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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