, febrile neutropenia, sepsis, and tumor flare.

Table 18 summarizes laboratory abnormalities in KEYNOTE-204.

Table 18: Laboratory Abnormalities (greater than or equal to 15%) That Worsened from Baseline in Patients with cHL in KEYNOTE-204 Newly added table for Study 204 to compare against Brentixuimab Vedotin; please refer to label for complete information.

KEYNOTE-087

Among the 210 patients with cHL who received KEYTRUDA in KEYNOTE-087 [see Clinical Studies (14.5)], the median duration of exposure to KEYTRUDA was 8.4 months (range: 1 day to 15.2 months). Serious adverse reactions occurred in 16% of patients who received KEYTRUDA. Serious adverse reactions that occurred in greater than or equal to 1% of patients included pneumonia, pneumonitis, pyrexia, dyspnea, graft versus host disease (GVHD) and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock.

Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 5% of patients and dosage interruption due to an adverse reaction occurred in 26%. Fifteen percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 19 and 20 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-087.

Table 19: Adverse Reactions (greater than or equal to 10%) in Patients with cHL Who Received KEYTRUDA in KEYNOTE-087 Formerly Table 17 in labeling.

Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each).

Table 20: Select Laboratory Abnormalities (greater than or equal to 15%) That Worsened from Baseline in Patients with cHL Who Received KEYTRUDA in KEYNOTE-087 Formerly Table 18 in labeling.

PMBCL

Among the 53 patients with PMBCL who received KEYTRUDA in KEYNOTE-170 [see Clinical Studies (14.6)], the median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 22.8 months). Serious adverse reactions occurred in 26% of patients. Serious adverse reactions that occurred in >2% of patients included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment.

Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 8% of patients and dosage interruption due to an adverse reaction occurred in 15%. Twenty-five percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 21 and 22 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-170.

Table 21: Adverse Reactions (greater than or equal to 10%) in Patients with PMBCL Who Received KEYTRUDA in KEYNOTE-170 Formerly Table 19 in labeling.

Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included hypothyroidism (8%), hyperthyroidism and pericarditis (4% each), and thyroiditis, pericardial effusion, pneumonitis, arthritis and acute kidney injury (2% each).

Table 22: Laboratory Abnormalities (greater than or equal to1 5%) That Worsened from Baseline in of Patients with PMBCL Who Received KEYTRUDA in KEYNOTE-170 Formerly Table 20 in labeling.

Further tables have been renumbered to account for addition of tables to labeling through the remainder of the subsection.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of KEYTRUDA as a single agent have been established in pediatric patients with cHL, PMBCL, MCC, MSI-H cancer, and TMB-H cancer. Use of KEYTRUDA in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.5, 14.6, 14.8, 14.14, 14.17)].

In KEYNOTE-051, 161 pediatric patients (62 pediatric patients aged 6 months to younger than 12 years and 99 pediatric patients aged 12 to 17 years) with advanced melanoma, lymphoma, or PD-L1 positive solid tumors received KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 24 months). Adverse reactions that occurred at a greater than or equal to10% higher rate in pediatric patients when compared to adults included pyrexia (33%), vomiting (30%), upper respiratory tract infection (29%), and headache (25%). Laboratory abnormalities that occurred at a greater than or equal to10% higher rate in pediatric patients when compared to adults were leukopenia (30%), neutropenia (26%), and Grade 3 anemia (17%).

The safety and effectiveness of KEYTRUDA in pediatric patients have not been established in the other approved indications [see Indications and Usage (1)].

8.5 Geriatric Use

Additions and/or revisions underlined:

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Newly added; please refer to label for complete information.

06/29/2020 (SUPPL-84)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

… The data described in this section were obtained in eleven randomized, controlled trials (KEYNOTE-002, KEYNOTE-006, KEYNOTE-010, KEYNOTE-042, KEYNOTE-045, KEYNOTE-177, KEYNOTE-048, KEYNOTE-189, KEYNOTE-407, KEYNOTE-181, and KEYNOTE-426) and twelve non-randomized, open- label trials (KEYNOTE-028, KEYNOTE-012, KEYNOTE-087, KEYNOTE-170, KEYNOTE-052, KEYNOTE-057, KEYNOTE-059, KEYNOTE-158, KEYNOTE-224, KEYNOTE-017, KEYNOTE-146, and KEYNOTE-629) …

Table 25: Laboratory Abnormalities Worsened from Baseline Occurring in

greater than or equal to20% of BCG-unresponsive NMIBC Patients Receiving KEYTRUDA in KEYNOTE-057

Newly added information:

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

Among the 153 patients with MSI-H or dMMR CRC enrolled in KEYNOTE-177 [see Clinical Studies (14.9)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 11.1 months (range: 1 day to 30.6 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Newly added information:

a kind of cancer called colon or rectal cancer. KEYTRUDA may be used as your first treatment when your cancer:
- has spread or cannot be removed by surgery (advanced colon or rectal cancer), and
- has been shown by a laboratory test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

Additions and/or revisions underlined:

a kind of cancer that is shown by a test to be tumor mutational burden-high (TMB-H). KEYTRUDA may be used in adults and children to treat:
- solid tumors that have spread or cannot be removed by surgery (advanced cancer), and
- you have received anti-cancer treatment, and it did not work or is no longer working, and
- you have no satisfactory treatment options.

It is not known if KEYTRUDA is safe and effective in children with TMB-H cancers of the brain or spinal cord (central nervous system cancers).

06/24/2020 (SUPPL-68)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

The data described in this section were obtained in ten randomized, controlled trials (KEYNOTE-002, KEYNOTE-006, KEYNOTE-010, KEYNOTE-042, KEYNOTE-045, KEYNOTE-048, KEYNOTE-189, KEYNOTE-407, KEYNOTE-181, and KEYNOTE-426) and twelve non-randomized, open-label trials (KEYNOTE-028, KEYNOTE-012, KEYNOTE-087, KEYNOTE-170, KEYNOTE-052, KEYNOTE-057, KEYNOTE-059, KEYNOTE-158, KEYNOTE-224, KEYNOTE-017, KEYNOTE-146, and KEYNOTE-629).

The data described in this section also included a single randomized, double-blind, placebo-controlled trial (KEYNOTE-054) in which KEYTRUDA was administered for the adjuvant treatment of 509 patients with melanoma with involvement of lymph node(s) following complete surgical resection. In these trials, KEYTRUDA was administered at 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks.

…

cSCC

Among the 105 patients with cSCC enrolled in KEYNOTE-629 [see Clinical Studies (14.17)], the median duration of exposure to KEYTRUDA was 5.8 months (range 1 day to 16.1 months). Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. Adverse reactions occurring in patients with cSCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (11%).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

…

Problems in other organs. Signs and symptoms of these problems may include:

changes in eyesight
severe or persistent muscle or joint pains
severe muscle weakness
low red blood cells (anemia)
swollen lymph nodes, rash or tender lumps on skin, cough, shortness of breath, vision changes, or eye pain (sarcoidosis)
confusion, fever, muscle weakness, balance problems, nausea, vomiting, stiff neck, memory problems, or seizures (encephalitis)
pain, numbness, tingling, or weakness in your arms or legs, or bladder or bowel problems, including the need to urinate more often, leaking of urine, trouble urinating, or constipation (myelitis)

shortness of breath, irregular heartbeat, feeling tired, or chest pain (myocarditis)

…

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

…

a kind of skin cancer called cutaneous squamous cell carcinoma (cSCC). KEYTRUDA may be used when your skin cancer:

has returned or spread, and
cannot be cured by surgery or radiation.

…

01/08/2020 (SUPPL-66)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Immune-Mediated Hepatitis (KEYTRUDA) and Hepatoxicity (KEYTRUDA in Combination with Axitinib)

Hepatoxicity in Combination with Axitinib

Additions and/or revisions underlined:

Fifty-nine percent of the patients with increased ALT received systemic corticosteroids.

5.4 Immune-Mediated Endocrinopathies

Newly added information:

Adrenal Insufficiency

KEYTRUDA can cause adrenal insufficiency (primary and secondary). Monitor for signs and symptoms of adrenal insufficiency. Administer corticosteroids and hormone replacement as clinically indicated.

Withhold KEYTRUDA for moderate (Grade 2) adrenal insufficiency and withhold or discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency [see Dosage and Administration (2.17) and Adverse Reactions (6.1)].

Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) adrenal insufficiency. The median time to onset was 5.3 months (range: 26 days to 16.6 months), and the median duration was not reached (range: 4 days to 1.9+ years). Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% of patients and withholding of KEYTRUDA in 0.3% of patients.

Systemic corticosteroids were required in 77% (17/22) of patients with adrenal insufficiency, including 9% who received high-dose corticosteroids (prednisone greater than or equal to 40 mg per day or equivalent) for median duration of 4 days (range: 1 to 6 days) followed by corticosteroid taper. Adrenal insufficiency resolved in 23% of the patients.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

… The data described in this section were obtained in ten randomized, controlled trials (KEYNOTE-002, KEYNOTE-006, KEYNOTE-010, KEYNOTE-042, KEYNOTE-045, KEYNOTE-048, KEYNOTE-189, KEYNOTE-407, KEYNOTE-181, and KEYNOTE-426) and eleven non-randomized, open-label trials (KEYNOTE-028, KEYNOTE-012, KEYNOTE-087, KEYNOTE-170, KEYNOTE-052, KEYNOTE-057, KEYNOTE-059 …

Table 20: Adverse Reactions Occurring in greater than or equal to10% of Patients Receiving KEYTRUDA in KEYNOTE-052 Following this table is the additional following footnote:

ß Includes edema peripheral, peripheral swelling

Table 22: Laboratory Abnormalities Worsened from Baseline Occurring in greater than or equal to 20% of Urothelial Carcinoma Patients Receiving KEYTRUDA in KEYNOTE-045

Newly added information:

BCG-unresponsive High-risk NMIBC

The safety of KEYTRUDA was investigated in KEYNOTE-057, a multicenter, open-label, single-arm trial that enrolled 148 patients with high-risk non-muscle invasive bladder cancer (NMIBC), 96 of whom had BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression.

The median duration of exposure to KEYTRUDA was 4.3 months (range: 1 day to 25.6 months).

KEYTRUDA was discontinued due to adverse reactions in 11% of patients. The most common adverse (>1%) reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (greater than or equal to 2%) were diarrhea (4%) and urinary tract infection (2%). Serious adverse reactions occurred in 28% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (greater than or equal to 2%) in KEYTRUDA-treated patients were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). Tables 23 and 24 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-057.

The following two tables are newly added; please refer to label for complete information.

Table 23: Adverse Reactions Occurring in greater than or equal to 10% of Patients Receiving KEYTRUDA in KEYNOTE-057

Table 24: Laboratory Abnormalities Worsened from Baseline Occurring in greater than or equal to 20% of BCG-unresponsive NMIBC Patients Receiving KEYTRUDA in KEYNOTE-057

Gastric Cancer

Esophageal Cancer

Cervical Cancer

Additions and/or revisions underlined:

… Tables 25 and 26 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-158.

RCC

Additions and/or revisions underlined:

Tables 27 and 28 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with KEYTRUDA and axitinib in KEYNOTE-426.

Endometrial Carcinoma

Additions and/or revisions underlined:

Tables 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with lenvatinib.

Table 30: Laboratory Abnormalities Worsened from Baseline Occurring in greater than or equal to 20% (All Grades) or greater than or equal to 3% (Grades 3-4) of Patients with Endometrial Carcinoma in KEYNOTE-146

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

a kind of bladder and urinary tract cancer called urothelial carcinoma.
- KEYTRUDA may be used when your cancer has not spread to nearby tissue in the bladder, but is at high-risk for spreading (high-risk non-muscle-invasive bladder cancer [NMIBC]) when:

your tumor is a type called “carcinoma in situ” (CIS), and
you have tried treatment with Bacillus Calmette-Guerin (BCG), and it did not work, and
you are not able to or have decided not to have surgery to remove your bladder.

PATIENT COUNSELING INFORMATION

Immune-Mediated Adverse Reactions

Additions and/or revisions underlined:

Adrenal Insufficiency: Advise patients to contact their healthcare provider immediately for extreme weakness, dizziness, or fainting [see Warnings and Precautions (5.4)].

07/30/2019 (SUPPL-55)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Previously treated recurrent or metastatic HNSCC

… Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3-4) and new or worsening hypothyroidism.

…

Gastric Cancer

Among the 259 patients with gastric cancer enrolled in KEYNOTE-059 , the median duration of exposure to KEYTRUDA was 2.1 months (range: 1 day to 21.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible. Adverse reactions occurring in patients with gastric cancer were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

Esophageal Cancer

Among the 314 patients with esophageal cancer enrolled in KEYNOTE-181 treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 2.1 months (range: 1 day to 24.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

Cervical Cancer

…

Among the 104 patients with HCC who received KEYTRUDA in KEYNOTE-224 ,the median duration of exposure to KEYTRUDA was 4.2 months (range: 1 day to 1.5 years). Adverse reactions occurring in patients with HCC were generally similar to those in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

MCC

Among the 50 patients with MCC enrolled in KEYNOTE-017,the median duration of exposure to KEYTRUDA was 6.6 months (range 1 day to 23.6 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

…

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(additions underlined)

…

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

…

a kind of cancer called squamous cell carcinoma of the esophagus. KEYTRUDA may be used when:

your cancer has returned or spread (advanced esophageal cancer), and
your tumor tests positive for “PD-L1” and you have received one or more types of treatment and it did not work or is no longer working.
…

07/30/2019 (SUPPL-56)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Previously treated recurrent or metastatic HNSCC

…

Gastric Cancer

Esophageal Cancer

Cervical Cancer

…

MCC

…

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(additions underlined)

…

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

…

a kind of cancer called squamous cell carcinoma of the esophagus. KEYTRUDA may be used when:

your cancer has returned or spread (advanced esophageal cancer), and
your tumor tests positive for “PD-L1” and you have received one or more types of treatment and it did not work or is no longer working.
…

06/10/2019 (SUPPL-52)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Immune-Related Pneumonitis

Addition of the following:

In KEYNOTE-048 enrolling 300 patients with HNSCC who received KEYTRUDA as a single agent pneumonitis occurred in 18 (6%) patients, including Grade 3 (1.3%), Grade 4 (0%), and Grade 5 (0.3%). Eight of the 18 patients received high-dose corticosteroids for a median duration of 14 days (range: 1 to 77 days). Pneumonitis led to discontinuation of KEYTRUDA in 2 (0.7%) patients. Pneumonitis resolved in 12 (66%) of the patients. Pneumonitis occurred in 15 (5.4%) patients of 276 patients with HNSCC receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grade 3 (1.1%), Grade 4 (0%), and Grade 5 (0.4%) pneumonitis. Four of the 15 patients received high-dose corticosteroids for a median duration of 16 days (range: 2 to 32 days). Pneumonitis led to discontinuation of KEYTRUDA in 5 (1.8%) patients. Pneumonitis resolved in 12 (80%) of the patients.

Additions and/or revisions underlined:

5.3 Immune-Mediated Hepatitis (KEYTRUDA) and Hepatoxicity (KEYTRUDA in Combination with Axitinib)

‘Administered as a single agent’ replaces ‘monotherapy’ in this subsection.

Additions and/or revisions underlined:

5.4 Immune-Mediated Endocrinopathies

6 Adverse Reactions

Additions and/or revisions underlined:

Immune-mediated hepatitis (KEYTRUDA) and hepatotoxicity (KEYTRUDA in combination with axitinib)

6.1 Clinical Trials Experience

… in two randomized, open-label, active-controlled clinical trials (KEYNOTE-042 and KEYNOTE-024), which enrolled 790 patients with NSCLC; in a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and two randomized, open-label, active- controlled trials (KEYNOTE-040 and KEYNOTE-048 single agent arms), which enrolled 909 patients with HNSCC … in combination with chemotherapy in a randomized, active-controlled trial (KEYNOTE-189), which enrolled 405 patients with nonsquamous NSCLC, in a randomized, open-label, active-controlled trial (KEYNOTE-048 combination arm), which enrolled 276 patients with HNSCC …

The data described in this section were obtained in nine randomized, controlled trials (KEYNOTE-002, KEYNOTE-006, KEYNOTE-010, KEYNOTE-042, KEYNOTE-045, KEYNOTE-048, KEYNOTE-189, KEYNOTE-407, and KEYNOTE 426) …

Newly added information following Table 13: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in greater than or equal to20% of NSCLC Patients Receiving KEYTRUDA in KEYNOTE-010:

First-line treatment of metastatic or unresectable, recurrent HNSCC

The safety of KEYTRUDA, as a single agent and in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, was investigated in KEYNOTE-048, a multicenter, open-label, randomized (1:1:1), active-controlled trial in patients with previously untreated, recurrent or metastatic HNSCC. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. A total of 576 patients received KEYTRUDA 200 mg every 3 weeks either as a single agent (n=300) or in combination with platinum and FU (n=276) every 3 weeks for 6 cycles followed by KEYTRUDA, compared to 287 patients who received cetuximab weekly in combination with platinum and FU every 3 weeks for 6 cycles followed by cetuximab.

The median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 24.2 months) in the KEYTRUDA single agent arm and was 5.8 months (range: 3 days to 24.2 months) in the combination arm. Seventeen percent of patients in the KEYTRUDA single agent arm and 18% of patients in the combination arm were exposed to KEYTRUDA for greater than or equal to 12 months. Fifty-seven percent of patients receiving KEYTRUDA in combination with chemotherapy started treatment with carboplatin.

KEYTRUDA was discontinued for adverse reactions in 12% of patients in the KEYTRUDA single agent arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were sepsis (1.7%) and pneumonia (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 31% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (greater than or equal to 2%) were pneumonia (2.3%), pneumonitis (2.3%), and hyponatremia (2%).

KEYTRUDA was discontinued for adverse reactions in 16% of patients in the combination arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 45% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (greater than or equal to 2%) were neutropenia (14%), thrombocytopenia (10%), anemia (6%), pneumonia (4.7%), and febrile neutropenia (2.9%).

Tables 14 and 15 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-048.

Table 14: Adverse Reactions Occurring in greater than or equal to 10% of Patients Receiving KEYTRUDA in KEYNOTE-048

Table 15: Laboratory Abnormalities Worsened from Baseline Occurring in greater than or equal to 20% of Patients Receiving KEYTRUDA in KEYNOTE-048

Additions and/or revisions underlined:

Previously treated recurrent or metastatic HNSCC

Among the 192 patients with HNSCC enrolled in KEYNOTE-012 …

The study population characteristics were: median age of 60 years …

RCC

The study population characteristics were: median age of 62 years (range: 30 to 89) …

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What is KEYTRUDA?

Additions and/or revisions underlined:

a kind of cancer called head and neck squamous cell cancer (HNSCC)
KEYTRUDA may be used with the chemotherapy medicines fluorouracil and a platinum as your first treatment when your head and neck cancer has spread or returned and cannot be removed by surgery. KEYTRUDA may be used alone as your first treatment when your head and neck cancer:

has spread or returned and cannot be removed by surgery, and
your tumor tests positive for “PD-L1”.

KEYTRUDA may be used alone when your head and neck cancer:

has spread or returned, and
you have received chemotherapy that contains platinum and it did not work or is no longer working.

04/19/2019 (SUPPL-54)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.3 Immune-Mediated Hepatitis, or Hepatoxicity (in Combination with Axitinib)

Addition of the following at the end of the subsection:

Hepatotoxicity (in Combination with Axitinib)

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used in monotherapy. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. The median time to onset of increased ALT was 2.3 months (range: 7 days to 19.8 months). Sixty-one percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT greater than or equal to 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 KEYTRUDA (3%) or axitinib (31%) monotherapy or with both (50%), 55% had no recurrence of ALT >3 times ULN.

6 Adverse Reactions

Additions to the bulleted line listing underlined:

Immune-mediated hepatitis, or hepatotoxicity (in combination with axitinib)

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

… which enrolled 405 patients with nonsquamous NSCLC; in combination with axitinib in a randomized, active controlled trial (KEYNOTE 426), which enrolled 429 patients with RCC; and in post-marketing use.

The data described in this section were obtained in eight randomized, controlled trials (KEYNOTE-002, KEYNOTE-006, KEYNOTE-010, KEYNOTE-042, KEYNOTE-045, KEYNOTE-189, and KEYNOTE-407, and KEYNOTE 426) and eight non-randomized …

Addition of the following to the end of 6.1 Section:

RCC

The safety of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426. Patients with medical conditions that required systemic corticosteroids or other immunosuppressive medications or had a history of severe autoimmune disease other than type 1 diabetes, vitiligo, Sjogren’s syndrome, and hypothyroidism stable on hormone replacement were ineligible. Patients received KEYTRUDA 200 mg intravenously every 3 weeks and axitinib 5 mg orally twice daily, or sunitinib 50 mg once daily for 4 weeks and then off treatment for 2 weeks. The median duration of exposure to the combination therapy of KEYTRUDA and axitinib was 10.4 months (range: 1 day to 21.2 months).

The median age of patients treated with KEYTRUDA in combination with axitinib was 62 years (range: 30 to 89), 40% of patients were 65 years or older, 71% were male, 80% were White, and the performance status as assessed by the Karnofsky Performance Status (KPS) was KPS 90-100 in 80% and KPS 70-80 in 20% of patients.

Fatal adverse reactions occurred in 3.3% of patients receiving KEYTRUDA in combination with axitinib. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism and 1 case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier’s gangrene, plasma cell myeloma, pleural effusion, pneumonitis, and respiratory failure.

Serious adverse reactions occurred in 40% of patients receiving KEYTRUDA in combination with axitinib. Serious adverse reactions in greater than or equal to 1% of patients receiving KEYTRUDA in combination with axitinib included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%).

Permanent discontinuation due to an adverse reaction of either KEYTRUDA or axitinib occurred in 31% of patients; 13% KEYTRUDA only, 13% axitinib only, and 8% both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of KEYTRUDA, axitinib, or the combination was hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%).

Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of KEYTRUDA infusions due to infusion-related reactions, occurred in 76% of patients receiving KEYTRUDA in combination with axitinib. This includes interruption of KEYTRUDA in 50% of patients. Axitinib was interrupted in 64% of patients and dose reduced in 22% of patients. The most common adverse reactions (>10%) resulting in interruption of KEYTRUDA were hepatotoxicity (14%) and diarrhea (11%), and the most common adverse reactions (>10%) resulting in either interruption or reduction of axitinib were hepatotoxicity (21%), diarrhea (19%), and hypertension (18%).

The most common adverse reactions (>20%) in patients receiving KEYTRUDA and axitinib were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar- plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.

Twenty-seven percent (27%) of patients treated with KEYTRUDA in combination with axitinib received an oral prednisone dose equivalent to greater than or equal to 40 mg daily for an immune-mediated adverse reaction.

Tables 23 and 24 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with KEYTRUDA and axitinib in KEYNOTE-426.

Newly added tables; please refer to label for complete information.

Table 23: Adverse Reactions Occurring in greater than or equal to 20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426

Table 24: Laboratory Abnormalities Worsened from Baseline Occurring in greater than or equal to 20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426

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Additions and/or revisions underlined:

Call or see your doctor right away if you develop any symptoms of the following problems or these symptoms get worse:

Liver problems, including hepatitis. Signs and symptoms of liver problems may include:

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

a kind of kidney cancer called renal cell carcinoma (RCC). KEYTRUDA may be used with the medicine axitinib as your first treatment when your kidney cancer has spread or cannot be removed by surgery (advanced RCC).

04/11/2019 (SUPPL-47)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Immune-Mediated Pneumonitis

(additions underlined)

…

In clinical studies enrolling 790 patients with NSCLC who received KEYTRUDA as a single agent as first- line therapy for advanced disease, pneumonitis occurred in 65 (8.2%) patients, including Grades 3-4 in 3.2% of patients. Forty-eight of the 65 patients received high-dose corticosteroids for a median duration of 5 days (range: 1 to 26 days). Pneumonitis occurred in 17% of patients with a history of prior thoracic radiation and 7.7% of patients who did not receive prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 29 (3.7%) patients. Pneumonitis resolved in 51% of the patients.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions, please refer to label)

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(additions underlined)

…

KEYTRUDA may be used alone as your first treatment when your lung cancer:

has not spread outside your chest (stage III) and you cannot have surgery or chemotherapy with radiation

your NSCLC has spread to other areas of your body (advanced NSCLC),

and

your tumor tests positive for “PD-L1”, and
does not have an abnormal “EGFR” or “ALK” gene.

…

02/15/2019 (SUPPL-40)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

The data described in this section were obtained in six randomized, controlled trials (KEYNOTE-002, KEYNOTE-006, KEYNOTE-010, KEYNOTE-045, KEYNOTE-189, and KEYNOTE-407) and eight non-randomized, open-label trials (KEYNOTE-012, KEYNOTE-087, KEYNOTE-170, KEYNOTE-052, KEYNOTE-059, KEYNOTE-158, KEYNOTE-224, and KEYNOTE-017). The data described in this section also included a single randomized, double-blind, placebo-controlled trial (KEYNOTE-054) in which KEYTRUDA was administered for the adjuvant treatment of 509 patients with melanoma with involvement of lymph node(s) following complete surgical resection. In these trials, KEYTRUDA was administered at 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks.

Adjuvant Treatment of Resected Melanoma

The safety of KEYTRUDA as a single agent was evaluated in KEYNOTE-054, a randomized (1:1) double- blind trial in which 1019 patients with completely resected stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=509) or placebo (n=502) for up to one year. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Seventy-six percent of patients received KEYTRUDA for 6 months or longer.

The study population characteristics were: median age of 54 years (range: 19 to 88); 25% age 65 or older; 62% male; 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had stage IIIA, 46% had stage IIIB, 18% had stage IIIC (1-3 positive lymph nodes), and 20% had stage IIIC (greater than or equal to 4 positive lymph nodes).

Two patients treated with KEYTRUDA died from causes other than disease progression; causes of death were drug reaction with eosinophilia and systemic symptoms and autoimmune myositis with respiratory failure. Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. Adverse reactions leading to permanent discontinuation occurred in 14% of patients receiving KEYTRUDA; the most common (greater than or equal to 1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 19% of patients; the most common (greater than or equal to 1%) were diarrhea (2.4%), pneumonitis (2%), increased ALT (1.4%), arthralgia (1.4%), increased AST (1.4%), dyspnea (1%), and fatigue (1%). Tables 6 and 7 summarize the adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-054.

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(Extensive changes; please refer to labeling)

12/28/2018 (SUPPL-37)

Approved Drug Label (PDF)

6 Adverse Reactions

6 ADVERSE REACTIONS

(Additions and/or revisions are underlined)

The following clinically significant adverse reactions are described elsewhere in the labeling.

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

…

The data described in this section were obtained in six randomized, controlled trials (KEYNOTE-002, KEYNOTE-006, KEYNOTE-010, KEYNOTE-045, KEYNOTE-189, and KEYNOTE-407) in and eight non-randomized, open-label trials (KEYNOTE-012, KEYNOTE-087, KEYNOTE-170, KEYNOTE-052, KEYNOTE-059, KEYNOTE-158, KEYNOTE-224, and KEYNOTE-017). In these trials, KEYTRUDA was administered at 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks.

Melanoma

Ipilimumab-Naive Melanoma

The safety of KEYTRUDA for the treatment of patients with unresectable or metastatic melanoma who had not received prior ipilimumab and who had received no more than one prior systemic therapy was investigated in KEYNOTE-006. KEYNOTE-006 was a multicenter, open-label, active-controlled trial where patients were randomized (1:1:1) and received KEYTRUDA 10 mg/kg every 2 weeks (n=278) or KEYTRUDA 10 mg/kg every 3 weeks (n=277) until disease progression or unacceptable toxicity or ipilimumab 3 mg/kg every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity (n=256). Patients with autoimmune disease, a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.

The median duration of exposure was 5.6 months (range: 1 day to 11.0 months) for KEYTRUDA and similar in both treatment arms. Fifty-one and 46% of patients received KEYTRUDA 10 mg/kg every 2 or 3 weeks, respectively, for ?6 months. No patients in either arm received treatment for more than one year.

The study population characteristics were: median age of 62 years (range: 18 to 89 years), 60% male, 98% White, 32% had an elevated lactate dehydrogenase (LDH) value at baseline, 65% had M1c stage disease, 9% with history of brain metastasis, and approximately 36% had been previously treated with systemic therapy which included a BRAF inhibitor (15%), chemotherapy (13%), and immunotherapy (6%).

In KEYNOTE-006, the adverse reaction profile was similar for the every 2 week and every 3 week schedule, therefore summary safety results are provided in a pooled analysis (n=555) of both KEYTRUDA arms. Adverse reactions leading to permanent discontinuation of KEYTRUDA occurred in 9% of patients. Adverse reactions leading to discontinuation of KEYTRUDA in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (?1%) was diarrhea (2.5%). Tables 2 and 3 summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-006.

Ipilimumab-Refractory Melanoma

The safety of KEYTRUDA in patients with unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, was investigated in KEYNOTE-002. KEYNOTE-002 was a multicenter, partially blinded (KEYTRUDA dose), randomized (1:1:1), active-controlled trial in which 528 patients received KEYTRUDA 2 mg/kg (n=178) or 10 mg/kg (n=179) every 3 weeks or investigator’s choice of chemotherapy (n=171), consisting of dacarbazine (26%), temozolomide (25%), paclitaxel and carboplatin (25%), paclitaxel (16%), or carboplatin (8%). Patients with autoimmune disease, severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; medical conditions that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or an active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.

The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.7 months (range: 1 day to 16.6 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 4.8 months (range: 1 day to 16.8 months). In the KEYTRUDA 2 mg/kg arm, 36% of patients were exposed to KEYTRUDA for ?6 months and 4% were exposed for greater than or equal to 2 months. In the KEYTRUDA 10 mg/kg arm, 41% of patients were exposed to KEYTRUDA for ?6 months and 6% of patients were exposed to KEYTRUDA for greater than or equal to 12 months.

The study population characteristics were: median age of 62 years (range: 15 to 89 years), 61% male, 98% White, 41% with an elevated LDH value at baseline, 83% with M1c stage disease, 73% received two or more prior therapies for advanced or metastatic disease (100% received ipilimumab and 25% a BRAF inhibitor), and 15% with history of brain metastasis.

In KEYNOTE-002, the adverse reaction profile was similar for the 2 mg/kg dose and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=357) of both KEYTRUDA arms. Adverse reactions resulting in permanent discontinuation occurred in 12% of patients receiving KEYTRUDA; the most common (?1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (?1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). Tables 4 and 5 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-002.

NSCLC

First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapy

The safety of KEYTRUDA in combination with pemetrexed and investigator’s choice of platinum (either carboplatin or cisplatin) was investigated in KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.2)]. A total of 607 patients received KEYTRUDA 200 mg, pemetrexed and platinum every 3 weeks for 4 cycles followed by KEYTRUDA and pemetrexed (n=405) or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 years or older, 59% male, 94% White and 3% Asian, and 18% with history of brain metastases at baseline.

KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (?2%) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%),

pneumonia (4%), increased blood creatinine (3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), increased ALT (2%), and pyrexia (2%).Table Tables 6 and 7 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE- 189.

…

In KEYNOTE-010, the adverse reaction profile was similar for the 2 mg/kg and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=682). Treatment was discontinued for adverse reactions in 8% of patients receiving KEYTRUDA. The most common adverse events resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (?1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). Tables 8 and 9 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-407.

…

HNSCC

Among the 192 patients with HNSCC enrolled in KEYNOTE, the median duration of exposure to KEYTRUDA was 3.3 months (range: 1 day to 27.9 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible for KEYNOTE-012.

The median age of patients was 60 years (range: 20 to 84), 35% were age 65 years or older, 83% were male, 77% were White, 15% were Asian, and 5% were Black. Sixty-one percent of patients had two or more lines of therapy in the recurrent or metastatic setting, and 95% had prior radiation therapy. Baseline ECOG PS was 0 (30%) or 1 (70%) and 86% had M1 disease.

KEYTRUDA was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The incidence of adverse reactions, including serious adverse reactions, was similar between dosage regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks); therefore, summary safety results are provided in a pooled analysis. The most common adverse reactions (occurring in greater than or equal to 20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3-4) and new or worsening hypothyroidism.

cHL

Among the 210 patients with cHL enrolled in KEYNOTE-087, the median duration of exposure to KEYTRUDA was 8.4 months (range: 1 day to 15.2 months). KEYTRUDA was discontinued due to adverse reactions in 5% of patients, and treatment was interrupted due to adverse reactions in 26%. Fifteen percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse reactions (?1%) included pneumonia, pneumonitis, pyrexia, dyspnea, graft versus host disease and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. Tables 10 and 11 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-087.

Other clinically important adverse reactions that occurred in less than 10% of patients on KEYNOTE-087 included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each).

Hyperbilirubinemia occurred in less than 15% of patients on KEYNOTE-087 (10% all Grades, 2.4% Grade 3-4).

PMBCL

Among the 53 patients with PMBCL treated in KEYNOTE-170, the median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 22.8 months).

KEYTRUDA was discontinued due to adverse reactions in 8% of patients, and treatment was interrupted due to adverse reactions in 15%. Twenty-five percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 26% of patients, and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. Tables 12 and 13 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-170.

Urothelial Carcinoma

Cisplatin Ineligible Patients with Urothelial Carcinoma

he safety of KEYTRUDA was investigated in KEYNOTE-052, a single-arm trial that enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible.

Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or either radiographic or clinical disease progression.

The median duration of exposure to KEYTRUDA was 2.8 months (range: 1 day to 15.8 months).

KEYTRUDA was discontinued due to adverse reactions in 11% of patients. Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (greater than or equal to 1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients. The most frequent serious adverse reactions (greater than or equal to 2%) were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

Immune-related adverse reactions that required systemic glucocorticoids occurred in 8% of patients, use of hormonal supplementation due to an immune-related adverse reaction occurred in 8% of patients, and 5% of patients required at least one steroid dose ?40 mg oral prednisone equivalent.

Table 14 summarizes adverse reactions in patients on KEYTRUDA in KEYNOTE-052.

Previously Treated Urothelial Carcinoma

The safety of KEYTRUDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma with disease progression following platinum-containing chemotherapy was investigated in KEYNOTE-045. KEYNOTE-045 was a multicenter, open-label, randomized (1:1), active-controlled trial in which 266 patients received KEYTRUDA 200 mg every 3 weeks or investigator’s choice of chemotherapy (n=255), consisting of paclitaxel (n=84), docetaxel (n=84) or vinflunine (n=87). Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible.

The median duration of exposure was 3.5 months (range: 1 day to 20 months) in patients who received KEYTRUDA and 1.5 months (range: 1 day to 14 months) in patients who received chemotherapy.

KEYTRUDA was discontinued due to adverse reactions in 8% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA occurred in 20% of patients; the most common (greater than or equal to 1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (greater than or equal to 2%) in KEYTRUDA-treated patients were urinary tract infection, pneumonia, anemia, and pneumonitis.

Tables 15 and 16 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-045.

Gastric Cancer

Among the 259 patients with gastric cancer enrolled in KEYNOTE-059, the median duration of exposure to KEYTRUDA was 2.1 months (range: 1 day to 21.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible. Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC.

Cervical Cancer

Among the 98 patients with cervical cancer enrolled in Cohort E of KEYNOTE-158, the median duration of exposure to KEYTRUDA was 2.9 months (range: 1 day to 22.1 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.

KEYTRUDA was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported included anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections [except UTIs] (4.1%).

Tables 17 and 18 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-158.

Other laboratory abnormalities occurring in ?10% of patients receiving KEYTRUDA were hypophosphatemia (19% all Grades; 6% Grades 3-4), increased INR (19% all Grades; 0% Grades 3-4), hypercalcemia (14% all Grades; 2.6% Grades 3-4), platelet count decreased (14% all Grades; 1.3% Grades 3-4), activated partial thromboplastin time prolonged (14% all Grades; 0% Grades 3-4), hypoglycemia (13% all Grades; 1.3% Grades 3-4), white blood cell decreased (13% all Grades; 2.6% Grades 3-4), and hyperkalemia (13% all Grades; 1.3% Grades 3-4).

HCC

Among the 104 patients with HCC who received KEYTRUDA in KEYNOTE-224, the median duration of exposure to KEYTRUDA was 4.2 months (range: 1 day to 1.5 years). Adverse reactions occurring in patients with HCC were generally similar to those in patients with melanoma or NSCLC, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

MCC

Among the 50 patients with MCC enrolled in KEYNOTE-017, the median duration of exposure to KEYTRUDA was 6.6 months (range 1 day to 23.6 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MCC were similar to those occurring in patients with melanoma or NSCLC. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

...

Data

Animal Data

Animal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development. A literature-based asessment of the effects of the PD-1 pathway on reproduction demonstrated that a central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering KEYTRUDA during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 knockout mice. Based on its mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing immune-mediated disorders or of altering the normal immune response.

8.2 Lactation

(Additions and/or revisions are underlined)

Risk Summary

There are no data on the presence of pembrolizumab in either animal or human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with KEYTRUDA and for 4 months after the final dose.

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions are underlined)

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating KEYTRUDA.

Contraception

BKEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for at least 4 months following the final dose.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

The safety and effectiveness of KEYTRUDA have been established in pediatric patients with cHL, PMBCL, and MSI-H cancer. Use of KEYTRUDA in pediatric patients with cHL, PMBCL, and MSI-H cancers is supported by evidence from adequate and well-controlled studies of KEYTRUDA in adults with additional pharmacokinetic and safety data in pediatric patients.

There is limited experience with KEYTRUDA in pediatric patients. In a trial (NCT02332668), 40 pediatric patients (16 children ages 2 years to less than 12 years and 24 adolescents ages 12 years to 18 years) with various cancers, including unapproved usages were administered KEYTRUDA 2 mg/kg every

3 weeks. Patients received KEYTRUDA for a median of 3 doses (range: 1-17 doses), with 34 patients (85%) receiving KEYTRUDA for 2 doses or more.

The safety profile in these pediatric patients was similar to that seen in adults; adverse reactions that occurred at a higher rate (?15% difference) in pediatric patients when compared to adults <65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), increased transaminases (28%) and

hyponatremia (18%).

The concentrations of pembrolizumab in pediatric patients were comparable to those observed in adult patients at the same dose regimen of 2 mg/kg every 3 weeks.

The safety and effectiveness of KEYTRUDA in pediatric patients have not been established in the other approved indications.

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17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Immune-Mediated Adverse Reactions

Inform patients of the risk of immune-mediated adverse reactions that may be severe or fatal, may occur after discontinuation of treatment, and may require corticosteroid treatment and interruption or discontinuation of KEYTRUDA. These reactions may include:

…

Infusion-Related Reactions

Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion- related reactions.
Complications of Allogeneic HSCT
Advise patients of the risk of post-allogeneic hematopoietic stem cell transplantation complications.
Embryo-Fetal Toxicity
Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose.
Lactation
Advise women not to breastfeed during treatment with KEYTRUDA and for 4 months after the final dose.
Laboratory Tests
Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests.

MEDICATION GUIDE

(Additions and/or revisions are underlined)

…

What should I tell my doctor before receiving KEYTRUDA? Before you receive KEYTRUDA, tell your doctor if you:

have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
have received an organ transplant, such as a kidney or liver
have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
have lung or breathing problems
have liver problems
have any other medical problems
are pregnant or plan to become pregnant

KEYTRUDA can harm your unborn baby.
Females who are able to become pregnant:
Your doctor will give you a pregnancy test before you start treatment with KEYTRUDA.
You should use an effective method of birth control during and for at least 4 months after the final dose of KEYTRUDA. Talk to your doctor about birth control methods that you can use during this time.
Tell your doctor right away if you think you may be pregnant or if you become pregnant during treatment with KEYTRUDA.

…

What are the possible side effects of KEYTRUDA?

KEYTRUDA can cause serious side effects. See “What is the most important information I should know about KEYTRUDA?”

Common side effects of KEYTRUDA when used alone include: feeling tired, pain, including pain in muscles, bones or joints and stomach-area (abdominal) pain, decreased appetite, itching, diarrhea, nausea, rash, fever, cough, shortness of breath, and constipation.

Common side effects of KEYTRUDA when given with certain chemotherapy medicines include: feeling tired or weak, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, trouble breathing, fever, hair loss, and inflammation of the nerves that may cause pain, weakness, and paralysis in the arms and legs.

In children, feeling tired, vomiting and stomach-area (abdominal) pain, and increased levels of liver enzymes and decreased levels of salt (sodium) in the blood are more common than in adults.

These are not all the possible side effects of KEYTRUDA. For more information, ask your doctor or pharmacist. Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

10/30/2018 (SUPPL-41)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

…

First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or nab- paclitaxel chemotherapy

The safety of KEYTRUDA in combination with carboplatin and investigator’s choice of either paclitaxel or nab-paclitaxel was investigated in Study KEYNOTE-407, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in 558 patients with previously untreated, metastatic squamous NSCLC. Safety data are available for the first 203 patients who received KEYTRUDA and chemotherapy (n=101) or placebo and chemotherapy (n=102). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to KEYTRUDA was 7 months (range: 1 day to 12 months). Sixty-one percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for greather than or equal to 6 months. A total of 139 of 203 patients (68%) received paclitaxel and 64 patients (32%) received nab-paclitaxel in combination with carboplatin. The study population characteristics were: median age of 65 years (range: 40 to 83); 52% age 65 or older; 78% male; 83% White; and 9% with history of brain metastases.

KEYTRUDA was discontinued for adverse reactions in 15% of patients, with no single type of adverse reaction accounting for the majority. Adverse reactions leading to interruption of KEYTRUDA occurred in 43% of patients; the most common (greater than or equal to 2%) were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%). The most frequent (greater thatn or equal to 2%) serious adverse reactions were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%). The adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs. 36%) and peripheral neuropathy (31% vs. 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

…

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

a kind of skin cancer called melanoma that has spread or cannot be removed by surgery (advanced melanoma).
a kind of lung cancer called non-small cell lung cancer (NSCLC).
- KEYTRUDA may be used with the chemotherapy medicines pemetrexed and a platinum as your first treatment when your lung cancer:
  - has spread (advanced NSCLC), and
  - is a type called “nonsquamous”, and
  - your tumor does not have an abnormal “EGFR” or “ALK” gene.
- KEYTRUDA may be used with the chemotherapy medicines carboplatin and either paclitaxel or nab-paclitaxel as your first treatment when your lung cancer:
  - has spread (advanced NSCLC), and
  - is a type called “squamous”.

…

08/20/2018 (SUPPL-35)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Immune-Mediated Nephritis and Renal Dysfunction

(Additions and/or revisions are underlined)

…Nephritis occurred in 1.7% of 405 patients receiving KEYTRUDA in combination with pemetrexed and platinum in the KEYNOTE-189 study, including Grade 3 (1%) and Grade 4 (0.5%) nephritis. The median time to onset was 3.2 months (range: 16 days to 11.1 months) and the duration ranged from 1.6 to 16.8+ months. Six (86%) of the 7 patients received systemic corticosteroids, with all 6 receiving high-dose corticosteroids for a median duration of 3 days (range: 1 to 17 days) followed by a corticosteroid taper. Nephritis led to discontinuation of KEYTRUDA in 5 (1.2%) patients. Nephritis resolved in 2 (29%) of the 7 patients.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

…The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to KEYTRUDA as a single agent in 2799 patients in three randomized, open-label, active-controlled clinical trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial (KEYNOTE-001), which enrolled 655 patients with melanoma and 550 patients with NSCLC. In addition, these data reflect exposure to KEYTRUDA as a single agent in a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), which enrolled 192 patients with HNSCC and in two non-randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087), which enrolled 241 patients with cHL; in combination with chemotherapy in a randomized, active-controlled trial (KEYNOTE-189), which enrolled 405 patients with nonsquamous NSCLC; and in post-marketing use. Across all trials, KEYTRUDA was administered at doses of 2 mg/kg intravenously every 3 weeks, 10 mg/kg intravenously every 2 weeks, 10 mg/kg intravenously every 3 weeks, or 200 mg intravenously every 3 weeks. Among the 2799 patients, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more.

The data described in this section were obtained in five randomized, active-controlled clinical trials (KEYNOTE-002, KEYNOTE-006, KEYNOTE-010, KEYNOTE-045, and KEYNOTE-189) in which KEYTRUDA was administered to 912 patients with melanoma,1087 patients with NSCLC, and 542 patients with urothelial carcinoma, and six non-randomized, open-label trials (KEYNOTE-012, KEYNOTE-087, KEYNOTE-170, KEYNOTE-052, KEYNOTE-059, and KEYNOTE-158)…

NSCLC

First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapy The safety of KEYTRUDA in combination with pemetrexed and investigator’s choice of platinum (either carboplatin or cisplatin) was investigated in Study KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations. A total of 607 patients received KEYTRUDA 200 mg, pemetrexed and platinum every 3 weeks for 4 cycles followed by KEYTRUDA and pemetrexed (n=405) or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 7.2 months (range: 1 day to 20.1 months). Sixty percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for greater than or equal to 6 months. Seventy-two percent of patients received carboplatin. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 years or older, 59% male, 94% White and 3% Asian, and 18% with history of brain metastases at baseline.

KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (greater than or equal to 2%) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%), pneumonia (4%), increased blood creatinine (3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), increased ALT (2%), and pyrexia (2%).

Table 5 summarizes the adverse reactions that occurred in at least 20% of patients treated with KEYTRUDA.

Table 6 summarizes the laboratory abnormalities that worsened from baseline in at least 20% of patients treated with KEYTRUDA.

Previously Treated NSCLC

Table 8 summarizes the laboratory abnormalities that worsened from baseline in at least 20% of patients treated with KEYTRUDA.

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MEDICATION GUIDE KEYTRUDA (key-true-duh) (pembrolizumab)

(Additions and/or revisions are underlined)

What is KEYTRUDA?

KEYTRUDA may be used with the chemotherapy medicines pemetrexed and a platinum as your first treatment when your lung cancer:

your tumor does not have an abnormal “EGFR” or “ALK” gene.

06/19/2018 (SUPPL-43)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

a kind of bladder and urinary tract cancer called urothelial carcinoma. KEYTRUDA may be used when your bladder or urinary tract cancer:
- you are not able to receive chemotherapy that contains a medicine called cisplatin, and your tumor tests positive for PD-L1, or …

06/12/2018 (SUPPL-34)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Other Immune-Mediated Adverse Reactions

(Additions and/or revisions are underlined)

Immune mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA. While immune-mediated adverse reactions usually occur during treatment with PD-1/PD-L1 blocking antibodies, they may occur after discontinuation of treatment.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

The data described in this section were obtained in five randomized, open-label, active-controlled clinical trials (KEYNOTE-002, KEYNOTE-006, KEYNOTE-010, KEYNOTE-021, and KEYNOTE-045) in which KEYTRUDA was administered to 912 patients with melanoma, 741 patients with NSCLC, and 542 patients with urothelial carcinoma, and five non-randomized, open-label trials (KEYNOTE-012, KEYNOTE-087, KEYNOTE-052, KEYNOTE-059, and KEYNOTE-158) in which KEYTRUDA was administered to 192 patients with HNSCC, 210 patients with cHL, 370 patients with urothelial carcinoma, 259 patients with gastric cancer, and 98 patients with cervical cancer. In these trials, KEYTRUDA was administered at 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks.

Cervical Cancer

Among the 98 patients with cervical cancer enrolled in Cohort E of Study KEYNOTE-158, the median duration of exposure to KEYTRUDA was 2.9 months (range: 1 day to 22.1 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.

Table 14 summarizes the adverse reactions occurring in at least 10% of patients receiving KEYTRUDA.

Table 15 summarizes the laboratory abnormalities that occurred in at least 20% of patients receiving KEYTRUDA.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients of the risk of immune-mediated adverse reactions that may be severe or fatal, may occur after discontinuation of treatment, and may require corticosteroid treatment and interruption or discontinuation of KEYTRUDA…

KEYTRUDA® (key-true-duh) (pembrolizumab) for injection MEDICATION GUIDE

(Extensive changes; please refer to labeling)

11/29/2017 (SUPPL-31)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Increased Mortality in Patients with Multiple Myeloma when KEYTRUDA is Added to a Thalidomide Analogue and Dexamethasone

(Newly added subsection)

In two randomized clinical trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD- L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

07/27/2017 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Immune-Mediated Skin Adverse Reactions

(new subsection added)

Immune-mediated rashes, including SJS, TEN (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and exclude other causes. Based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

6 Adverse Reactions

(additions underlined)

The following adverse reactions are discussed in greater detail in other sections of the labeling.

Immune-mediated pneumonitis
Immune-mediated colitis
Immune-mediated hepatitis
Immune-mediated endocrinopathies
Immune-mediated nephritis and renal dysfunction
Immune-mediated skin adverse reactions
Other immune-mediated adverse reactions

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(additions underlined)

…

Call or see your doctor right away if you develop any symptoms of the following problems or these symptoms get worse:

…

Skin problems. Signs of skin problems may include:

rash
itching
blisters, peeling or skin sores
painful sores or ulcers in your mouth or in your nose, throat, or genital area
…

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Severe skin reactions: Advise patients to contact their healthcare provider immediately for any signs or symptoms of severe skin reactions, SJS or TEN.

…

07/27/2017 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Other Immune-Mediated Adverse Reactions

(additions underlined)

…

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA versus the risk of possible organ rejection in these patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(additions underlined)

…

Rejection of a transplanted organ. People who have had an organ transplant may have an increased risk of organ transplant rejection if they are treated with KEYTRUDA. Your doctor should tell you what signs and symptoms you should report and monitor you, depending on the type of organ transplant that you have had.

…

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Advise patients of the risk of solid organ transplant rejection and to contact their healthcare provider immediately for signs or symptoms of organ transplant rejection.
Advise patients of the risk of post-allogeneic hematopoietic stem cell transplantation complications.

…

05/23/2017 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Other Immune-Mediated Adverse Reactions

Addition is underlined:

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. These immune- mediated reactions may involve any organ system.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

There is limited experience with KEYTRUDA in pediatric patients. In a study, 40 pediatric patients

(16 children ages 2 years to less than 12 years) and 24 adolescents ages 12 years to 18 years with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumors were

administered KEYTRUDA 2 mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3 doses (range 1-17 doses), with 34 patients (85%) receiving KEYTRUDA for 2 doses or more.

The concentrations of pembrolizumab in pediatric patients were comparable to those observed in adult patients at the same dose regimen of 2 mg/kg every 3 weeks.

... Efficacy for pediatric patients with cHL or MSI-H cancers is extrapolated from the results in the respective adult populations.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

Addition of the following:

a kind of cancer that is shown by a laboratory test to be a microsatellite instability-high (MSI-H) or a mismatch repair deficient (dMMR) solid tumor. KEYTRUDA may be used in adults and children to treat:

cancer that has spread or cannot be removed by surgery (advanced cancer), and
has progressed following treatment, and you have no satisfactory treatment options, or
you have colon or rectal cancer, and you have received chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan but it did not work or is no longer working.

It is not known if KEYTRUDA is safe and effective in children with MSI-H cancers of the brain or spinal cord (central nervous system cancers).

05/18/2017 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Infusion-Related Reactions

(Additions and/or revisions are underlined)

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients receiving KEYTRUDA.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions are underlined)

There is limited experience in pediatric patients. KEYTRUDA was evaluated in a study of 40 pediatric patients with advanced melanoma, PD-L1 positive advanced, relapsed, or refractory solid tumors or lymphoma; 2 of the 40 had hematologic malignancies, 1 of whom had cHL…

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Of 3991 patients with melanoma, NSCLC, HNSCC, cHL or urothelial carcinoma who were treated with KEYTRUDA in clinical studies, 46% were 65 years and over and 16% were 75 years and over…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE KEYTRUDA® (key-true-duh) (pembrolizumab) injection

(Additions and/or revisions are underlined)

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

• KEYTRUDA may be used alone when your lung cancer:

o tests positive for “PD-L1” and,

as your first treatment if you have not received chemotherapy to treat your advanced NSCLC and your tumor does not have an abnormal “EGFR” or “ALK” gene…
• KEYTRUDA may be used with the chemotherapy medicines pemetrexed and carboplatin as your first treatment when your lung cancer:
o has spread (advanced NSCLC) and
o is a type of lung cancer called “nonsquamous”.
a kind of bladder and urinary tract cancer called urothelial carcinoma. KEYTRUDA may be used when your bladder or urinary tract cancer:
o has spread or cannot be removed by surgery (advanced urothelial cancer) and,
o you are not able to receive chemotherapy that contains a medicine called cisplatin, or
o you have received chemotherapy that contains platinum, and it did not work or is no longer working.
What are the possible side effects of KEYTRUDA?
KEYTRUDA can cause serious side effects. See “What is the most important information I should know about KEYTRUDA?”
Common side effects of KEYTRUDA when used alone include: feeling tired, itching, diarrhea…

10/24/2016 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Immune-Mediated Pneumonitis (addition underlined)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases.

Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), Grade 2 (1.3%), Grade 3 (0.9%), Grade 4 (0.3%), and Grade 5 (0.1%) pneumonitis. The median time to onset was 3.3 months (range: 2 days to 19.3 months), and the median duration was 1.5 months (range: 1 day to 17.2+ months). Sixty-three (67%) of the 94 patients received systemic corticosteroids, with 50 of the 63 receiving high-dose corticosteroids for a median duration of 8 days (range: 1 day to 10.1 months) followed by a corticosteroid taper. Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (6.9%) than in patients who did not receive prior thoracic radiation (2.9%). Pneumonitis led to discontinuation of KEYTRUDA in 36 (1.3%) patients. Pneumonitis resolved in 55 (59%) of the 94 patients.

5.2 Immune-Mediated Colitis (addition underlined)

KEYTRUDA can cause immune-mediated colitis.

Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), Grade 3 (1.1%), and Grade 4 (<0.1%) colitis. The median time to onset was 3.5 months (range: 10 days to 16.2 months), and the median duration was 1.3 months (range: 1 day to 8.7+ months). Thirty-three (69%) of the 48 patients received systemic corticosteroids, with 27 of the 33 requiring high-dose corticosteroids for a median duration of 7 days (range: 1 day to 5.3 months) followed by a corticosteroid taper. Colitis led to discontinuation of KEYTRUDA in 15 (0.5%) patients. Colitis resolved in 41 (85%) of the 48 patients.

5.3 Immune-Mediated Hepatitis (addition underlined)

KEYTRUDA can cause immune-mediated hepatitis.

Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), Grade 3 (0.4%), and Grade 4 (<0.1%) hepatitis. The median time to onset was 1.3 months (range: 8 days to 21.4 months), and the median duration was 1.8 months (range: 8 days to 20.9+ months). Thirteen (68%) of the 19 patients received systemic corticosteroids, with 12 of the 13 receiving high-dose corticosteroids for a median duration of 5 days (range: 1 to 26 days) followed by a corticosteroid taper. Hepatitis led to discontinuation of KEYTRUDA in 6 (0.2%) patients. Hepatitis resolved in 15 (79%) of the 1619 patients.

5.4 Immune-Mediated Endocrinopathies (addition underlined)

Hypophysitis

KEYTRUDA can cause hypophysitis.

Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), Grade 3 (0.3%), and Grade 4 (<0.1%) hypophysitis. The median time to onset was 3.7 months (range: 1 day to 11.9 months), and the median duration was 4.7 months (range: 8+ days to 12.7+ months). Sixteen (94%) of the 17 patients received systemic corticosteroids, with 6 of the 16 receiving high-dose corticosteroids. Hypophysitis led to discontinuation of KEYTRUDA in 4 (0.1%) patients. Hypophysitis resolved in 7 (41%) of the 17 patients.

Thyroid Disorders

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism and thyroiditis.

Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and Grade 3 (0.1%) hyperthyroidism. The median time to onset was 1.4 months (range: 1 day to 21.9 months), and the median duration was 2.1 months (range: 3 days to 15.0+ months). Hyperthyroidism led to discontinuation of KEYTRUDA in 2 (<0.1%) patients. Hyperthyroidism resolved in 71 (74%) of the 96 patients.

Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and Grade 3 (0.1%) hypothyroidism. The median time to onset was 3.5 months (range: 1 day to hs), and the median duration was not reached (range: 2 days to 27.7+ months). Hypothyroidism led to discontinuation of KEYTRUDA in 1 (<0.1%) patient. Hypothyroidism resolved in 48 (20%) of the 237 patients. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC occurring in 28 (15%) of 192 patients receiving KEYTRUDA, including Grade 3 (0.5%) hypothyroidism.

Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. The median time of onset was 1.2 months (range: 0.5 to 3.5 months).

Type 1 Diabetes mellitus

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients receiving KEYTRUDA.

5.5 Immune-Mediated Nephritis and Renal Dysfunction (addition underlined)

KEYTRUDA can cause immune-mediated nephritis.

Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), Grade 3 (0.1%), and Grade 4 (<0.1%) nephritis. The median time to onset was 5.1 months (range: 12 days to 12.8 months), and the median duration was 3.3 months (range: 12 days to3.3 8.9+ months). Eight (89%) of the 9 patients received systemic corticosteroids, with 7 of the 8 receiving high-dose corticosteroids for a median duration of 15 days (range: 3 days to 4.0 months) followed by a corticosteroid taper. Nephritis led to discontinuation of KEYTRUDA in 3 (0.1%) patients. Nephritis resolved in 5 (56%) of the 9 patients.

5.6 Other Immune-Mediated Adverse Reactions (addition underlined)

KEYTRUDA can cause other clinically important immune-mediated adverse reactions.

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients treated with KEYTRUDA: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%)…

5.7 Infusion-Related Reactions (addition underlined)

KEYTRUDA can cause severe or life-threatening infusion-related reactions, which have been reported in 6 (0.2%) of 2799 patients receiving KEYTRUDA.

6 Adverse Reactions

6.1 Clinical Trials Experience (addition underlined)

The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to KEYTRUDA in 2799 patients in three randomized, open-label, active-controlled clinical trials, which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial which enrolled 655 patients with melanoma and 550 patients with NSCLC … Among the 2799 patients, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more.

The data described below were obtained in three randomized, open-label, active-controlled clinical trials which enrolled 912 patients with melanoma, 682 patients with NSCLC, and one non-randomized, open- label, multi-cohort trial which enrolled 192 patients with HNSCC.

NSCLC

KEYTRUDA was The safety of KEYTRUDA was investigated in Trial 3, a multicenter, open-label, randomized (1:1:1), active-controlled trial, in patients with advanced NSCLC who had documented disease progression following treatment with platinum-based chemotherapy and, if positive for EGFR or ALK genetic aberrations, appropriate therapy for these aberrations. A total of 991 patients received KEYTRUDA 2 mg/kg (n=339) or 10 mg/kg (n=343) every 3 weeks or docetaxel (n=309) at 75 mg/m2 every 3 weeks. Patients with autoimmune disease, medical conditions that required systemic corticosteroids or other immunosuppressive medication, or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 3.5 months (range 1 day to 20.8 months). The data described below reflect exposure to KEYTRUDA 2 mg/kg in 31% of patients exposed to KEYTRUDA for ?6 months. In the KEYTRUDA 10 mg/kg arm, 34% of patients were exposed to KEYTRUDA for ?6 months.

The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 years or older, 61% male, 72% white and 21% Asian, 8% with advanced localized disease, 91% with metastatic disease, and 15% with history of brain metastases. Twenty-nine percent received two or more prior systemic treatments for advanced or metastatic disease.

Table 5 summarizes the adverse reactions that occurred in at least 10% of patients treated with KEYTRUDA.

Table 5: Selected* Adverse Reactions Occurring in ?10% of Patients Receiving KEYTRUDA (Trial 3) (Revised – Refer to label)

Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%).

Table 6: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ?20% of NSCLC Patients Receiving KEYTRUDA (Trial 3) (Revised- Refer to label)

Other laboratory abnormalities occurring in ?20% of patients receiving KEYTRUDA were hyperglycemia (44% all Grades; 4.1% Grades 3-4), anemia (37% all Grades; 3.8% Grades 3-4), hypertriglyceridemia (36% all Grades; 1.8% Grades 3-4), lymphopenia (35% all Grades; 9% Grades 3-4), hypoalbuminemia (34% all Grades; 1.6% Grades 3-4), and hypercholesterolemia (20% all Grades; 0.7% Grades 3-4).

6.2 Immunogenicity (addition underlined)

…In clinical studies in patients treated with pembrolizumab at a dose of 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every two or three weeks, 26 (2.0%) of 1289 evaluable patients tested positive for treatment-emergent anti-pembrolizumab antibodies. Among the 26 patients who tested positive for treatment emergent anti-pembrolizumab antibodies, only 4 patients were tested for neutralizing antibodies and one was positive…

8 Use in Specific Populations

8.5 Geriatric Use (addition underlined)

Of 3145 patients with melanoma, NSCLC, or HNSCC who were treated with KEYTRUDA in clinical studies, 43% were 65 years and over and 12% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE (addition underlined)

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

• a kind of skin cancer called melanoma. KEYTRUDA may be used when your melanoma has spread or cannot be removed by surgery (advanced melanoma).

• a kind of lung cancer called non-small cell lung cancer (NSCLC). KEYTRUDA may be used when your lung cancer:

has spread (advanced NSCLC) and,
tests positive for “PD-L1” and,

you have not received chemotherapy to treat your advanced NSCLC and your tumor does not have an abnormal “EGFR” or “ALK” gene, or
you have received chemotherapy that contains platinum to treat your advanced NSCLC, and it did not work or it is no longer working, and

if your tumor has an abnormal “EGFR” or “ALK” gene, you have also received an EGFR or ALK inhibitor medicine and it did not work or is no longer working.

• a kind of cancer called head and neck squamous cell cancer (HNSCC). KEYTRUDA may be used when your HNSCC:

has returned or spread (advanced HNSCC) and
you have received chemotherapy that contains platinum to treat your advanced HNSCC, and it did not work or is no longer working.

10/24/2016 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Immune-Mediated Pneumonitis (addition underlined)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases.

1 day to 17.2+ months). Sixty-three (67%) of the 94 patients received systemic corticosteroids, with 50 of the 63 receiving high-dose corticosteroids for a median duration of 8 days (range: 1 day to 10.1 months) followed by a corticosteroid taper. Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (6.9%) than in patients who did not receive prior thoracic radiation (2.9%). Pneumonitis led to discontinuation of KEYTRUDA in 36 (1.3%) patients. Pneumonitis resolved in 55 (59%) of the 94 patients.

5.2 Immune-Mediated Colitis (addition underlined)

KEYTRUDA can cause immune-mediated colitis.

5.3 Immune-Mediated Hepatitis (addition underlined)

KEYTRUDA can cause immune-mediated hepatitis.

5.4 Immune-Mediated Endocrinopathies (addition underlined)

Hypophysitis

KEYTRUDA can cause hypophysitis.

Thyroid Disorders

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism and thyroiditis.

Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%)

and Grade 3 (0.1%) hyperthyroidism. The median time to onset was 1.4 months (range: 1 day to

21.9 months), and the median duration was 2.1 months (range: 3 days to 15.0+ months). Hyperthyroidism led to discontinuation of KEYTRUDA in 2 (<0.1%) patients. Hyperthyroidism resolved in 71 (74%) of the 96 patients.

Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%)

and Grade 3 (0.1%) hypothyroidism. The median time to onset was 3.5 months (range: 1 day to

hs), and the median duration was not reached (range: 2 days to 27.7+ months). Hypothyroidism led to discontinuation of KEYTRUDA in 1 (<0.1%) patient. Hypothyroidism resolved in 48 (20%) of the

237 patients. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC

occurring in 28 (15%) of 192 patients receiving KEYTRUDA, including Grade 3 (0.5%) hypothyroidism.

Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. The median time of onset was 1.2 months (range: 0.5 to 3.5 months).

Type 1 Diabetes mellitus

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients receiving KEYTRUDA.

5.5 Immune-Mediated Nephritis and Renal Dysfunction (addition underlined)

KEYTRUDA can cause immune-mediated nephritis.

5.6 Other Immune-Mediated Adverse Reactions (addition underlined)

KEYTRUDA can cause other clinically important immune-mediated adverse reactions.

5.7 Infusion-Related Reactions (addition underlined)

KEYTRUDA can cause severe or life-threatening infusion-related reactions, which have been reported in 6 (0.2%) of 2799 patients receiving KEYTRUDA.

6 Adverse Reactions

6.1 Clinical Trials Experience (addition underlined)

NSCLC

Table 5 summarizes the adverse reactions that occurred in at least 10% of patients treated with KEYTRUDA.

Table 5: Selected* Adverse Reactions Occurring in ?10% of Patients Receiving KEYTRUDA (Trial 3) (Revised – Refer to label)

Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%).

Table 6: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ?20% of NSCLC Patients Receiving KEYTRUDA (Trial 3) (Revised- Refer to label)

6.2 Immunogenicity (addition underlined)

8 Use in Specific Populations

8.5 Geriatric Use (addition underlined)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE (addition underlined)

What is KEYTRUDA?

KEYTRUDA is a prescription medicine used to treat:

• a kind of skin cancer called melanoma. KEYTRUDA may be used when your melanoma has spread or cannot be

removed by surgery (advanced melanoma).

• a kind of lung cancer called non-small cell lung cancer (NSCLC). KEYTRUDA may be used when your lung cancer:

has spread (advanced NSCLC) and,
tests positive for “PD-L1” and,

you have not received chemotherapy to treat your advanced NSCLC and your tumor does not have an abnormal “EGFR” or “ALK” gene, or
you have received chemotherapy that contains platinum to treat your advanced NSCLC, and it did not work or it is no longer working, and
if your tumor has an abnormal “EGFR” or “ALK” gene, you have also received an EGFR or ALK inhibitor medicine and it did not work or is no longer working.

• a kind of cancer called head and neck squamous cell cancer (HNSCC). KEYTRUDA may be used when your

HNSCC:

has returned or spread (advanced HNSCC) and
you have received chemotherapy that contains platinum to treat your advanced HNSCC, and it did not work or is no longer working.

08/05/2016 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

Immune-Mediated Endocrinopathies

In all melanoma instances where Trials 1, 2, and 6 had been previously noted, it has been updated to read Trials 1,2, and 3

Under all NSCLC sections, in all instances where Trial 1 is noted, it has been updated to Trial 3

Thyroid Disorders

HNSCC (bolded addition)

New or worsening hypothyroidism occurred in 28 (14.6%) of 192 patients receiving KEYTRUDA in Trial 4, including Grade 3 (0.5%) hypothyroidism. Of these 28 patients, 15 had no prior history of hypothyroidism.

Immune-Mediated Nephritis and Renal Dysfunction

In all melanoma instances where Trials 1, 2, and 6 had been previously noted, it has been updated to read Trials 1,2, and 3

Under all NSCLC sections, in all instances where Trial 1 is noted, it has been updated to Trial 3

Infusion-Related Reactions

In all melanoma instances where Trials 1, 2, and 6 had been previously noted, it has been updated to read Trials 1,2, and 3

Under all NSCLC sections, in all instances where Trial 1 is noted, it has been updated to Trial 3

Other Immune-Mediated Adverse Reactions

In all melanoma instances where Trials 1, 2, and 6 had been previously noted, it has been updated to read Trials 1,2, and 3

Under all NSCLC sections, in all instances where Trial 1 is noted, it has been updated to Trial 3

6 Adverse Reactions

Clinical Trials Experience (additions are bolded)

The data described below were obtained in two randomized, open-label, active-controlled clinical trials which enrolled 912 patients with unresectable or metastatic melanoma and two non-randomized, open label, multi-cohort trials which enrolled 550 patients with NSCLC and 192 patients with HNSCC. In these trials, KEYTRUDA was administered at 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks.

HNSCC (additional subsection)

Among the 192 patients with HNSCC enrolled in Trial 4, the median duration of exposure to KEYTRUDA was 3.3 months (range: 1 day to 27.9 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible for Trial 4. The median age of patients was 60 years (range: 20 to 84), 35% were age 65 years or older, 83% were male, 77% were White, 15% were Asian, and 5% were Black. Sixty-one percent of patients had two or more lines of therapy in the recurrent or metastatic setting, and 95% had prior radiation therapy. Baseline ECOG PS was 0 (30%) or 1 (70%) and 86% had M1 disease.

KEYTRUDA was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The incidence of adverse reactions, including serious adverse reactions, was similar between dosage regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks); these data were pooled. The most common adverse reactions (occurring in =20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3-4) and new or worsening hypothyroidism.

Immunogenicity (additions are bolded)

In clinical studies in patients treated with pembrolizumab at a dose of 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every two or three weeks, 20 (1.7%) of 1149 evaluable patients tested positive for treatment-emergent anti-pembrolizumab antibodies. Among the 20 patients who tested positive for treatment emergent anti-pembrolizumab antibodies, only 4 patients were tested for neutralizing antibodies and one was positive. There was no evidence of an altered pharmacokinetic profile or increased infusion reactions with anti-pembrolizumab binding antibody development.

Melanoma

Ipilimumab-Naive Melanoma (Trial 1)

Ipilimumab-Refractory Melanoma (Trial 2)

NSCLC

Among the 550 patients with metastatic NSCLC enrolled in Trial 3

8 Use in Specific Populations

Geriatric Use (updates are bolded)

Of 2309 patients treated with KEYTRUDA in clinical studies, 43% were 65 years and over.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MG - What are the possible side effects of KEYTRUDA?

KEYTRUDA can cause serious side effects. See “What is the most important information I should know about

KEYTRUDA?”

Common side effects of KEYTRUDA include:

in people who receive KEYTRUDA: feeling tired, decreased appetite, and shortness of breath (addition bolded)

These are not all the possible side effects of KEYTRUDA. For more information, ask your doctor or pharmacist.

MG - What is KEYTRUDA? (addition of the following)

A kind of cancer called head and neck squamous cell cancer (HNSCC). KEYTRUDA may be used when your HNSCC:

has returned or spread and
you have tried chemotherapy that contains platinum, and it did not work or is no longer working.

MG - What is the most important information I should know about KEYTRUDA?

KEYTRUDA is a medicine that may treat your melanoma, lung cancer, or head and neck cancer (addition bolded)