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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. For patients with TNBC treated
with KEYTRUDA
in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and
as clinically indicated. 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, other transplant (including corneal graft) 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

In KEYNOTE-522, when KEYTRUDA
was administered
with neoadjuvant chemotherapy (carboplatin and paclitaxel followed
by doxorubicin
or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778)
to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including
1 each of adrenal crisis, autoimmune encephalitis,
hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20%
of patients due to adverse reactions.
The most common reactions (≥1%) resulting in permanent discontinuation
were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%).

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.

ALT = alanine aminotransferase; AST = aspartate aminotransferase.

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

Selected Safety Information