advertising [0.1%):<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 19 patients. Immune-Mediated Endocrinopathies Hypophysitis Keytruda can cause hypophysitis. Monitor for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold Keytruda for moderate (Grade 2) hypophysitis and withhold or discontinue Keytruda for severe (Grade 3) or life-threatening (Grade 4) hypophysitis [see Dosage and Administration (2.9) and Adverse Reactions (6.1) ]. 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. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue Keytruda for severe (Grade 3) or life-threatening (Grade 4) hyperthyroidism [see Dosage and Administration (2.9) and Adverse Reactions (6.1) ]. 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 18.9 months), 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. Of these 28 patients, 15 had no prior history of 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. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold Keytruda and administer anti-hyperglycemics in patients with severe hyperglycemia [see Dosage and Administration (2.9) and Adverse Reactions (6.1) ] . Immune-Mediated Nephritis and Renal Dysfunction Keytruda can cause immune-mediated nephritis. Monitor patients for changes in renal function. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater nephritis. Withhold Keytruda for moderate (Grade 2), and permanently discontinue Keytruda for severe (Grade 3) or life-threatening (Grade 4) nephritis [see Dosage and Administration (2.9) and Adverse Reactions (6.1) ]. 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 to 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. Immune-Mediated Skin Adverse Reactions 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. [See Dosage and Administration (2.9) .] Other Immune-Mediated Adverse Reactions Keytruda can cause other clinically important immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system. 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 immune-mediated 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 [see Dosage and Administration (2.9) and Adverse Reactions (6.1) ]. 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%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. In addition, myelitis and myocarditis were reported in other clinical trials, including cHL, and post-marketing use. 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. Infusion-Related Reactions 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. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue Keytruda [see Dosage and Administration (2.9) ] . Complications of Allogeneic HSCT after Keytruda Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with Keytruda. Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with Keytruda on any trial, 6 patients (26%) developed graft-versus-host-disease (GVHD), one of which was fatal, and 2 patients (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, one of which was fatal. 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. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly. Embryofetal Toxicity Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment with Keytruda and for 4 months after the last dose of Keytruda [see Use in Specific Populations (8.1 , 8.3) ]. Adverse Reactions The following adverse reactions are discussed in greater detail in other sections of the labeling. Immune-mediated pneumonitis [see Warnings and Precautions (5.1) ]. Immune-mediated colitis [see Warnings and Precautions (5.2) ] . Immune-mediated hepatitis [see Warnings and Precautions (5.3) ] . Immune-mediated endocrinopathies [see Warnings and Precautions (5.4) ] . Immune-mediated nephritis and renal dysfunction [see Warnings and Precautions (5.5) ] . Immune-mediated skin adverse reactions [see Warnings and Precautions (5.6) ] . Other immune-mediated adverse reactions [see Warnings and Precautions (5.7) ] . Infusion-related reactions [see Warnings and Precautions (5.8) ]. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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 (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 in a non-randomized, open-label, multi-cohort trial (KEYNOTE-012) which enrolled 192 patients with HNSCC and 241 cHL patients in two non-randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087). Across all studies, 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, 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 four non-randomized, open-label trials (KEYNOTE-012, KEYNOTE-087, KEYNOTE-052 and KEYNOTE-059) in which Keytruda was administered to 192 patients with HNSCC, 210 patients with cHL, 370 patients with urothelial carcinoma, and 259 patients with gastric 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. 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 Study 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) [see Clinical Studies (14.1) ] . 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%). The most common adverse reactions (reported in at least 20% of patients) were fatigue and diarrhea. Table 1 and Table 2 summarize the incidence of selected adverse reactions and laboratory abnormalities that occurred in patients receiving Keytruda. Table 1: Selected * Adverse Reactions Occurring in 10% of Patients Receiving Keytruda in KEYNOTE-006 Keytruda 10 mg/kg every 2 or 3 weeks Ipilimumab n=555 n=256 Adverse Reaction All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) * Adverse reactions occurring at same or higher incidence than in the ipilimumab arm Graded per NCI CTCAE v4.0 Includes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and exfoliative rash. Includes skin hypopigmentation General Disorders and Administration Site Conditions Fatigue 28 0.9 28 3.1 Skin and Subcutaneous Tissue Disorders Rash 24 0.2 23 1.2 Vitiligo 13 0 2 0 Musculoskeletal and Connective Tissue Disorders Arthralgia 18 0.4 10 1.2 Back pain 12 0.9 7 0.8 Respiratory, Thoracic and Mediastinal Disorders Cough 17 0 7 0.4 Dyspnea 11 0.9 7 0.8 Metabolism and Nutrition Disorders Decreased appetite 16 0.5 14 0.8 Nervous System Disorders Headache 14 0.2 14 0.8 Other clinically important adverse reactions occurring in 10% of patients receiving Keytruda were diarrhea (26%), nausea (21%), and pruritus (17%). Table 2: Selected * Laboratory Abnormalities Worsened from Baseline Occurring in 20% of Melanoma Patients Receiving Keytruda in KEYNOTE-006 Keytruda 10 mg/kg every 2 or 3 weeks Ipilimumab Laboratory Test All Grades % Grades 3-4 % All Grades % Grades 3-4 % * Laboratory abnormalities occurring at same or higher incidence than in ipilimumab arm Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (520 to 546 patients) and ipilimumab (237 to 247 patients); hypertriglyceridemia: Keytruda n=429 and ipilimumab n=183; hypercholesterolemia: Keytruda n=484 and ipilimumab n=205. Graded per NCI CTCAE v4.0 Chemistry Hyperglycemia 45 4.2 45 3.8 Hypertriglyceridemia 43 2.6 31 1.1 Hyponatremia 28 4.6 26 7 Increased AST 27 2.6 25 2.5 Hypercholesterolemia 20 1.2 13 0 Hematology Anemia 35 3.8 33 4.0 Lymphopenia 33 7 25 6 Other laboratory abnormalities occurring in 20% of patients receiving Keytruda were increased hypoalbuminemia (27% all Grades; 2.4% Grades 3-4), increased ALT (23% all Grades; 3.1% Grades 3-4), and increased alkaline phosphatase (21% all Grades, 2.0% Grades 3-4). 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 evaluated in Study 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%) [see Clinical Studies (14.1) ] . The trial excluded 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. 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). The data described below reflect exposure to Keytruda 2 mg/kg in 36% of patients exposed to Keytruda for 6 months and in 4% of patients exposed for 12 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 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%). The most common adverse reactions (reported in at least 20% of patients) of Keytruda were fatigue, pruritus, rash, constipation, nausea, diarrhea, and decreased appetite. Table 3 summarizes the incidence of adverse reactions occurring in at least 10% of patients receiving Keytruda. Table 3: Selected * Adverse Reactions Occurring in 10% of Patients Receiving Keytruda in KEYNOTE-002 Keytruda 2 mg/kg or 10 mg/kg every 3 weeks Chemotherapy n=357 n=171 Adverse Reaction All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) * Adverse reactions occurring at same or higher incidence than in chemotherapy arm Chemotherapy: dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatin Graded per NCI CTCAE v4.0 Includes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, and rash pruritic General Disorders and Administration Site Conditions Pyrexia 14 0.3 9 0.6 Asthenia 10 2.0 9 1.8 Skin and Subcutaneous Tissue Disorders Pruritus 28 0 8 0 Rash 24 0.6 8 0 Gastrointestinal Disorders Constipation 22 0.3 20 2.3 Diarrhea 20 0.8 20 2.3 Abdominal pain 13 1.7 8 1.2 Respiratory, Thoracic and Mediastinal Disorders Cough 18 0 16 0 Musculoskeletal and Connective Tissue Disorders Arthralgia 14 0.6 10 1.2 Other clinically important adverse reactions occurring in patients receiving Keytruda were fatigue (43%), nausea (22%), decreased appetite (20%), vomiting (13%), and peripheral neuropathy (1.7%). Table 4: Selected * Laboratory Abnormalities Worsened from Baseline Occurring in 20% of Melanoma Patients Receiving Keytruda in KEYNOTE-002 Keytruda 2 mg/kg or 10 mg/kg every 3 weeks Chemotherapy Laboratory Test All Grades % Grades 3-4 % All Grades % Grades 3-4 % * Laboratory abnormalities occurring at same or higher incidence than in chemotherapy arm. Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (range: 320 to 325 patients) and chemotherapy (range: 154 to 161 patients); hypertriglyceridemia: Keytruda n=247 and chemotherapy n=116; bicarbonate decreased: Keytruda n=263 and chemotherapy n=123. Graded per NCI CTCAE v4.0 Chemistry Hyperglycemia 49 6 44 6 Hypoalbuminemia 37 1.9 33 0.6 Hyponatremia 37 7 24 3.8 Hypertriglyceridemia 33 0 32 0.9 Increased Alkaline Phosphatase 26 3.1 18 1.9 Increased AST 24 2.2 16 0.6 Bicarbonate Decreased 22 0.4 13 0 Hypocalcemia 21 0.3 18 1.9 Increased ALT 21 1.8 16 0.6 Other laboratory abnormalities occurring in 20% of patients receiving Keytruda were anemia (44% all Grades; 10% Grades 3-4) and lymphopenia (40% all Grades; 9% Grades 3-4). NSCLC Previously Treated NSCLC The safety of Keytruda was investigated in Study KEYNOTE-010, 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/m 2 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. 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%). 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 in KEYNOTE-010 Keytruda 2 or 10 mg/kg every 3 weeks n=682 Docetaxel 75 mg/m 2 every 3 weeks n=309 Adverse Reaction All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) * Adverse reactions occurring at same or higher incidence than in docetaxel arm Graded per NCI CTCAE v4.0 Includes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic Metabolism and Nutrition Disorders Decreased appetite 25 1.5 23 2.6 Gastrointestinal Disorders Nausea 20 1.3 18 0.6 Constipation 15 0.6 12 0.6 Vomiting 13 0.9 10 0.6 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 23 3.7 20 2.6 Cough 19 0.6 14 0 Musculoskeletal and Connective Tissue Disorders Arthralgia 11 1.0 9 0.3 Back pain 11 1.5 8 0.3 Skin and Subcutaneous Tissue Disorders Rash 17 0.4 8 0 Pruritus 11 0 3 0.3 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 in KEYNOTE-010 Keytruda 2 or 10 mg/kg every 3 weeks Docetaxel 75 mg/m 2 every 3 weeks Laboratory Test All Grades % Grades 3-4 % All Grades % Grades 3-4 % * Laboratory abnormalities occurring at same or higher incidence than in docetaxel arm. Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (range: 631 to 638 patients) and docetaxel (range: 274 to 277 patients). Graded per NCI CTCAE v4.0 Chemistry Hyponatremia 32 8 27 2.9 Alkaline phosphatase increased 28 3.0 16 0.7 Aspartate aminotransferase increased 26 1.6 12 0.7 Alanine aminotransferase increased 22 2.7 9 0.4 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). Previously Untreated Nonsquamous NSCLC, in Combination with Chemotherapy The safety of Keytruda in combination with pemetrexed and carboplatin was investigated in a randomized (1:1) open-label cohort in Study KEYNOTE-021 . Patients with previously untreated, metastatic nonsquamous NSCLC received Keytruda 200 mg with pemetrexed and carboplatin (n=59), or pemetrexed and carboplatin alone (n=62). 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 [see Clinical Studies (14.2) ] . The median duration of exposure to Keytruda was 8 months (range: 1 day to 16 months). Sixty-eight percent of patients in the Keytruda arm were exposed to Keytruda 200 mg for 6 months. The study population characteristics were: median age of 64 years (range: 37 to 80), 48% age 65 years or older, 39% male, 87% White and 8% Asian, 97% with metastatic disease, and 12% with brain metastases. Keytruda was discontinued for adverse reactions in 10% of patients. The most common adverse reaction resulting in discontinuation of Keytruda ( 2%) was acute kidney injury (3.4%). Adverse reactions leading to interruption of Keytruda occurred in 39% of patients; the most common ( 2%) were fatigue (8%), neutrophil count decreased (8%), anemia (5%), dyspnea (3.4%), and pneumonitis (3.4%). Table 7 summarizes the adverse reactions that occurred in at least 20% of patients treated with Keytruda. KEYNOTE-021 was not designed to demonstrate a statistically significant difference in adverse reaction rates for pembrolizumab plus chemotherapy, as compared to chemotherapy alone, for any specified adverse reaction listed in Table 7. Table 7: Adverse Reactions Occurring in 20% of Patients in KEYNOTE-021 Keytruda Pemetrexed Carboplatin n=59 Pemetrexed Carboplatin n=62 Adverse Reaction All Grades * (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) * Graded per NCI CTCAE v4.0 Includes rash, rash generalized, rash macular, rash maculo-papular, and rash pruritic. General Disorders and Administration Site Conditions Fatigue 71 3.4 50 0 Peripheral edema 22 0 18 0 Gastrointestinal Disorders Nausea 68 1.7 56 0 Constipation 51 0 37 1.6 Vomiting 39 1.7 27 0 Diarrhea 37 1.7 23 1.6 Skin and Subcutaneous Tissue Disorders Rash 42 1.7 21 1.6 Pruritus 24 0 4.8 0 Alopecia 20 0 3.2 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 39 3.4 21 0 Cough 24 0 18 0 Metabolism and Nutrition Disorders Decreased appetite 31 0 23 0 Nervous System Disorders Headache 31 0 16 1.6 Dizziness 24 0 16 0 Dysgeusia 20 0 11 0 Psychiatric Disorders Insomnia 24 0 15 0 Infections and Infestations Upper respiratory tract infection 20 0 3.2 0 Musculoskeletal and Connective Tissue Disorders Arthralgia 15 0 24 1.6 Table 8: Laboratory Abnormalities Worsened from Baseline in 20% of Patients in KEYNOTE-021 Keytruda Pemetrexed Carboplatin Pemetrexed Carboplatin Laboratory Test * All Grades % Grades 3-4 % All Grades % Grades 3-4 % * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda pemetrexed carboplatin (range: 56 to 58 patients) and pemetrexed carboplatin (range: 55 to 61 patients). Graded per NCI CTCAE v4.0 Chemistry Hyperglycemia 74 9 61 5 Lymphocytes decreased 53 23 60 28 Aspartate aminotransferase increased 51 3.5 46 1.7 Hypertriglyceridemia 50 0 43 0 Alanine aminotransferase increased 40 3.5 32 1.7 Creatinine increased 34 3.4 19 1.7 Hyponatremia 33 5 35 3.5 Hypoalbuminemia 32 0 31 0 Hypocalcemia 30 5 19 1.7 Hypokalemia 29 5 22 1.7 Hypophosphatemia 29 5 24 11 Alkaline phosphatase increased 28 0 9 0 Hematology Hemoglobin decreased 83 17 84 19 Neutrophils decreased 47 14 43 8 Platelets decreased 24 9 36 10 HNSCC Among the 192 patients with HNSCC enrolled in Study KEYNOTE-012, 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); 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 [see Warnings and Precautions (5.4) ] . cHL Among the 210 patients with cHL enrolled in Study KEYNOTE-087 [see Clinical Studies (14.4) ] , 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 realize
the advantages Keytruda hiking
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