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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.
Pneumonitis occurred in 7%
(41/580) of adult patients with
resected NSCLC who
received KEYTRUDA as a
single agent for adjuvant
treatment of NSCLC,
including fatal (0.2%), Grade
4 (0.3%), and Grade 3 (1%)
adverse reactions. Patients
received high-dose
corticosteroids for a median
duration of 10 days (range: 1
day to 2.3 months).
Pneumonitis led to
discontinuation of
KEYTRUDA in 26 (4.5%) of
patients. Of the patients who
developed pneumonitis, 54%
interrupted KEYTRUDA, 63%
discontinued KEYTRUDA,
and 71% had resolution.

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. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment, including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism.

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 as a single agent (reported in ≥20% of patients) were fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism.
Adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred.

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 final dose.

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

Selected Safety Information