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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. 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.

References:
1. Referenced with permission from the
NCCN Clinical Practice Guidelines in Oncology
(NCCN Guidelines®)
for Colon Cancer
V.1.2023. © National
Comprehensive Cancer
Network, Inc. 2023. All
rights reserved. Accessed
March 31, 2023. To view
the most recent and
complete version of the
guidelines, go online to
NCCN.org. 2. Referenced
with permission from the
NCCN Clinical Practice
Guidelines in Oncology
(NCCN Guidelines®)
for Rectal Cancer
V.1.2023. © National
Comprehensive Cancer
Network, Inc. 2023.
All rights reserved.
Accessed March 31,
2023. To view the most
recent and complete
version of the guidelines,
go online to NCCN.org.
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Hamilton SR, Allegra CJ,
et al. Molecular
biomarkers for the
evaluation of colorectal
cancer: guideline from
the American Society
for Clinical Pathology,
College of American
Pathologists, Association
for Molecular Pathology,
and the American Society
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J Clin Oncol. 2017;35(13):
1453-1486. doi:10.1200/
JCO.2016.71.9807
4. Giardiello FM, Allen JI,
Axilbund JE, et al.
Guidelines on genetic
evaluation and
management of Lynch
syndrome: a consensus
statement by the US
Multi-Society Task Force
on colorectal cancer.
Am J Gastroenterol.
2014;109:1159-1179.
5. Rubenstein JH,
Enns R, Heidelbaugh J,
et al. American
Gastroenterological Association Institute
Guideline on the
Diagnosis and
Management of
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Gastroenterology.
2015;149:777-782.

US-OVC-00634 05/23

Selected Safety Information