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SELECT ADVERSE REACTIONS
REPORTED WITH KEYTRUDA

Selected Immune-mediated Adverse Reactions

Adverse reaction KEYTRUDA
(N=2,799)
All grades
% (n)		 Grade 3
%		 Grade 4
%		 Grade 5
%
Pneumonitis 3.4 (94) 0.9 0.3 0.1
Pneumonitis in
NSCLC (N=790)		 8.2 (65) 3.2a –
Pneumonitis in
HNSCC
(monotherapy) (N=300)		 6.0 (18) 1.3 – 0.3
Pneumonitis in
HNSCC
(combination with platinum and FU) (N=276)		 5.4 (15) 1.1 – 0.4
Colitis 1.7 (48) 1.1 <0.1 –
Hepatitis 0.7 (19) 0.4 <0.1 –
Adrenal insufficiency 0.8 (22) 0.3 <0.1 –
Hypophysitis 0.6 (17) 0.3 <0.1 –
Hyperthyroidism 3.4 (96) 0.1 – –
Hypothyroidism 8.5 (237) 0.1 – –
Hypothyroidism in
HNSCC
(monotherapy and combination with platinum and FU) (N=1,185)		 16 (188) 0.3 – –
Nephritis 0.3 (9) 0.1 <0.1 –

aGrades 3–4.

  • Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%).
  • Pneumonitis occurred in 17% of 790 patients with advanced NSCLC and a history of prior thoracic radiation vs 7.7% of patients who did not receive prior thoracic radiation.
  • Of 2,799 patients receiving KEYTRUDA, immune-mediated type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 6 (0.2%) patients, and thyroiditis occurred in 16 (0.6%) patients.
  • Nephritis occurred in 1.7% (7/405) of patients with mNSCLC receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy.
  • 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. Grades 3 and 4 increased ALT and AST were seen in 20% and 13% of patients, respectively.
  • Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur with KEYTRUDA.
  • The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2,799 patients treated with KEYTRUDA: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.
  • Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients.
  • KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2,799) of patients.
  • Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed GVHD (1 fatal case) and 2 (9%) developed severe hepatic VOD after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD‑1 receptor–blocking antibody before transplantation.
  • In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after treatment with KEYTRUDA.
  • In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD‑1 or PD‑L1 blocking antibody in this combination is not recommended outside of controlled trials.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; cHL = classical Hodgkin lymphoma; FU = fluorouracil; GVHD = graft-versus-host disease; HNSCC = head and neck squamous cell carcinoma; HSCT = hematopoietic stem cell transplantation; mNSCLC = metastatic NSCLC; NSCLC = non–small cell lung cancer; PD‑1 = programmed death receptor-1; PD‑L1 = programmed death ligand 1; VOD = veno-occlusive disease.

SAFETY DATA FROM KEYNOTE-189

  • Permanent discontinuation rate due to adverse reactions: 20% with KEYTRUDA
    • Most common adverse reactions resulting in discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%).

Adverse Reactions Occurring in ≥20% of Patients in the KEYNOTE-189 Trial

Adverse reactions All gradesb
% 		Grades 3–4b
%
KEYTRUDA + plat/pem
(n=405) 		Plat/pem
(n=202) 		KEYTRUDA + plat/pem
(n=405) 		Plat/pem
(n=202)
Gastrointestinal
Nausea
56 52 3.5 3.5
Constipation
35 32 1 0.5
Diarrhea
31 21 5 3
Vomiting
24 23 3.7 3
General
Fatiguec
56 58 12 6
Pyrexia
20 15 0.2 0
Metabolism and Nutrition
Decreased
appetite
28 30 1.5 0.5
Skin and Subcutaneous Tissue
Rashd
25 17 2 2.5
Respiratory, Thoracic, and Mediastinal
Cough
21 28 0 0
Dyspnea
21 26 3.7 5

bGraded per NCI-CTCAE v4.03.

cIncludes asthenia and fatigue.

dIncludes genital rash, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, and rash pustular.

plat/pem = cisplatin or carboplatin and pemetrexed; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Events.

 

SAFETY DATA FROM KEYNOTE-407

  • KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%).
  • 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.

SAFETY DATA FROM KEYNOTE-042

  • Safety was evaluated in 1,251 patients with previously untreated stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC. All patients had tumors expressing PD-L1.
  • Permanent discontinuation rate due to adverse reactions: 19% with KEYTRUDA.
  • Most common adverse reactions resulting in discontinuation were pneumonitis (3.0%), death due to unknown cause (1.6%), and pneumonia (1.4%).

Adverse Reactions Occurring in ≥10% of Patients in KEYNOTE-042

Adverse reactions All gradese
% 		Grades 3–5e
%
KEYTRUDA
(n=636) 		Chemotherapy
(n=615) 		KEYTRUDA
(n=636) 		Chemotherapy
(n=615)
General
Fatiguef
25 33 3.1 3.9
Pyrexia
10 8 0.3 0
Metabolism and Nutritional
Decreased appetite
17 21 1.7 1.5
Respiratory, Thoracic, and Mediastinal
Dyspnea
17 11 2.0 0.8
Cough
16 11 0.2 0.3
Skin and Subcutaneous Tissue
Rashg
15 8 1.3 0.2
Gastrointestinal
Constipation
12 21 0 0.2
Diarrhea
12 12 0.8 0.5
Nausea
12 32 0.5 1.1
Endocrine
Hypothyroidism
12 1.5 0.2 0
Infections
Pneumonia
12 9 7 6
Investigations
Weight loss
10 7 0.9 0.2

eGraded per NCI-CTCAE v4.03.

fIncludes fatigue and asthenia.

gIncludes rash, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, and rash pustular.

SAFETY DATA FROM KEYNOTE‑010

  • KEYTRUDA 2 mg/kg or 10 mg/kg Q3W was discontinued due to adverse reactions in 8% of 682 patients with mNSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%).
  • The adverse reaction profile was similar for the 2 mg/kg and 10 mg/kg dose of KEYTRUDA; therefore, summary safety results are provided in a pooled analysis (n=682).

Selected Adverse Reactions Occurring in ≥10% of Patients Treated With KEYTRUDA and at the Same or Higher Incidence Than in the Docetaxel Arm

Adverse reactions All gradesh
% 		Grades 3–4h
%
KEYTRUDA 2 mg/kg or 10 mg/kg Q3W (n=682) Docetaxel 75 mg/m2 Q3W (n=309) KEYTRUDA 2 mg/kg or 10 mg/kg Q3W (n=682) Docetaxel 75 mg/m2 Q3W (n=309)
Metabolism and Nutrition
Decreased
appetite
25 23 1.5 2.6
Respiratory, Thoracic, and Mediastinal
Dyspnea
23 20 3.7 2.6
Cough
19 14 0.6 0
Gastrointestinal
Nausea
20 18 1.3 0.6
Constipation
15 12 0.6 0.6
Vomiting
13 10 0.9 0.6
Skin and Subcutaneous Tissue
Rashi
17 8 0.4 0
Pruritus
11 3 0 0.3
Musculoskeletal and Connective Tissue
Arthralgia
11 9 1 0.3
Back pain
11 8 1.5 0.3
  • Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%), asthenia (11%), and pyrexia (11%).

hGraded per NCI-CTCAE v4.0.

iIncludes rash, rash erythematous, rash macular, rash maculopapular, rash papular, and rash pruritic.

Q3W = every 3 weeks.


INDICATIONS

  • ADVANCED MELANOMA:KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.
  • ADJUVANT THERAPY:KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.
  • FIRST-LINE COMBINATION THERAPY IN NONSQUAMOUS mNSCLC:KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non‒small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
  • FIRST-LINE COMBINATION THERAPY IN SQUAMOUS mNSCLC:KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein‑bound, is indicated for the first‑line treatment of patients with metastatic squamous non–small cell lung cancer (NSCLC)NSCLC.
  • FIRST-LINE MONOTHERAPY IN NONSQUAMOUS AND SQUAMOUS ADVANCED NSCLC:KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.
  • SECOND-LINE OR GREATER MONOTHERAPY IN NONSQUAMOUS AND SQUAMOUS mNSCLC:KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.
  • THIRD-LINE OR GREATER mSCLC:KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
  • FIRST-LINE COMBINATION THERAPY IN METASTATIC OR UNRESECTABLE, RECURRENT HNSCC:KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).
  • FIRST-LINE MONOTHERAPY IN METASTATIC OR UNRESECTABLE, RECURRENT HNSCC:KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) ≥1] as determined by an FDA-approved test.
  • SECOND-LINE MONOTHERAPY IN RECURRENT OR METASTATIC HNSCC:KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.
  • RECURRENT OR METASTATIC HEAD AND NECK SQUAMOUS CELL CARCINOMA ON OR AFTER PLATINUM-CONTAINING CHEMOTHERAPY:KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.
  • REFRACTORY OR RELAPSED cHL:KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • REFRACTORY OR RELAPSED PMBCL:KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.
  • FIRST-LINE MONOTHERAPY—CISPLATIN (PD-L1 EXPRESSION [COMBINED POSITIVE SCORE (CPS) ≥10]) AND PLATINUM CHEMOTHERAPY INELIGIBLE:KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) ≥10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
  • SECOND-LINE MONOTHERAPY—POST–PLATINUM FAILURE:KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
  • FIRST-LINE MONOTHERAPY—CISPLATIN (PD-L1 EXPRESSION [COMBINED POSITIVE SCORE (CPS) ≥10]) AND PLATINUM CHEMOTHERAPY INELIGIBLE:KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) ≥10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
  • SECOND-LINE MONOTHERAPY—POST–PLATINUM FAILURE:KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
  • HIGH-RISK NON‑MUSCLE INVASIVE BLADDER CANCER:KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non‑muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
  • ADVANCED MSI-H/dMMR CANCERS:KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)
    • solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
    • colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
    This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.
  • ADVANCED GASTRIC OR GEJ CANCER:KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • ADVANCED ESOPHAGEAL SQUAMOUS CELL CARCINOMA:KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.
  • ADVANCED CERVICAL CANCER:KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • HEPATOCELLULAR CARCINOMA:KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • ADVANCED MERKEL CELL CARCINOMA:KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • ADVANCED RENAL CELL CARCINOMA:KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).
EGFR = epidermal growth factor receptor; ALK = anaplastic lymphoma kinase; PD‑L1 = programmed death ligand 1; HER2/neu = human epidermal growth factor receptor 2. mNSCLC = metastatic NSCLC;
EGFR = epidermal growth factor receptor;
ALK = anaplastic lymphoma kinase;
PD-L1 = programmed death ligand 1. PD-L1 = programmed death ligand 1. PD-L1 = programmed death ligand 1;
CPS = combined positive score;
HER2/neu = human epidermal growth factor
receptor 2. PD-L1 = programmed death ligand 1;
CPS = combined positive score.
SELECTED SAFETY INFORMATION for KEYTRUDA® (pembrolizumab)
  • Immune-Mediated Pneumonitis
    • KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3–4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3–5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3–5 in 1.5% of patients.
    • Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.
  • Immune-Mediated Colitis
    • KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.
  • Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

    Immune-Mediated Hepatitis

    • KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

    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. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.
  • Immune-Mediated Endocrinopathies
    • KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). 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. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.
    • Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.
  • Immune-Mediated Nephritis and Renal Dysfunction
    • KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.
  • Immune-Mediated Skin Reactions
    • Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and 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.
  • Other Immune-Mediated Adverse Reactions
    • Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.
    • The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.
    • Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.
  • Infusion-Related Reactions
    • KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.
  • Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
    • Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions.
    • In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.
  • Increased Mortality in Patients With Multiple Myeloma
    • In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials.
  • Embryofetal Toxicity
    • Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.
  • Adverse Reactions
    • In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation 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%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).
    • In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%).
    • In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).
    • In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein‑bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. 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.
    • In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%).
    • In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).
    • Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.
    • In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%).
    • In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).
    • In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. 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 most common adverse reactions (≥20%) 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 who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.
    • In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).
    • In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. 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. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).
    • In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).
    • In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).
    • In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%).
    • Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.
    • Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.
    • In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).
    • Adverse reactions occurring in patients with hepatocellular carcinoma (HCC) were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, 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%).
    • Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3–4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).
    • In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).
  • Lactation
    • Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose.
  • Pediatric Use
    • There is limited experience in pediatric patients. In a trial, 40 pediatric patients (16 children aged 2 years to younger than 12 years and 24 adolescents aged 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 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 these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), increased transaminases (28%), and hyponatremia (18%).
ALT = alanine aminotransferase; AST = aspartate aminotransferase; cHL = classical Hodgkin lymphoma; FU = fluorouracil; HNSCC = head and neck squamous cell carcinoma; MCC = Merkel cell carcinoma; NMIBC = non-muscle invasive bladder cancer; NSCLC = non–small cell lung cancer; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; PMBCL = primary mediastinal large B-cell lymphoma; SCLC = small cell lung cancer. Before prescribing KEYTRUDA, please read the accompanying Prescribing Information. The Medication Guide also is available.

US-LAM-00358 10/19 US-LAM-00358 10/19
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