Severe and Fatal Immune-Mediated
Adverse Reactions

• 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 programmed death 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. Immune-mediated adverse reactions, which may be severe or fatal,
  can occur in any organ system or tissue,
  can affect more than one body system simultaneously, and can occur at any
  time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.
• Monitor patients closely for symptoms
  and signs that may be clinical manifestations
  of underlying immune-mediated adverse reactions. Early identification and
  management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.
  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.
• Withhold or permanently discontinue KEYTRUDA depending on severity of
  the immune-mediated adverse reaction. In
  general, if KEYTRUDA requires interruption
  or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement
  to Grade 1 or less. Upon improvement to
  Grade 1 or less, initiate corticosteroid taper
  and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose
  adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

• KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in
  patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients
  receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation
  of KEYTRUDA in 1.3% (36) and withholding
  in 0.9% (26) of patients. All patients who
  were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59%
  of the 94 patients.

Immune-Mediated Colitis

• KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has
  been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases
  of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated
  colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required
  in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15)
  and withholding in 0.5% (13) of patients.
  All patients who were withheld reinitiated KEYTRUDA after symptom improvement;
  of these, 23% had recurrence. Colitis
  resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

• KEYTRUDA can cause immune-mediated
  hepatitis. Immune-mediated hepatitis
  occurred in 0.7% (19/2799) of patients
  receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6)
  and withholding in 0.3% (9) of patients.
  All patients who were withheld reinitiated KEYTRUDA after symptom improvement;
  of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

• KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or
  higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending
  on severity. 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%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of
  these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA
  in <0.1% (1) and withholding in 0.3% (8)
  of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

• KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently
  discontinue KEYTRUDA depending
  on severity. Hypophysitis occurred in
  0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to
  permanent discontinuation of KEYTRUDA
  in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

• KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with
  or without endocrinopathy. Hypothyroidism
  can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism
  as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred
  in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%).
  None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.
• Hyperthyroidism occurred in 3.4% (96/2799)
  of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA
  in <0.1% (2) and withholding in 0.3% (7)
  of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred
  in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%)
  and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients.
  All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
  The majority of patients with hypothyroidism required long-term thyroid hormone replacement.

Type 1 Diabetes Mellitus (DM), Which
Can Present With Diabetic Ketoacidosis

• Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1)
  and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With
Renal Dysfunction

• KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis
  occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic
Adverse Reactions

• KEYTRUDA can cause immune-mediated
  rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome,
  drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred
  in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding
  of KEYTRUDA in 0.6% (16) of patients.
  All patients who were withheld reinitiated KEYTRUDA after symptom improvement;
  of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

• The following clinically significant
  immune-mediated adverse reactions
  occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of
  these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis
  and demyelination, myasthenic syndrome/
  myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur.
  If uveitis occurs in combination with other immune-mediated adverse reactions,
  consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment
  with systemic steroids to reduce the risk
  of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

• 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 for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

• Fatal and other serious complications can
  occur in patients who receive allogeneic
  HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced
  intensity conditioning, and steroid-requiring febrile syndrome (without an identified
  infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatments and allogeneic HSCT. Follow patients closely for evidence
  of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior
  to or after an allogeneic HSCT.

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 an anti–PD-1/PD-L1 treatment
  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

• The most common adverse reactions for KEYTRUDA (reported in ≥20% of patients) were fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism.

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 last dose.

Before prescribing
KEYTRUDA^® (pembrolizumab), please read the accompanying Prescribing Information. The Medication Guide also is available.

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