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, 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-A39, when KEYTRUDA
was administered in combination with
enfortumab vedotin to patients with locally
advanced or metastatic urothelial cancer
(n=440), fatal adverse reactions occurred in
3.9% of patients, including acute respiratory
failure (0.7%), pneumonia (0.5%), and
pneumonitis/ILD (0.2%). Serious adverse
reactions occurred in 50% of patients
receiving KEYTRUDA in combination with
enfortumab vedotin; the serious adverse
reactions in ≥2% of patients were rash
(6%), acute kidney injury (5%), pneumonitis/
ILD (4.5%), urinary tract infection (3.6%),
diarrhea (3.2%), pneumonia (2.3%), pyrexia
(2%), and hyperglycemia (2%). Permanent
discontinuation of KEYTRUDA occurred
in 27% of patients. The most common
adverse reactions (≥2%) resulting in
permanent discontinuation of KEYTRUDA
were pneumonitis/ILD (4.8%) and rash
(3.4%). The most common adverse
reactions (≥20%) occurring in patients
treated with KEYTRUDA in combination
with enfortumab vedotin were rash (68%),
peripheral neuropathy (67%), fatigue (51%),
pruritus (41%), diarrhea (38%), alopecia
(35%), weight loss (33%), decreased
appetite (33%), nausea (26%), constipation
(26%), dry eye (24%), dysgeusia (21%), and
urinary tract infection (21%).

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.

Geriatric Use

Of the 564 patients with locally advanced
or metastatic urothelial cancer treated
with KEYTRUDA in combination with
enfortumab vedotin, 44% (n=247) were
65-74 years and 26% (n=144) were 75
years or older. No overall differences in
safety or effectiveness were observed
between patients 65 years of age or older
and younger patients. Patients 75 years
of age or older treated with KEYTRUDA
in combination with enfortumab vedotin
experienced a higher incidence of fatal
adverse reactions than younger patients.
The incidence of fatal adverse reactions
was 4% in patients younger than 75 and
7% in patients 75 years or older.

ILD = interstitial lung disease.

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

Reference: 1. FDA approves enfortumab
vedotin-ejfv with pembrolizumab for locally
advanced or metastatic urothelial cancer.
U.S. Food and Drug Administration.
Updated December 15, 2023. Accessed
February 5, 2024. https://www.fda.gov/
drugs/resources-information-approved-
drugs/fda-approves-enfortumab-vedotin-
ejfv-pembrolizumab-locally-advanced-or-
metastatic-urothelial-cancer