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Immune-mediated adverse reactions: Immune-mediated adverse reactions, including severe and fatal cases, have occurred in patients receiving Pembrolizumab (KEYTRUDA). Immune-mediated adverse reactions can occur after discontinuation of treatment. In clinical trials, most immune-mediated adverse reactions were reversible and managed with interruptions of Pembrolizumab (KEYTRUDA), administration of corticosteroids and/or supportive care. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously.
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 Pembrolizumab (KEYTRUDA) and consider administration of 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. Restart Pembrolizumab (KEYTRUDA) if the adverse reaction remains at Grade 1 or less following corticosteroid taper. If another episode of a severe adverse reaction occurs, permanently discontinue Pembrolizumab (KEYTRUDA). [See General under Dosage & Administration and Clinical Trials Experience under Adverse Reactions.]
Immune-mediated pneumonitis: Pneumonitis (including fatal cases) has been reported in patients receiving Pembrolizumab (KEYTRUDA) [see Clinical Trials Experience under Adverse Reactions]. Monitor patients for signs and symptoms of pneumonitis. If pneumonitis is suspected, evaluate with radiographic imaging and exclude other causes. Administer corticosteroids for Grade 2 or greater events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper), withhold Pembrolizumab (KEYTRUDA) for moderate (Grade 2) pneumonitis, and permanently discontinue Pembrolizumab (KEYTRUDA) for severe (Grade 3), life-threatening (Grade 4) or recurrent moderate (Grade 2) pneumonitis. [See General under Dosage & Administration and Immune-mediated adverse reactions as previously mentioned.]
Immune-mediated colitis: Colitis has been reported in patients receiving Pembrolizumab (KEYTRUDA) [see Clinical Trials Experience under Adverse Reactions]. Monitor patients for signs and symptoms of colitis and exclude other causes. Administer corticosteroids for Grade 2 or greater events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper), withhold Pembrolizumab (KEYTRUDA) for moderate (Grade 2) or severe (Grade 3) colitis, and permanently discontinue Pembrolizumab (KEYTRUDA) for life-threatening (Grade 4) colitis. [See General under Dosage & Administration and Immune-mediated adverse reactions as previously mentioned.]
Immune-mediated hepatitis: Hepatitis has been reported in patients receiving Pembrolizumab (KEYTRUDA) [see Clinical Trials Experience under Adverse Reactions]. Monitor patients for changes in liver function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and symptoms of hepatitis and exclude other causes. Administer corticosteroids (initial dose of 0.5-1 mg/kg/day [for Grade 2 events] and 1- 2 mg/kg/day [for Grade 3 or greater events] prednisone or equivalent followed by a taper) and, based on severity of liver enzyme elevations, withhold or discontinue Pembrolizumab (KEYTRUDA). [See General under Dosage & Administration and Immune-mediated adverse reactions as previously mentioned.]
Immune-mediated nephritis: Nephritis has been reported in patients receiving Pembrolizumab (KEYTRUDA) [see Clinical Trials Experience under Adverse Reactions]. Monitor patients for changes in renal function and exclude other causes. Administer corticosteroids for Grade 2 or greater events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper), withhold Pembrolizumab (KEYTRUDA) for moderate (Grade 2), and permanently discontinue Pembrolizumab (KEYTRUDA) for severe (Grade 3) or life-threatening (Grade 4) nephritis. [See General under Dosage & Administration and Immune-mediated adverse reactions as previously mentioned.]
Immune-mediated endocrinopathies: Adrenal insufficiency (primary and secondary) has been reported in patients receiving Pembrolizumab (KEYTRUDA). Hypophysitis has also been reported in patients receiving Pembrolizumab (KEYTRUDA) [see Clinical Trials Experience under Adverse Reactions]. Monitor patients for signs and symptoms of adrenal insufficiency and hypophysitis (including hypopituitarism) and exclude other causes. Administer corticosteroids to treat adrenal insufficiency and other hormone replacement as clinically indicated, withhold Pembrolizumab (KEYTRUDA) for moderate (Grade 2), withhold or discontinue Pembrolizumab (KEYTRUDA) for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency or hypophysitis. [See General under Dosage & Administration and Immune-mediated adverse reactions as previously mentioned.]
Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients receiving Pembrolizumab (KEYTRUDA) [see Clinical Trials Experience under Adverse Reactions]. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold Pembrolizumab (KEYTRUDA) in cases of severe hyperglycemia until metabolic control is achieved.
Thyroid disorders, including hyperthyroidism, hypothyroidism and thyroiditis, have been reported in patients receiving Pembrolizumab (KEYTRUDA) and can occur at any time during treatment; therefore, monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and clinical signs and symptoms of thyroid disorders. Hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids. Hyperthyroidism may be managed symptomatically. Withhold or discontinue Pembrolizumab (KEYTRUDA) for severe (Grade 3) or life-threatening (Grade 4) hyperthyroidism. [See General under Dosage & Administration, Clinical Trials Experience under Adverse Reactions, and Immune-mediated adverse reactions as previously mentioned.]
For patients with severe (Grade 3) or life-threatening (Grade 4) endocrinopathy that improves to Grade 2 or lower and is controlled with hormone replacement, continuation of Pembrolizumab (KEYTRUDA) may be considered.
Severe skin reactions: Immune-mediated severe skin reactions have been reported in patients treated with Pembrolizumab (KEYTRUDA). Monitor patients for suspected severe skin reactions and exclude other causes. Based on the severity of the adverse reaction, withhold or permanently discontinue Pembrolizumab (KEYTRUDA) and administer corticosteroids [see General under Dosage & Administration]. Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with fatal outcome, have been reported in patients treated with Pembrolizumab (KEYTRUDA). For signs or symptoms of SJS or TEN, withhold Pembrolizumab (KEYTRUDA) and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue Pembrolizumab (KEYTRUDA). [See General under Dosage & Administration.]
Other immune-mediated adverse reactions: The following additional clinically significant, immune-mediated adverse reactions were reported in less than 1% of patients treated with Pembrolizumab (KEYTRUDA) in KEYNOTE-001, KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010: uveitis, myositis, Guillain-Barré syndrome, pancreatitis, encephalitis, sarcoidosis, myasthenic syndrome/myasthenia gravis (including exacerbation), myelitis, and vasculitis. The following was reported in other clinical studies with Pembrolizumab (KEYTRUDA) or in postmarketing use: myocarditis and sclerosing cholangitis.
Cases of these immune-mediated adverse reactions, some of which were severe, have been reported in clinical trials or in postmarketing use.
Transplant-related adverse reactions: Solid organ transplant rejection has been reported in the postmarketing setting in patients treated with Pembrolizumab (KEYTRUDA). Treatment with Pembrolizumab (KEYTRUDA) may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with Pembrolizumab (KEYTRUDA) versus the risk of possible organ rejection in these patients.
Acute graft-versus-host-disease (GVHD), including fatal GVHD, after treatment with Pembrolizumab (KEYTRUDA) has been reported in patients with a history of allogeneic hematopoietic stem cell transplant (HSCT). Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after treatment with Pembrolizumab (KEYTRUDA). Consider the benefit of treatment with Pembrolizumab (KEYTRUDA) versus the risk of possible GVHD in patients with a history of allogeneic HSCT.
Elevated liver enzymes when Pembrolizumab (KEYTRUDA) is given in combination with axitinib for RCC: When Pembrolizumab (KEYTRUDA) is given with axitinib, higher than expected frequencies of Grades 3 and 4 ALT and AST elevations have been reported in patients with advanced RCC [see Clinical Trials Experience under Adverse Reactions]. 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. Follow medical management guidelines for both drugs. [See General under Dosage & Administration and the prescribing information for axitinib.]
Increased mortality in patients with multiple myeloma when Pembrolizumab (KEYTRUDA) is added to a thalidomide analogue and dexamethasone: In two randomized clinical trials in patients with multiple myeloma, the addition of Pembrolizumab (KEYTRUDA) to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1blocking 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.
Infusion-related reactions: Severe infusion reactions, including hypersensitivity and anaphylaxis, have been reported in 6 (0.2%) of 2799 patients receiving Pembrolizumab (KEYTRUDA) in KEYNOTE-001, KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010. For severe infusion reactions, stop infusion and permanently discontinue Pembrolizumab (KEYTRUDA) [see General under Dosage & Administration]. Patients with mild or moderate infusion reaction may continue to receive Pembrolizumab (KEYTRUDA) with close monitoring; premedication with antipyretic and antihistamine may be considered.
Use in Children: In KEYNOTE-051, 161 pediatric patients (62 children ages 6 months to less than 12 years and 99 adolescents ages 12 years to 17 years) with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumors were administered Pembrolizumab (KEYTRUDA) 2 mg/kg every 3 weeks. Patients received Pembrolizumab (KEYTRUDA) for a median of 4 doses (range 1-35 doses), with 138 patients (86%) receiving Pembrolizumab (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.
The safety profile in these pediatric patients was similar to that seen in adults treated with pembrolizumab. The most common adverse reactions (reported in at least 20% of pediatric patients) were pyrexia, vomiting, headache, abdominal pain, anemia, cough, and constipation.
Efficacy for pediatric patients with cHL or TMB-H cancer is extrapolated from the results in the respective adult populations [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
