Pembrolizumab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous [preservative free]:

Keytruda: 100 mg/4 mL (4 mL) [contains polysorbate 80]

Solution Reconstituted, Intravenous [preservative free]:

Keytruda: 50 mg (1 ea [DSC]) [contains polysorbate 80]

Pharmacology

Mechanism of Action

Pembrolizumab is a highly selective anti-PD-1 humanized monoclonal antibody which inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor on T-cells to block PD-1 ligands (PD-L1 and PD-L2) from binding. Blocking the PD-1 pathway inhibits the negative immune regulation caused by PD-1 receptor signaling (Hamid 2013). Anti-PD-1 antibodies (including pembrolizumab) reverse T-cell suppression and induce antitumor responses (Robert 2014).

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 6 L.

Excretion

Clearance: First dose: 252 mL/day; steady state: 195 mL/day.

Half-Life Elimination

22 days.

Use: Labeled Indications

Cervical cancer (recurrent or metastatic): Treatment of recurrent or metastatic cervical cancer in patients whose tumors express PD-L1 (combined positive score [CPS] ≥1), as determined by an approved test, and with disease progression on or after chemotherapy

Endometrial carcinoma (advanced): Treatment of advanced endometrial carcinoma (in combination with lenvatinib) that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) in patients who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.

Esophageal cancer (recurrent locally advanced or metastatic): Treatment of recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus in patients whose tumors express PD-L1 (CPS ≥10) as determined by an approved test, with disease progression after one or more prior lines of systemic therapy.

Gastric cancer (recurrent locally advanced or metastatic): Treatment of recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma in patients whose tumors express PD-L1 (CPS ≥1), as determined by an approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy, and if appropriate, HER2/neu-targeted therapy

Head and neck cancer, squamous cell (recurrent or metastatic):

First-line treatment (in combination with platinum and fluorouracil) of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC)

First-line, single-agent treatment of metastatic or unresectable recurrent HNSCC in patients whose tumors express PD-L1 (CPS ≥1), as determined by an approved test

Single-agent treatment of recurrent or metastatic HNSCC in patients with disease progression on or after platinum-containing chemotherapy

Hepatocellular carcinoma (advanced): Treatment of hepatocellular carcinoma in patients who have been previously treated with sorafenib

Hodgkin lymphoma, classical (relapsed or refractory): Treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma or patients who have relapsed after 3 or more prior lines of therapy

Melanoma:

Adjuvant treatment of melanoma with lymph node(s) involvement following complete resection

Treatment of unresectable or metastatic melanoma

Merkel cell carcinoma (recurrent or metastatic): Treatment of recurrent locally advanced or metastatic Merkel cell carcinoma in adult and pediatric patients

Microsatellite instability-high cancer (unresectable or metastatic):

Solid tumors: Treatment of unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors in adult and pediatric patients that have progressed following prior treatment and have no satisfactory alternate treatment options.

Limitation of use: Safety and efficacy in pediatric patients with MSI-H central nervous system cancers have not been established.

Colorectal cancer: Treatment of unresectable or metastatic, MSI-H or mismatch repair deficient colorectal cancer in adult and pediatric patients that have progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Non-small cell lung cancer:

First-line, single-agent treatment of non-small cell lung cancer (NSCLC) in patients with stage III NSCLC (who are not candidates for surgical resection or definitive chemoradiation) or in patients with metastatic NSCLC, and with tumors with PD-L1 expression (tumor proportion score [TPS] ≥1%), as determined by an approved test, and with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations

First-line treatment (in combination with pemetrexed and platinum chemotherapy) of metastatic nonsquamous NSCLC in patients with no EGFR or ALK genomic tumor aberrations

First-line treatment (in combination with carboplatin and either paclitaxel or paclitaxel [protein bound]) of metastatic squamous NSCLC

Single-agent treatment of metastatic NSCLC in patients with tumors with PD-L1 expression (TPS ≥1%), as determined by an approved test, and with disease progression on or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression (on approved EGFR- or ALK-directed therapy) prior to receiving pembrolizumab.

Primary mediastinal large B-cell lymphoma (relapsed or refractory): Treatment of primary mediastinal large B-cell lymphoma (PMBCL) in adult and pediatric patients with refractory disease or who have relapsed after 2 or more prior lines of therapy

Limitation of use: Not recommended for treatment of PMBCL in patients who require urgent cytoreductive therapy

Renal cell carcinoma (advanced): First-line treatment of advanced renal cell carcinoma (in combination with axitinib)

Small cell lung cancer (metastatic): Treatment of metastatic small cell lung cancer in patients with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy

Urothelial carcinoma (locally advanced or metastatic):

Treatment of locally advanced or metastatic urothelial cancer in patients who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS ≥10) as determined by an approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status

Treatment of locally advanced or metastatic urothelial cancer in patients with disease progression during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to pembrolizumab or any component of the formulation.

Dosage and Administration

Dosing: Adult

Cervical cancer (recurrent or metastatic): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Chung 2019).

Endometrial carcinoma (advanced): IV: 200 mg once every 3 weeks (in combination with lenvatinib) until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Makker 2019).

Esophageal cancer (recurrent locally advanced or metastatic): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Shah 2019).

Gastric cancer (recurrent locally advanced or metastatic): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Fuchs 2018).

Head and neck cancer, squamous cell, (unresectable/recurrent or metastatic), single-agent therapy: IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

Head and neck cancer, squamous cell, (unresectable/recurrent or metastatic), combination therapy: IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (initially in combination with 6 cycles of fluorouracil and either carboplatin or cisplatin) (Rischin 2019).

Hepatocellular carcinoma (advanced): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Zhu 2018).

Hodgkin lymphoma, classical (relapsed or refractory): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

Melanoma (adjuvant treatment): IV: 200 mg once every 3 weeks until disease recurrence, unacceptable toxicity, or for up to 12 months in patients without disease recurrence (Eggermont 2018).

Melanoma (unresectable or metastatic): IV: 200 mg once every 3 weeks until disease progression or unacceptable toxicity.

Off-label dosing: 2 mg/kg once every 3 weeks until disease progression or unacceptable toxicity (Ribas 2015).

Merkel cell carcinoma, recurrent or metastatic: IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

Off-label dosing: 2 mg/kg once every 3 weeks for up to 2 years or until complete response, or until disease progression or unacceptable toxicity (Nghiem 2016).

Microsatellite instability-high cancer (unresectable or metastatic): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

Non-small cell lung cancer (stage III or metastatic), single-agent therapy: IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Mok 2019; Reck 2016).

Off-label dosing (in patients with metastatic NSCLC with disease progression following platinum-containing chemotherapy): 2 mg/kg once every 3 weeks for 24 months or until disease progression or unacceptable toxicity (Herbst 2016).

Non-small cell lung cancer (metastatic, nonsquamous), combination therapy: IV: 200 mg once every 3 weeks (in combination with pemetrexed and either cisplatin or carboplatin) for 4 cycles, followed by pembrolizumab monotherapy of 200 mg once every 3 weeks (with or without optional indefinite pemetrexed maintenance therapy) until disease progression, unacceptable toxicity, or (in patients without disease progression) for a total duration of pembrolizumab therapy of up to 35 cycles or 24 months (Gandhi 2018; Langer 2016).

Non-small cell lung cancer (metastatic, squamous), combination therapy: IV: 200 mg once every 3 weeks (in combination with carboplatin and either paclitaxel or paclitaxel [protein bound]) for 4 cycles, followed by pembrolizumab monotherapy of 200 mg once every 3 weeks until radiographic disease progression, unacceptable toxicity, or (in patients without disease progression) for a total duration of pembrolizumab therapy of up to 35 cycles (Paz-Ares 2018).

Primary mediastinal large B-cell lymphoma (relapsed or refractory): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Zinzani 2017).

Renal cell carcinoma (advanced): IV: 200 mg once every 3 weeks (in combination with axitinib) until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Rini 2019).

Small cell lung cancer (metastatic): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

Urothelial carcinoma (locally advanced or metastatic): IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months (Bellmunt 2017).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: FDA approval through an accelerated process; well-controlled trials in pediatric patients are scant and dosing based on adult efficacy and safety trials and pediatric pharmacokinetic and safety data.

Hodgkin lymphoma, classical (relapsed or refractory): Children ≥2 years and Adolescents: IV: 2 mg/kg/dose; maximum dose: 200 mg/dose; administer once every 3 weeks until disease progression, unacceptable toxicity, or in patients without disease progression, for up to 24 months

Merkel cell carcinoma (recurrent locally advanced or metastatic): Children ≥2 years and Adolescents: IV: 2 mg/kg/dose; maximum dose: 200 mg/dose; administer once every 3 weeks until disease progression, unacceptable toxicity, or in patients without disease progression, for up to 24 months

Microsatellite instability-high cancer (MSI-H) (unresectable or metastatic); non-CNS solid tumors that have progressed following prior treatment without satisfactory alternative treatment options: Children ≥2 years and Adolescents: IV: 2 mg/kg/dose; maximum dose: 200 mg/dose; administer once every 3 weeks until disease progression, unacceptable toxicity, or in patients without disease progression, for up to 24 months

Primary mediastinal large B-cell lymphoma (PMBCL) (relapsed or refractory): Children ≥2 years and Adolescents: IV: 2 mg/kg/dose; maximum dose: 200 mg/dose; administer once every 3 weeks until disease progression, unacceptable toxicity, or in patients without disease progression, for up to 24 months

Dosing adjustment for toxicity: Children ≥2 years and Adolescents: In general, no dosage reductions of pembrolizumab are recommended and depending of severity of identified toxicity, pembrolizumab therapy is either withheld or discontinued to manage toxicities.

Colitis (immune-mediated):

Grade 2 or 3: Withhold pembrolizumab; administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper); may resume upon recovery to grade 0 or 1 toxicity after corticosteroid taper.

Grade 4: Permanently discontinue pembrolizumab; administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Dermatologic toxicity (immune-mediated):

Grade 3 severe skin reactions or suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN): Withhold pembrolizumab and refer for specialized care for assessment and treatment; may require corticosteroids (based on the severity).

Grade 4 severe skin reactions or confirmed SJS or TEN: Permanently discontinue pembrolizumab and refer for specialized care for assessment and treatment; may require corticosteroids (based on the severity).

Endocrinopathies (immune-mediated):

Grade 3 or 4: Withhold pembrolizumab until clinically stable.

Hyperglycemia, severe: Also administer antihyperglycemics.

Hyperthyroidism, severe (grade 3) or life-threatening (grade 4): Manage with thionamides and beta blockers as appropriate; may resume upon recovery to grade 0 or 1 toxicity or discontinue.

Hypophysitis, grade 2 (symptomatic): Also administer corticosteroids (followed by a taper) and hormone-replacement therapy if appropriate; may resume upon recovery to grade 0 or 1 toxicity or discontinue.

Hypophysitis, grade 3 or 4: Withhold or discontinue pembrolizumab (based on severity); also administer corticosteroids (followed by a taper) and hormone-replacement therapy as clinically indicated.

Hematologic toxicity (in patients with classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma), grade 4: Withhold pembrolizumab until resolution to grade 0 or 1.

Pneumonitis (immune-mediated):

Grade 2: Withhold pembrolizumab; administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper); may resume upon recovery to grade 0 or 1 toxicity after corticosteroid taper.

Grade 3 or 4 or recurrent grade 2: Permanently discontinue pembrolizumab; administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Other immune-mediated toxicities:

Grade 2 or grade 3 (based on the severity and type of reaction): Withhold pembrolizumab; may require corticosteroids (based on severity). Upon improvement to grade 0 or 1, initiate corticosteroid taper and continue to taper over at least 1 month. Restart pembrolizumab if the adverse reaction remains at grade 0 or 1 following corticosteroid taper. May consider other systemic immunosuppressants if not controlled by corticosteroids (based on limited data).

Grade 3 (based on the severity and type of reaction) or grade 4: Permanently discontinue pembrolizumab; also administer corticosteroids (may consider other systemic immunosuppressants if not controlled by corticosteroids [based on limited data]).

Recurrent immune-mediated adverse reactions, grades 3 or 4: Permanently discontinue pembrolizumab; also administer corticosteroids (may consider other systemic immunosuppressants if not controlled by corticosteroids [based on limited data]).

Inability to taper corticosteroids: Permanently discontinue pembrolizumab if unable to reduce corticosteroid dose within 12 weeks after last pembrolizumab dose (ie, in adults, prednisone <10 mg/day [or equivalent]); may consider other systemic immunosuppressants if not controlled by corticosteroids (based on limited data).

Persistent grade 2 or 3 adverse reaction (excluding endocrinopathy) that does not recover to grade 0 or 1 within 12 weeks after the last pembrolizumab dose: Permanently discontinue pembrolizumab; also administer corticosteroids (may consider other systemic immunosuppressants if not controlled by corticosteroids [based on limited data]).

Infusion-related reaction:

Grade 1 or 2: Interrupt infusion or slow the infusion rate.

Grade 3 or 4: Permanently discontinue pembrolizumab.

Dosing: Adjustment for Toxicity

No dosage reductions of pembrolizumab are recommended; treatment is withheld or discontinued to manage toxicities. Concomitant medications may also require treatment interruption, dosage reduction, and/or discontinuation.

Colitis (immune mediated):

Grade 2 or 3: Withhold pembrolizumab; administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper); may resume upon recovery to grade 0 or 1 toxicity after corticosteroid taper.

Grade 4: Permanently discontinue pembrolizumab; administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Dermatologic toxicity (immune mediated):

Grade 3 skin reactions or suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN): Withhold pembrolizumab and refer for specialized care for assessment and treatment; may require corticosteroids (based on the severity).

Grade 4 skin reactions or confirmed SJS or TEN: Permanently discontinue pembrolizumab and refer for specialized care for assessment and treatment; may require corticosteroids (based on the severity).

Endocrinopathies (immune mediated):

Grade 3 or 4: Withhold pembrolizumab until clinically stable.

Hyperglycemia, severe: Also administer antihyperglycemics.

Hyperthyroidism, severe (grade 3) or life-threatening (grade 4): Manage with thionamides and beta blockers as appropriate; may resume upon recovery to grade 0 or 1 toxicity or discontinue.

Hypophysitis, grade 2 (symptomatic): Also administer corticosteroids (followed by a taper) and hormone-replacement therapy if appropriate; may resume upon recovery to grade 0 or 1 toxicity or discontinue.

Hypophysitis, grade 3 or 4: Withhold or discontinue pembrolizumab (based on severity); also administer corticosteroids (followed by a taper) and hormone-replacement therapy as clinically indicated.

Hematologic toxicity (in patients with classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma), grade 4: Withhold pembrolizumab until resolution to grade 0 or 1.

Nephritis (immune mediated):

Grade 2: Withhold pembrolizumab; administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper); may resume upon recovery to grade 0 or 1 toxicity after corticosteroid taper.

Grade 3 or 4: Permanently discontinue pembrolizumab; administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Pneumonitis (immune mediated):

Grade 2: Withhold pembrolizumab; administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper); may resume upon recovery to grade 0 or 1 toxicity after corticosteroid taper.

Grade 3 or 4 or recurrent grade 2: Permanently discontinue pembrolizumab; administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Other immune-mediated toxicities:

Grade 2 or grade 3 (based on the severity and type of reaction): Withhold pembrolizumab; may require corticosteroids (based on severity). Upon improvement to grade 0 or 1, initiate corticosteroid taper and continue to taper over at least 1 month. Restart pembrolizumab if the adverse reaction remains at grade 0 or 1 following corticosteroid taper. May consider other systemic immunosuppressants if not controlled by corticosteroids (based on limited data).

Grade 3 (based on the severity and type of reaction) or grade 4: Permanently discontinue pembrolizumab; also administer corticosteroids (may consider other systemic immunosuppressants if not controlled by corticosteroids [based on limited data]).

Recurrent immune-mediated adverse reactions, grades 3 or 4: Permanently discontinue pembrolizumab; also administer corticosteroids (may consider other systemic immunosuppressants if not controlled by corticosteroids [based on limited data]).

Inability to taper corticosteroids: Permanently discontinue pembrolizumab if unable to reduce corticosteroid dose to prednisone <10 mg/day (or equivalent) within 12 weeks after last pembrolizumab dose (may consider other systemic immunosuppressants if not controlled by corticosteroids [based on limited data]).

Persistent grade 2 or 3 adverse reaction (excluding endocrinopathy) that does not recover to grade 0 or 1 within 12 weeks after the last pembrolizumab dose: Permanently discontinue pembrolizumab; also administer corticosteroids (may consider other systemic immunosuppressants if not controlled by corticosteroids [based on limited data]).

Infusion-related reaction:

Grade 1 or 2: Interrupt infusion or slow the infusion rate.

Grade 3 or 4: Permanently discontinue pembrolizumab.

Reconstitution

Injection solution (100 mg/4 mL vial): Withdraw appropriate volume from vial and transfer to IV bag containing NS or D5W; final concentration should be between 1 to 10 mg/mL. Mix by gently inverting bag. Discard unused portion of the vial.

Lyophilized powder (50 mg vial): Reconstitute by adding 2.3 mL SWFI along the vial wall (do not add directly to lyophilized powder); resulting vial concentration is 25 mg/mL. Slowly swirl vial; do not shake. Allow up to 5 minutes for bubbles to dissipate. Reconstituted solution is a clear to slightly opalescent and colorless to slightly yellow solution; discard if visible particles present. Withdraw appropriate volume from vial and transfer to IV bag containing NS or D5W; final concentration should be between 1 to 10 mg/mL. Mix by gently inverting bag. Discard unused portion of the vial.

Administration

IV: Infuse over 30 minutes through a 0.2 to 5 micron sterile, nonpyrogenic, low-protein binding inline or add-on filter. Do not infuse other medications through the same infusion line.

Interrupt or slow the infusion for grade 1 or 2 infusion-related reactions; permanently discontinue for grade 3 or 4 infusion-related reactions.

Head and neck squamous cell carcinoma (unresectable/recurrent, metastatic) and non-small cell lung cancer (metastatic): When administered in combination with chemotherapy, administer pembrolizumab prior to chemotherapy when administered on the same day.

Storage

Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F); protect injection solution vials from light and do not shake or freeze. Reconstituted solutions and solutions diluted for infusion in NS or D5W may be stored at room temperature for up to 6 hours (infusion must be completed within 6 hours of reconstitution) or refrigerated at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of reconstitution (discard after 6 hours at room temperature or 24 hours refrigerated). Do not freeze. If refrigerated, allow to reach room temperature prior to administration.

Drug Interactions

Thalidomide Analogues: Pembrolizumab may enhance the adverse/toxic effect of Thalidomide Analogues. Specifically, mortality may be increased when this combination is used for treatment of refractory multiple myeloma. Avoid combination

Adverse Reactions

Incidence of adverse reactions include unapproved dosing regimens.

>10%:

Cardiovascular: Peripheral edema (14% to 15%), cardiac arrhythmia (11%)

Central nervous system: Fatigue (23% to 43%), pain (22%), headache (11% to 14%)

Dermatologic: Pruritus (11% to 28%), skin rash (13% to 24%), vitiligo (13%)

Endocrine & metabolic: Hyperglycemia (19% to 52%), hyponatremia (10% to 46%), hypoalbuminemia (27% to 44%), hypertriglyceridemia (33% to 43%), hypophosphatemia (19% to 29%), hypocalcemia (15% to 27%), hyperkalemia (13% to 23%), decreased serum bicarbonate (22%), hypercalcemia (14% to 22%), hypercholesterolemia (20%), hypokalemia (15% to 20%), hypoglycemia (13% to 19%), hypothyroidism (9% to 18%), hypomagnesemia (16%), weight loss (10% to 15%)

Gastrointestinal: Diarrhea (12% to 28%), decreased appetite (15% to 25%), constipation (12% to 22%), abdominal pain (13% to 22%), nausea (11% to 22%), vomiting (11% to 19%)

Genitourinary: Urinary tract infection (15% to 19%), hematuria (12% to 13%)

Hematologic & oncologic: Lymphocytopenia (24% to 54%; grades 3/4: 1% to 25%), anemia (17% to 54%; grades 3/4: 4% to 24%), leukopenia (35%; grades 3/4: 9%), neutropenia (7% to 30%; grades 3/4: 1% to 11%), thrombocytopenia (12% to 27%; grades 3/4: 4%), increased INR (19% to 21%), hemorrhage (19%; grades 3/4: 5%), prolonged partial thromboplastin time (14%)

Hepatic: Increased serum alkaline phosphatase (17% to 42%), increased serum transaminases (27% to 34%), increased serum aspartate aminotransferase (20% to 34%), increased serum alanine aminotransferase (9% to 33%), increased liver enzymes (13%)

Immunologic: Graft versus host disease (followed by allogeneic hematopoietic stem cell transplantation: 26%)

Infection: Infection (16%)

Neuromuscular & skeletal: Musculoskeletal pain (21% to 32%), arthralgia (10% to 18%), myalgia (12%), back pain (11% to 12%), asthenia (10% to 11%)

Renal: Increased serum creatinine (11% to 35%)

Respiratory: Upper respiratory tract infection (13% to 28%), cough (14% to 26%), dyspnea (10% to 23%), pneumonia (12%), flu-like symptoms (11%)

Miscellaneous: Fever (10% to 28%)

1% to 10%:

Cardiovascular: Facial edema (10%), pericarditis (4%), pericardial effusion (2%)

Central nervous system: Peripheral neuropathy (2% to 10%), insomnia (7%), dizziness (5%), peripheral sensory neuropathy (1%)

Endocrine & metabolic: Hyperthyroidism (3% to 10%), thyroiditis (≤2%)

Gastrointestinal: Dysphagia (8%), stomatitis (3% to 4%; grades 3/4: 1%), colitis (2%)

Hepatic: Hyperbilirubinemia (10%), hepatic sinusoidal obstruction syndrome (followed by allogeneic hematopoietic stem cell transplantation: 9%), ascites (grades 3/4: 8%), hepatitis (≤3%)

Immunologic: Antibody development (2%; neutralizing: <1%)

Neuromuscular & skeletal: Neck pain (6%), arthritis (2%), myositis (≤1%)

Ophthalmic: Uveitis (≤1%)

Renal: Acute renal failure (2%)

Respiratory: Pneumonitis (2% to 8%)

Miscellaneous: Infusion related reaction (≤9%)

Frequency not defined:

Cardiovascular: Acute myocardial infarction, cardiac failure, cardiac tamponade, edema, pulmonary embolism, septic shock

Central nervous system: Confusion, polyneuropathy

Dermatologic: Cellulitis, dermatitis, erythematous rash, follicular rash, maculopapular rash

Genitourinary: Uterine hemorrhage

Hematologic & oncologic: Rectal hemorrhage

Infection: Candidiasis, Clostridioides difficile associated diarrhea, herpes zoster infection, sepsis

Neuromuscular & skeletal: Osteomyelitis

Respiratory: Epistaxis, hemoptysis, pleural effusion, respiratory failure

Miscellaneous: Fistula, physical health deterioration

<1%, postmarketing, and/or case reports: Anaphylaxis, chronic inflammatory demyelinating polyneuropathy (Maleissye 2016), diabetic ketoacidosis, encephalitis, Guillain-Barré syndrome, hemolytic anemia, hypersensitivity reaction, hypophysitis, myasthenia gravis, myelitis, myocarditis, nephritis, organ transplant rejection (solid), pancreatitis, sarcoidosis, subacute cutaneous lupus erythematosus (Blakeway 2019), type 1 diabetes mellitus, vasculitis

Warnings/Precautions

Concerns related to adverse effects:

• Dermatologic toxicity: Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN, some fatal), exfoliative dermatitis, and bullous pemphigoid may occur with pembrolizumab. Monitor for suspected severe skin reactions and exclude other causes. Based on the severity of the dermatologic toxicity, withhold or permanently discontinue pembrolizumab and administer corticosteroids. Withhold pembrolizumab for signs/symptoms of SJS or TEN and refer for specialized care for assessment and management. Permanently discontinue pembrolizumab if SJS or TEN is confirmed.
• Diabetes mellitus: Type 1 diabetes mellitus has occurred (including diabetic ketoacidosis). Monitor closely for hyperglycemia and other signs/symptoms of diabetes. Insulin therapy may be required; if severe hyperglycemia is observed, administer antihyperglycemics and withhold pembrolizumab treatment until glucose control has been accomplished.
• Gastrointestinal toxicity: Immune-mediated colitis has occurred, including cases of grade 2 to 4 colitis. The median time to onset of colitis was 3.5 months (range: 10 days to 16.2 months) and the median duration was 1.3 months (range: 1 day to over 8 months). In many patients, colitis was managed with high-dose systemic corticosteroids for a median duration of 7 days (range: 1 day to 5.3 months), followed by a corticosteroid taper. Most patients with colitis experienced resolution. May require treatment interruption, systemic corticosteroid therapy, and/or permanent discontinuation. Monitor for signs and symptoms of colitis; administer systemic corticosteroids for ≥ grade 2 colitis.
• Hepatotoxicity: Immune-mediated hepatitis occurred (grades 2 to 4 hepatitis). The median onset for hepatitis was 1.3 months (range: 8 days to 21.4 months); the median duration was 1.8 months (range: 8 days to over 20 months). Hepatitis resolved in most patients. Administer corticosteroids (prednisone 0.5 to 1 mg/kg/day [or equivalent] for grade 2 hepatitis, and prednisone 1 to 2 mg/kg/day [or equivalent] for ≥ grade 3, each followed by a taper), and withhold or discontinue therapy based on the severity of liver enzyme elevations. Systemic corticosteroids were used to manage immune-mediated hepatitis in many patients; the median duration of high-dose corticosteroid therapy was 5 days (range: 1 to 26 days), followed by a taper. Monitor for liver function changes. May require treatment interruption, systemic corticosteroids (for grade 2 or higher toxicity), and/or permanent discontinuation. Pembrolizumab/axitinib combination therapy may result in higher frequencies of grades 3 and 4 ALT and AST elevations (compared to single-agent therapy). The median time to onset of ALT elevation was 2.3 months (range: 7 days to ~20 months) for pembrolizumab/axitinib combination therapy, and over half of patients with ALT elevation required systemic corticosteroids; resolution of grades 2 to 4 ALT elevation occurred in most patients. When rechallenged with either pembrolizumab, axitinib, or both, over half of patients did not experience recurrence of ALT elevation to >3 times ULN. Monitor liver enzymes at baseline and then periodically during treatment; consider more frequent liver enzyme monitoring than for pembrolizumab (or axitinib) monotherapy. If liver enzymes are elevated, withhold pembrolizumab and axitinib, and consider corticosteroids as needed.
• Hypersensitivity: Hypersensitivity and anaphylaxis have been observed (rare).
• Hypophysitis: Immune-mediated hypophysitis occurred (grades 2, 3, and 4). The median time to onset was 3.7 months (range: 1 day to 12 months) and the median duration was 4.7 months (range: 8 days to over 12 months). Most cases were managed with systemic corticosteroids. Nearly half of patients with hypophysitis experienced resolution. Monitor for signs/symptoms of hypophysitis (eg, hypopituitarism, adrenal insufficiency). May require treatment interruption, systemic corticosteroids and hormone replacement therapy (as clinically indicated), and/or permanent discontinuation.
• Infusion-related reactions: Infusion-related reactions (including severe and life-threatening cases) have occurred. Monitor for signs/symptoms of a reaction (eg, rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever). Interrupt infusion and permanently discontinue for severe (grade 3) or life-threatening (grade 4) infusion-related reactions.
• Nephrotoxicity: Immune-mediated nephritis has occurred. The onset for autoimmune nephritis was 3.2 to 5.1 months (range: 12 days to 12.8 months) and the median duration was 3.3 months (range: 12 days to over 16 months). Grade 2 or higher nephritis should be managed with systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg/day [or equivalent], followed by a taper). Most patients required systemic corticosteroids. The median duration of corticosteroid use was 3 to 15 days (range: 1 day to 4 months), followed by a taper. Nephritis resolved in approximately one-third to one-half of affected patients. Monitor for renal function changes. May require treatment interruption, systemic corticosteroids (for ≥ grade 2 toxicity), and/or permanent discontinuation.
• Pulmonary toxicity: Immune-mediated pneumonitis has been observed, including grade 3, grade 4, and fatal cases. In patients with NSCLC, a higher incidence of pneumonitis was reported in patients who had received prior thoracic radiation. The median time to development was 3.3 months (range: 2 days to ~19 months) and the median duration was 1.5 months (range: 1 day to over 17 months). Many patients required initial management with high-dose systemic corticosteroids; the median duration of initial corticosteroid therapy was 5 to 16 days (range: 1 day to ~10 months) followed by a corticosteroid taper. Pneumonitis resolved in over half of the affected patients. May require treatment interruption, corticosteroid therapy (prednisone 1 to 2 mg/kg /day [or equivalent] followed by a taper, for ≥ grade 2 pneumonitis), and/or permanent discontinuation. Monitor for signs and symptoms of pneumonitis; if pneumonitis is suspected, evaluate with radiographic imaging and administer systemic corticosteroids for ≥ grade 2 pneumonitis. Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation.
• Thyroid disorders: Immune-mediated hyperthyroidism, hypothyroidism, and thyroiditis have occurred. The median onset for hyperthyroidism was 1.4 months (range: 1 day to ~22 months) and the median duration was 2.1 months (range: 3 days to over 15 months). Hyperthyroidism resolved in nearly three-fourths of affected patients. Hypothyroidism occurred with a median onset of 3.5 months (range: 1 day to 19 months) and median duration was not reached (range: 2 days to over 27 months). Hypothyroidism resolved in one-fifth of affected patients. The incidence of new or worsening hypothyroidism was higher in patients with squamous cell cancer of the head and neck (as a single agent or in combination with chemotherapy). Monitor for changes in thyroid function (at baseline, periodically during treatment, and as clinically indicated) and for signs/symptoms of thyroid disorders. Administer thionamides and beta-blockers for hyperthyroidism as appropriate; may require treatment interruption and/or permanent discontinuation. Isolated hypothyroidism may be managed with replacement therapy. Thyroiditis occurred with a median onset of 1.2 months (range 0.5 to 3.5 months).
• Other immune-mediated toxicities: Other clinically relevant immune-mediated disorders have been observed (may involve any organ system or tissue, and may be severe or fatal), including rash, exfoliative dermatitis, bullous pemphigoid, uveitis, arthritis, vasculitis, myositis, Guillain-Barré syndrome, pancreatitis, hemolytic anemia, sarcoidosis, serum sickness, myasthenia gravis, myelitis, myocarditis, and encephalitis. While immune-mediated toxicity generally occurs during treatment with pembrolizumab, adverse reactions may also develop after therapy discontinuation. If an immune-mediated adverse event is suspected, evaluate appropriately to confirm or exclude other causes; withhold treatment and administer systemic corticosteroids based on severity of reaction. Upon resolution to grade 0 or 1, initiate corticosteroid taper (continue tapering over at least 1 month). When reaction remains at ≤ grade 1 during taper may reinitiate pembrolizumab. Immune-mediated adverse reactions that do not resolve with systemic corticosteroids may be managed with other systemic immunosuppressants (based on limited data). Discontinue permanently for severe or grade 3 immune-mediated adverse event that is recurrent or life-threatening.

Disease-related concerns:

• Autoimmune disorders: Anti-PD-1 monoclonal antibodies generate an immune response that may aggravate underlying autoimmune disorders or prior immune-related adverse events. A retrospective study analyzed the safety and efficacy of treatment with anti-PD-1 monoclonal antibodies (eg, pembrolizumab, nivolumab) in melanoma patients with preexisting autoimmune disease or prior significant ipilimumab-mediated adverse immune events. Results showed that while immune toxicities associated with this class of therapy did occur, most reactions were mild and easily manageable and did not require permanent drug therapy discontinuation. A significant percentage of patients achieved clinical response with anti-PD-1 monoclonal antibody therapy, despite baseline autoimmunity or prior ipilimumab-related adverse events (Menzies 2017).
• Hematopoietic stem cell transplant: Patients who received allogeneic hematopoietic stem cell transplant (HSCT) after being treated with pembrolizumab experienced immune-mediated complications (some fatal) including graft versus host disease (GVHD) and severe sinusoidal obstructive syndrome (SOS; formerly called veno-occlusive disease) following reduced-intensity conditioning. Fatal hyperacute GVHD post HSCT has also been reported in lymphoma patients who received an anti PD-1 antibody prior to transplant. These complications may occur despite intervening therapy between pembrolizumab and HSCT. Monitor closely for early signs/symptoms of transplant-related complications (eg, hyperacute GVHD, severe [grade 3 to 4] acute GVHD, steroid-requiring febrile syndrome, SOS, and other immune-mediated adverse reactions) and manage promptly. In patients who received allogeneic HSCT prior to receiving pembrolizumab, acute GVHD (including fatal GVHD) has been reported after pembrolizumab treatment. Patients who experienced GVHD following transplant may be at increased risk for GVHD following pembrolizumab; assess the GVHD risks versus pembrolizumab treatment benefits in patients with a history of allogeneic HSCT.
• Multiple myeloma: An increase in mortality was noted in 2 clinical studies in patients with multiple myeloma who received pembrolizumab in combination with a thalidomide analogue and dexamethasone. Causes of death in the experimental arm (containing pembrolizumab, dexamethasone, and a thalidomide analogue [pomalidomide or lenalidomide]) included myocarditis, Stevens-Johnson syndrome, MI, pericardial hemorrhage, cardiac failure, respiratory tract infection, neutropenic sepsis, sepsis, multiple organ dysfunction, respiratory failure, intestinal ischemia, cardiopulmonary arrest, suicide, pulmonary embolism, cardiac arrest, pneumonia, sudden death, and large intestine perforation. Multiple myeloma is not an approved indication for PD-1 or PD-L1 blocking antibodies; pembrolizumab should not be used to treat multiple myeloma in combination with a thalidomide analogue and dexamethasone unless as part of a clinical trial.
• Solid organ transplant: Solid organ transplant rejection has been reported in postmarketing surveillance. Pembrolizumab may increase the risk of rejection; consider benefit versus risk of pembrolizumab treatment in solid organ transplant patients.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Other warnings/precautions:

• Appropriate use: Select patients for recurrent or metastatic cervical cancer, metastatic esophageal cancer, metastatic gastric cancer, metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC; first-line single agent treatment), non-small cell lung cancer (NSCLC; single-agent treatment), or cisplatin-ineligible locally advanced or metastatic urothelial cancer based on PD-L1 expression. If PD-L1 expression is not detected in a gastric cancer archived specimen, evaluate feasibility of obtaining a tumor biopsy to test for PD-L1 expression. Information on tests to detect PD-L1 expression in cervical cancer, esophageal cancer, gastric cancer, HNSCC, NSCLC, or urothelial carcinoma may be found at http://www.fda.gov/companiondiagnostics.

Monitoring Parameters

PD-L1 expression status in patients with cervical cancer, esophageal cancer, gastric cancer, first-line (single agent) treatment of head and neck squamous cell carcinoma, non-small cell lung cancer (when used as single-agent therapy), or cisplatin-ineligible urothelial cancer; liver function tests (AST, ALT, and total bilirubin; in patients receiving pembrolizumab/axitinib, monitor liver enzymes at baseline and periodically during treatment; consider monitoring more frequently); renal function; thyroid function (at baseline, periodically during treatment and as clinically indicated); glucose; CBC with differential (in patients with Hodgkin lymphoma or primary mediastinal large B-cell lymphoma); pregnancy test (prior to initiation of pembrolizumab treatment in females of reproductive potential); signs/symptoms of colitis, dermatologic toxicity, hypophysitis, thyroid disorders, pneumonitis, infusion reactions

Pregnancy

Pregnancy Considerations

Pembrolizumab is a humanized monoclonal antibody (IgG₄). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).

Based on the mechanism of action, pembrolizumab may cause fetal harm if administered during pregnancy; an alteration in the immune response or immune mediated disorders may develop following in utero exposure.

Verify pregnancy status prior to initiation of pembrolizumab treatment in females of reproductive potential. Females of reproductive potential should use effective contraception during therapy and for at least 4 months after treatment is complete.

Patient Education

What is this drug used for?

• It is used to treat cancer.

Frequently reported side effects of this drug

• Bone pain
• Muscle pain
• Joint pain
• Nausea
• Vomiting
• Lack of appetite
• Constipation
• Diarrhea
• Flu-like signs
• Abdominal pain
• Headache
• Weight loss
• Hair loss
• Change in taste
• Trouble sleeping
• Back pain
• Common cold symptoms

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain.
• Thyroid, pituitary, or adrenal gland problems like mood changes, behavioral changes, weight changes, constipation, deeper voice, dizziness, passing out, cold sensation, severe fatigue, hair loss, persistent headache, or decreased sex drive.
• Bowel problems like black, tarry, or bloody stools; fever; mucus in stools; vomiting; vomiting blood; severe abdominal pain; constipation; or diarrhea.
• Brain problem like change in balance, confusion, fever, trouble with memory, muscle weakness, seizures, neck rigidity, severe nausea, or severe vomiting.
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.
• Infusion reaction
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting.
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse.
• Chest pain
• Fast heartbeat
• Abnormal heartbeat
• Bruising
• Bleeding
• Vision changes
• Eye pain
• Severe eye irritation
• Swollen glands
• Severe loss of strength and energy
• Passing out
• Dizziness
• Chills
• Flushing
• Sweating a lot
• Burning or numbness feeling
• Inability to move
• White patches on skin
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.