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Pembrolizumab

Class: Antineoplastic Agents
Chemical Name: Anti-(human protein PDCD1 (programmed cell death 1)) (human-Mus musculus monoclonal heavy chain), disulfide with human-Mus musculus monoclonal light chain immunoglobulin G4 dimer
Molecular Formula: C6504H10004N1716O2036S46 (peptide)
CAS Number: 1374853-91-4
Brands: Keytruda

Medically reviewed on Oct 15, 2018

Warning

Special Alerts:

[Posted 05/18/2018]

AUDIENCE: Oncology, Pharmacy, Risk Manager

ISSUE: FDA is alerting health care professionals, oncology clinical investigators, and the public about decreased survival associated with the use of pembrolizumab (Keytruda) or atezolizumab (Tecentriq) as single therapy (monotherapy) in clinical trials to treat patients with metastatic urothelial cancer who have not received prior therapy and who have low expression of the protein programmed death ligand 1 (PD-L1).

In two ongoing clinical trials (KEYNOTE-361 and IMVIGOR-130), the Data Monitoring Committees' (DMC) early reviews found patients in the monotherapy arms of both trials with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy.

Health care professionals should be aware that the populations enrolled in the ongoing clinical trials were eligible for platinum-containing chemotherapy, and therefore differ from those enrolled in the trials that led to the accelerated approvals of both pembrolizumab and atezolizumab in the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.

BACKGROUND: Both pembrolizumab and atezolizumab are currently approved under accelerated approval for the treatment of locally advanced or metastatic urothelial carcinoma patients who are not eligible for cisplatin-containing chemotherapy, irrespective of PD-L1 status. Pembrolizumab and atezolizumab are also currently approved by the FDA for the treatment of multiple types of other cancers.

RECOMMENDATION: Patients should talk to their doctor if they have questions or concerns about either drug. Patients taking pembrolizumab or atezolizumab for other approved uses should continue to take their medication as directed by their health care professional.

FDA recommends providers select patients for the treatment of locally advanced or metastatic urothelial cancer using the criteria described in Section 14 of each label. These criteria supported the approvals for pembrolizumab and atezolizumab for initial monotherapy in cisplatin-ineligible patients.

Introduction

See also: Xeloda

Antineoplastic agent; humanized anti-programmed-death receptor-1 (anti-PD-1) monoclonal antibody.1 7 8

Uses for Pembrolizumab

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Melanoma

Treatment of unresectable or metastatic melanoma1 9 10 11 12 (designated an orphan drug by FDA for this use).4

Non-small Cell Lung Cancer (NSCLC)

Used as a single agent for the treatment of previously untreated metastatic NSCLC with high programmed-death ligand-1 (PD-L1) expression (defined as PD-L1 expression of any intensity on ≥50% of tumor cells [i.e., tumor proportion score ≥50%]) and without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic aberrations.1 13 FDA-approved diagnostic test required to confirm presence of high PD-L1 expression prior to initiation of therapy.1

Used in combination with pemetrexed and carboplatin for the treatment of previously untreated metastatic nonsquamous NSCLC.1 14 Accelerated approval based on objective response rate and progression-free survival.1 Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.1

Used as a single agent for the treatment of PD-L1-positive (defined as PD-L1 expression of any intensity on ≥1% of tumor cells [i.e., tumor proportion score ≥1%]) metastatic NSCLC that has progressed during or following platinum-based chemotherapy and, if the tumor is EGFR mutation- or ALK-positive, during or following therapy with an FDA-labeled EGFR or ALK inhibitor.1 15 FDA-approved diagnostic test required to confirm presence of PD-L1 expression prior to initiation of therapy.1

Head and Neck Cancer

Treatment of recurrent or metastatic head and neck squamous cell carcinoma that has progressed during or following platinum-containing therapy.1 16 17

Accelerated approval based on objective response rate and duration of response.1 Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.1

Hodgkin Lymphoma

Treatment of refractory classical Hodgkin lymphoma (cHL) or cHL that has relapsed following ≥3 prior therapies1 18 (designated an orphan drug by FDA for treatment of this cancer).4

Accelerated approval based on objective response rate and duration of response.1 Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.1

Urothelial Carcinoma

Treatment of locally advanced or metastatic urothelial carcinoma that has progressed during or following platinum-containing therapy or within 12 months of platinum-containing therapy in the neoadjuvant or adjuvant setting.1 20

Treatment of locally advanced or metastatic urothelial carcinoma in patients who are not candidates for cisplatin-containing therapy.1 19 Accelerated approval based on objective response rate and duration of response.1 Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.1

Solid Tumors with High Microsatellite Instability or Mismatch Repair Deficiency

Treatment of unresectable or metastatic solid tumors with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) that have progressed following prior therapy in patients who are not candidates for other treatment options; in the treatment of unresectable or metastatic MSI-H or dMMR colorectal cancer, use in patients with disease progression following therapy with a fluoropyrimidine, oxaliplatin, and irinotecan.1

Accelerated approval based on objective response rate and duration of response.1 Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.1

Not indicated for use in pediatric patients with MSI-H CNS malignancies.1

Gastric Cancer

Treatment of recurrent, locally advanced or metastatic, PD-L1-positive (defined as a combined positive score of ≥1%, reflecting the proportion of PD-L1-staining tumor cells, macrophages, or lymphocytes relative to tumor cells in the tumor microenvironment22 ) gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, that has progressed during or following ≥2 prior therapies, including fluoropyrimidine- and platinum-containing chemotherapy, and, if the tumor overexpresses the human epidermal growth factor receptor type 2 (HER2) protein, during or following therapy with an anti-HER2 agent.1

FDA-approved diagnostic test required to confirm presence of PD-L1 expression prior to initiation of therapy.1

Accelerated approval based on objective response rate and duration of response.1 Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.1

Pembrolizumab Dosage and Administration

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Commercially available as injection concentrate and lyophilized powder.1 Lyophilized powder must be reconstituted and then diluted to prepare final infusion solution.1 Injection concentrate must be diluted prior to IV administration.1 (See Storage under Stability.)

Do not infuse simultaneously through the same IV line with other drugs.1

Administer using a sterile, nonpyrogenic, low-protein-binding 0.2- to 5-μm inline or add-on filter.1

Reconstitution (Lyophilized Powder for Injection)

Reconstitute vial containing 50 mg of pembrolizumab with 2.3 mL of sterile water for injection to provide a solution containing 25 mg/mL; direct diluent toward wall of vial.1 Gently swirl vial to ensure dissolution.1 Allow solution to stand for up to 5 minutes to let bubbles dissipate.1 Do not shake reconstituted solution.1

Reconstituted solution should be clear to slightly opalescent and colorless to slightly yellow.1 Do not use if visible particles are present.1

Dilution

Dilute appropriate dose of reconstituted pembrolizumab solution or commercially available injection concentrate in a sufficient volume of 0.9% sodium chloride injection or 5% dextrose injection to yield a final concentration of 1–10 mg/mL.1 Mix the diluted solution by gentle inversion.1 Discard any partially used vials.1

Rate of Administration

Administer by IV infusion over 30 minutes.1

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Consult published protocols for information on dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens with pembrolizumab.

Pediatric Patients

Hodgkin Lymphoma
IV

2 mg/kg (up to a maximum of 200 mg) every 3 weeks.1 Continue therapy for up to 24 months or until disease progression or unacceptable toxicity occurs.1

Solid Tumors with High Microsatellite Instability or Mismatch Repair Deficiency
IV

2 mg/kg (up to a maximum of 200 mg) every 3 weeks.1 Continue therapy for up to 24 months or until disease progression or unacceptable toxicity occurs.1

Therapy Interruption for Toxicity
IV

Follow recommendations for therapy interruption in adults.1

Adults

Melanoma
IV

200 mg every 3 weeks.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

NSCLC
Monotherapy for Metastatic NSCLC
IV

200 mg every 3 weeks.1 Continue therapy for up to 24 months or until disease progression or unacceptable toxicity occurs.1

Selection based on presence of PD-L1 expression.1 (See Non-small Cell Lung Cancer [NSCLC] under Uses.)

Combination Therapy for Metastatic Nonsquamous NSCLC
IV

200 mg every 3 weeks (use in combination with pemetrexed and carboplatin).1 Continue therapy for up to 24 months or until disease progression or unacceptable toxicity occurs.1

Administer pembrolizumab prior to pemetrexed and carboplatin.1

Head and Neck Cancer
IV

200 mg every 3 weeks.1 Continue therapy for up to 24 months or until disease progression or unacceptable toxicity occurs.1

Hodgkin Lymphoma
IV

200 mg every 3 weeks.1 Continue therapy for up to 24 months or until disease progression or unacceptable toxicity occurs.1

Urothelial Carcinoma
IV

200 mg every 3 weeks.1 Continue therapy for up to 24 months or until disease progression or unacceptable toxicity occurs.1

Solid Tumors with High Microsatellite Instability or Mismatch Repair Deficiency
IV

200 mg every 3 weeks.1 Continue therapy for up to 24 months or until disease progression or unacceptable toxicity occurs.1

Gastric Cancer
IV

200 mg every 3 weeks.1 Continue therapy for up to 24 months or until disease progression or unacceptable toxicity occurs.1

Selection based on presence of PD-L1 expression; consider obtaining new tumor specimen if PD-L1 expression not detected in archival tumor specimen.1 (See Gastric Cancer under Uses.)

Therapy Interruption for Toxicity

Discontinue therapy in patients experiencing any life-threatening immune-mediated adverse effect (except for endocrinopathies controlled with hormone replacement therapy or hematologic toxicity in patients with cHL), patients with persistent grade 2 or 3 immune-mediated adverse effects (except for endocrinopathies controlled with hormone replacement therapy) that do not recover to grade 0 or 1 within 12 weeks of the last dose of pembrolizumab, and those unable to reduce corticosteroid dosage to ≤10 mg of prednisone (or equivalent) daily within 12 weeks.1 (See Warnings/Precautions under Cautions.)

Discontinue therapy if severe or grade 3 immune-mediated adverse effects recur.1

Hematologic Toxicity

If grade 4 hematologic toxicity occurs in patients with cHL, interrupt therapy until toxicity resolves to grade 0 or 1.1

Immune-mediated Pneumonitis

If grade 2 immune-mediated pneumonitis occurs, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated Pneumonitis under Cautions.)

If grade 3 or 4 immune-mediated pneumonitis occurs or grade 2 immune-mediated pneumonitis recurs, discontinue drug.1

Immune-mediated GI Effects

If grade 2 or 3 immune-mediated colitis occurs, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated GI Effects under Cautions.)

If grade 4 immune-mediated colitis occurs, discontinue drug.1

Immune-mediated Hepatic Effects

For ALT or AST concentrations >3 to 5 times the ULN or total bilirubin concentrations >1.5 to 3 times the ULN, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated Hepatic Effects under Cautions.)

For ALT or AST concentrations >5 times the ULN or total bilirubin concentrations >3 times the ULN, discontinue drug.1

If ALT or AST concentration increases by ≥50% from baseline for ≥1 week in patients with liver metastasis and baseline grade 2 serum aminotransferase elevations, discontinue drug.1

Immune-mediated Endocrine Effects

If grade 2 immune-mediated hypophysitis or severe hyperglycemia occurs, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated Endocrine Effects under Cautions.)

If grade 3 or 4 immune-mediated hypophysitis or hyperthyroidism occurs, interrupt therapy or discontinue drug.1

Immune-mediated Renal Effects

If grade 2 immune-mediated nephritis occurs, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated Renal Effects under Cautions.)

If grade 3 or 4 immune-mediated nephritis occurs, discontinue drug.1

Immune-mediated Dermatologic Effects

If grade 3 immune-mediated skin reaction occurs or Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated Dermatologic Effects under Cautions.)

If grade 4 immune-mediated skin reaction occurs or Stevens-Johnson syndrome or toxic epidermal necrolysis is confirmed, discontinue drug.1

Other Immune-mediated Adverse Effects

If any other severe or grade 3 immune-mediated adverse effects occur, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Other Immune-mediated Effects under Cautions.)

Infusion-related Effects

If grade 3 or 4 infusion-related reactions occur, discontinue drug.1

Prescribing Limits

Pediatric Patients

Hodgkin Lymphoma
IV

Maximum 200 mg per dose.1

Maximum 24 months of therapy.1

Solid Tumors with High Microsatellite Instability or Mismatch Repair Deficiency
IV

Maximum 200 mg per dose.1

Maximum 24 months of therapy.1

Adults

NSCLC
IV

Maximum 24 months of therapy.1

Head and Neck Cancer
IV

Maximum 24 months of therapy.1

Hodgkin Lymphoma
IV

Maximum 24 months of therapy.1

Urothelial Carcinoma
IV

Maximum 24 months of therapy.1

Solid Tumors with High Microsatellite Instability or Mismatch Repair Deficiency
IV

Maximum 24 months of therapy.1

Gastric Cancer
IV

Maximum 24 months of therapy.1

Special Populations

Hepatic Impairment

No special dosage recommendations at this time.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Renal Impairment

No special dosage recommendations at this time.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Geriatric Patients

No special dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Pembrolizumab

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • No known contraindications.1

Warnings/Precautions

Immune-mediated Pneumonitis

Immune-mediated pneumonitis, sometimes fatal, reported; may occur more frequently in patients with a history of thoracic irradiation.1

Monitor patients for manifestations of pneumonitis.1 If pneumonitis is suspected, evaluate patients using radiographic imaging.1

If grade 2 or greater pneumonitis occurs, temporarily withhold or discontinue pembrolizumab and initiate systemic corticosteroid therapy (1–2 mg/kg of prednisone daily [or equivalent]) followed by tapering of the corticosteroid dosage.1 (See Therapy Interruption for Toxicity under Dosage and Administration.)

Immune-mediated GI Effects

Immune-mediated colitis reported.1

Monitor patients for manifestations of colitis.1

If grade 2 or greater colitis occurs, temporarily withhold or discontinue pembrolizumab and initiate systemic corticosteroid therapy (1–2 mg/kg of prednisone daily [or equivalent]) followed by tapering of the corticosteroid dosage.1 (See Therapy Interruption for Toxicity under Dosage and Administration.)

Immune-mediated Hepatic Effects

Immune-mediated hepatitis reported.1 3

Monitor patients for changes in liver function.1

If elevations in AST, ALT, or bilirubin concentrations occur, temporarily withhold or discontinue pembrolizumab.1 (See Therapy Interruption for Toxicity under Dosage and Administration.)

If grade 2 hepatitis occurs, initiate systemic corticosteroid therapy at a dosage of 0.5–1 mg/kg of prednisone daily (or equivalent) followed by tapering of the corticosteroid dosage.1 If grade 3 or greater hepatitis occurs, initiate systemic corticosteroid therapy at a dosage of 1–2 mg/kg of prednisone daily (or equivalent) followed by tapering of the corticosteroid dosage.1

Immune-mediated Endocrine Effects

Immune-mediated endocrinopathies, including hypophysitis, thyroid dysfunction (i.e., hyperthyroidism, hypothyroidism, thyroiditis), and diabetes mellitus, reported.1

Hypophysitis

Monitor for manifestations of hypophysitis (including hypopituitarism and adrenal insufficiency).1

If immune-mediated hypophysitis occurs, temporarily withhold or discontinue pembrolizumab and initiate systemic corticosteroid therapy and hormone replacement therapy as clinically indicated.1 (See Therapy Interruption for Toxicity under Dosage and Administration.)

Thyroid Dysfunction

Evaluate thyroid function prior to initiation of therapy, periodically during therapy, and as clinically indicated.1 Monitor for manifestations of thyroid dysfunction.1

If immune-mediated hypothyroidism occurs, initiate thyroid hormone replacement therapy as clinically indicated.1

If immune-mediated hyperthyroidism occurs, initiate appropriate medical therapy (i.e., antithyroid agents, β-adrenergic blocking agents [β-blockers]) as clinically indicated; if grade 3 or greater, temporarily withhold or discontinue pembrolizumab.1 (See Therapy Interruption for Toxicity under Dosage and Administration.)

Diabetes Mellitus

Monitor for manifestations of diabetes mellitus (e.g., hyperglycemia).1

If immune-mediated type 1 diabetes mellitus occurs, initiate insulin therapy.1 If severe hyperglycemia occurs, temporarily withhold pembrolizumab and initiate antidiabetic agents.1 (See Therapy Interruption for Toxicity under Dosage and Administration.)

Immune-mediated Renal Effects

Immune-mediated nephritis reported.1

Monitor patients for changes in renal function.1

If grade 2 or greater nephritis occurs, temporarily withhold or discontinue pembrolizumab and initiate systemic corticosteroid therapy (1–2 mg/kg of prednisone daily [or equivalent]) followed by tapering of the corticosteroid dosage.1 (See Therapy Interruption for Toxicity under Dosage and Administration.)

Immune-mediated Dermatologic Effects

Immune-mediated rash, including Stevens-Johnson syndrome, toxic epidermal necrolysis (sometimes fatal), exfoliative dermatitis, and bullous pemphigoid, reported.1

Monitor patients for severe skin reactions.1 If an immune-mediated skin reaction is suspected, ensure adequate evaluation to exclude other causes.1

If grade 3 or greater immune-mediated rash occurs, temporarily withhold or discontinue pembrolizumab and initiate systemic corticosteroid therapy.1 (See Therapy Interruption for Toxicity under Dosage and Administration.)

If Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, temporarily withhold pembrolizumab and refer patient for evaluation and treatment by a specialist.1 If Stevens-Johnson syndrome or toxic epidermal necrolysis is confirmed, discontinue pembrolizumab.1

Other Immune-mediated Effects

Other immune-mediated adverse effects (e.g., uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures in a patient with inflammatory foci in brain parenchyma, Guillain-Barré syndrome, myasthenia gravis, myelitis, myocarditis, vasculitis) reported.1 3 6

Immune-mediated rejection of solid organ transplants also reported.1 Weigh risk of possible organ rejection against potential benefits of the drug.1

If an immune-mediated adverse effect is suspected, ensure adequate evaluation to exclude other causes.1

Depending on severity of immune-mediated adverse effect, temporarily withhold pembrolizumab and initiate systemic corticosteroid therapy.1 (See Therapy Interruption for Toxicity under Dosage and Administration.) Once toxicity has resolved to grade 0 or 1, taper corticosteroid dosage over ≥1 month.1 If toxicity remains at grade 1 or less following tapering of the corticosteroid dosage, resume pembrolizumab.1 If immune-mediated adverse effects inadequately controlled by systemic corticosteroid therapy, may consider systemic immunosuppressant therapy.1 If severe or grade 3 immune-mediated adverse effects occur, temporarily withhold or discontinue pembrolizumab.1

Infusion-related Effects

Severe or life-threatening infusion-related reactions, including hypersensitivity reactions and anaphylaxis, reported.1

Monitor patients for signs and symptoms of infusion-related reactions.1

If grade 3 or 4 infusion-related reaction occurs, stop infusion and discontinue pembrolizumab.1

Allogeneic Stem Cell Transplantation-related Immune-mediated Complications

Immune-mediated complications (sometimes fatal), including graft-versus-host disease (GVHD) and hepatic veno-occlusive disease, reported in patients who underwent allogeneic stem cell transplantation following pembrolizumab therapy.1 Such complications may occur despite other intervening therapy between pembrolizumab administration and transplantation.1

Closely monitor for early manifestations of stem cell transplantation-related immune-mediated complications (e.g., hyperacute GVHD, grade 3 or 4 acute GVHD, corticosteroid-requiring febrile syndrome, hepatic veno-occlusive disease) and manage promptly if they occur.1

Treatment-related Mortality

Increased mortality reported in patients with multiple myeloma receiving pembrolizumab in combination with an immunomodulatory agent (i.e., lenalidomide, pomalidomide); pembrolizumab is not currently FDA-labeled for use in patients with multiple myeloma.1 21

In clinical trials, risk of death was increased by 61 or 106% in patients with multiple myeloma receiving pembrolizumab in combination with pomalidomide or lenalidomide, respectively, and low-dose dexamethasone compared with those receiving the immunomodulatory agent and low-dose dexamethasone.21 These trials were terminated at FDA's request.21

Patients with multiple myeloma should not receive an anti-PD-1 or anti-PD-L1 antibody in combination with an immunomodulatory agent and dexamethasone outside of a controlled clinical trial.1 FDA recommends that ongoing clinical trials evaluating anti-PD-1 or anti-PD-L1 agents given in combination with an immunomodulatory agent or in combination with other drugs for use in hematologic malignancies be evaluated for permanent discontinuance or protocol amendments.21

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 May disrupt maternal immune tolerance to the fetus and increase risk of fetal loss (abortion, stillbirth); also may increase risk of immune-mediated disorders or alter normal immune response of the developing fetus.1

Avoid pregnancy during therapy.1 Women of childbearing potential should use a highly effective contraceptive method while receiving pembrolizumab and for 4 months after the last dose.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Immunogenicity

Potential for immunogenicity.1 Development of binding antibodies and neutralizing antibodies to pembrolizumab reported.1 Effects on pharmacokinetics or safety (i.e., infusion-related reactions) of the drug not observed.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether pembrolizumab is distributed into milk.1 Discontinue nursing during therapy and for 4 months after the last dose.1

Pediatric Use

Efficacy not established in pediatric patients with melanoma, NSCLC, squamous cell carcinoma of the head and neck, urothelial carcinoma, or gastric cancer.1

Efficacy in pediatric patients with MSI-H solid tumors or cHL is supported by extrapolation of data from clinical studies of pembrolizumab in adults, pharmacokinetic analysis indicating that age (range of 15–94 years) does not affect clearance of the drug, and limited data indicating that exposure to pembrolizumab is similar in pediatric patients and adults.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Safety profile generally similar in pediatric patients and adults, but some adverse effects (i.e., fatigue, vomiting, abdominal pain, elevated serum aminotransferase concentrations, hyponatremia) may occur more frequently in pediatric patients.1

Geriatric Use

In clinical trials evaluating pembrolizumab in patients with melanoma, NSCLC, squamous cell carcinoma of the head and neck, cHL, and urothelial carcinoma, 46% of patients were ≥65 years of age and 16% were ≥75 years of age; no overall differences in safety or efficacy relative to younger adults.1

Hepatic Impairment

Clearance not affected by mild hepatic impairment.1 Limited data in patients with moderate or severe hepatic impairment.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Renal Impairment

Clearance not affected by renal impairment (estimated GFR ≥15 mL/minute per 1.73 m2).1 (See Elimination: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Melanoma: Pruritus,1 11 rash,1 11 constipation,1 fatigue,9 arthralgia,1 cough, 1 decreased appetite,1 pyrexia,1 abdominal pain,1 vitiligo,1 back pain,1 dyspnea,1 asthenia,9 hypothyroidism,9 nausea,1 hyperglycemia,1 hypertriglyceridemia,1 hypoalbuminemia,1 hyponatremia,1 anemia,1 lymphopenia,1 elevated ALT/AST concentrations,1 elevated alkaline phosphatase concentrations,1 decreased bicarbonate concentrations,1 hypocalcemia,1 hypercholesterolemia.1

Combination therapy with pemetrexed and carboplatin in patients with previously untreated metastatic nonsquamous NSCLC: Fatigue,1 14 nausea,1 14 constipation,1 14 rash,1 14 dyspnea,1 vomiting,1 14 diarrhea,1 14 decreased appetite,1 headache,1 cough,1 dizziness,1 14 insomnia,1 pruritus,1 14 peripheral edema,1 14 alopecia,1 14 dysgeusia,1 14 upper respiratory tract infection,1 increased lacrimation,14 hyperglycemia,1 elevated ALT/AST concentrations,1 hypertriglyceridemia,1 neutropenia,1 elevated Scr,1 hypocalcemia,1 hypokalemia,1 hypophosphatemia,1 elevated alkaline phosphatase concentrations.1

Monotherapy in patients with previously treated PD-L1-positive metastatic NSCLC: Decreased appetite,1 dyspnea,1 nausea,1 cough,1 rash,1 constipation,1 vomiting,1 arthralgia,1 back pain,1 pruritus,1 hyponatremia,1 elevated alkaline phosphatase concentrations,1 elevated ALT/AST concentrations.1

Head and neck squamous cell carcinoma: Fatigue,1 decreased appetite,1 dyspnea.1 Increased frequency of facial edema and new or worsening hypothyroidism compared with patients with melanoma or NSCLC.1

cHL: Fatigue,1 18 cough,1 18 pyrexia,1 18 musculoskeletal pain,1 diarrhea,1 18 rash,1 18 vomiting,1 18 hypothyroidism,1 18 nausea,1 18 upper respiratory tract infection,1 18 dyspnea,1 headache,1 18 pruritus,1 18 arthralgia,1 18 peripheral neuropathy,1 elevated ALT/AST concentrations,1 anemia,1 thrombocytopenia,1 neutropenia.1

Locally advanced or metastatic urothelial carcinoma in cisplatin-ineligible patients: Fatigue,1 19 musculoskeletal pain,1 decreased appetite,1 constipation,1 rash,1 diarrhea,1 pruritus,1 19 urinary tract infection,1 abdominal pain,1 nausea,1 cough,1 peripheral edema,1 hematuria,1 vomiting,1 dyspnea,1 pyrexia,1 arthralgia,1 weight loss,1 anemia,1 elevated ALT/AST concentrations,1 elevated Scr,1 hyponatremia.1

Previously treated locally advanced or metastatic urothelial carcinoma: Musculoskeletal pain,1 pruritus,1 20 rash,1 cough,1 vomiting,1 dyspnea,1 hematuria,1 elevated alkaline phosphatase concentrations,1 elevated Scr,1 elevated AST concentrations.1

Gastric cancer: Adverse effects similar to those in patients with melanoma or NSCLC.1

Interactions for Pembrolizumab

No formal drug interaction studies to date.1

Pembrolizumab Pharmacokinetics

Absorption

Bioavailability

Steady-state concentrations achieved within 16 weeks.1

AUC, peak plasma concentration, and trough concentration are dose proportional over the dosage range of 2–10 mg/kg every 3 weeks; systemic accumulation is 2.1-fold when administered every 3 weeks.1

Based on dose-exposure efficacy and safety relationships, no clinically important differences between 200 mg every 3 weeks and 2 mg/kg every 3 weeks in patients with melanoma or NSCLC.1

Special Populations

Exposure in pediatric patients 2–18 years of age is similar to that in adults.1

Distribution

Extent

Not known whether pembrolizumab is distributed into milk.1

Elimination

Half-life

22 days.1

Clearance is approximately 23% lower at steady state than following initial dose; difference not clinically important.1

Special Populations

Mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN, or total bilirubin concentration >1 times but not >1.5 times the ULN with any AST concentration) does not affect clearance.1 Limited data for moderate or severe hepatic impairment.1

Renal impairment (estimated GFR ≥15 mL/minute per 1.73 m2) does not affect clearance.1

Age, gender, race, and tumor burden do not have meaningful effects on pharmacokinetics of pembrolizumab.1

Stability

Storage

Parenteral

Powder for Injection

Unreconstituted drug: 2–8°C.1

Reconstituted drug: Room temperature for up to 6 hours after reconstitution (including infusion time) or 2–8°C for up to 24 hours after reconstitution.1 Do not freeze.1

Diluted infusion solution: Room temperature for up to 6 hours after reconstitution (including infusion time) or 2–8°C for up to 24 hours after reconstitution.1 Do not freeze.1

Injection Concentrate

2–8°C in original package to protect from light.1 Do not freeze.1

Diluted infusion solution: Room temperature for up to 6 hours after dilution (including infusion time) or 2–8°C for up to 24 hours after dilution.1 Do not freeze.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Dextrose 5% in water1

Sodium chloride 0.9%1

Actions

  • An IgG4 kappa immunoglobulin that is highly selective for PD-1, an immune-checkpoint receptor expressed on activated T-cells, monocytes, B-cells, natural killer (NK) T-cells, and dendritic cells.1 3 5 8

  • Overexpression of PD-1 ligands on surface of tumor cells results in activation of PD-1 activity and suppression of cytotoxic T-cell activity.1 8

  • Blocks interaction between PD-1 and its ligands, resulting in enhanced immune response, including enhanced antitumor immune response.1 8

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of reading the manufacturer's medication guide before beginning treatment and each time the drug is administered.1 2

  • Risk of immune-mediated pneumonitis.1 2 Importance of informing clinician immediately if new or worsening cough, chest pain, or shortness of breath occurs.1 2

  • Risk of immune-mediated colitis.1 2 Importance of informing clinician immediately if diarrhea, severe abdominal pain, or changes in stool occur.1 2

  • Risk of immune-mediated hepatitis.1 2 Importance of informing clinician immediately if signs and symptoms of liver damage (e.g., jaundice, nausea, vomiting, dark urine, abdominal pain [particularly in right upper quadrant], easy bruising or bleeding, lack of appetite) occur.1 2

  • Risk of immune-mediated hypophysitis.1 2 Importance of informing clinician immediately if persistent or unusual headache, extreme weakness, dizziness or fainting, or vision changes occur.1 2

  • Risk of immune-mediated nephritis.1 2 Importance of informing clinician immediately if signs and symptoms of renal damage (e.g., decreased urine output, change in color of urine) occur.1 2

  • Risk of immune-mediated hyperthyroidism or hypothyroidism.1 Importance of informing clinician immediately if symptoms of abnormal thyroid function occur.1 2

  • Risk of immune-mediated type 1 diabetes mellitus.1 Importance of informing clinician immediately if signs and symptoms of diabetes mellitus occur.1

  • Risk of immune-mediated severe skin reactions.1 2 Importance of informing clinician immediately if severe skin reactions or signs and symptoms of Stevens-Johnson syndrome or toxic epidermal necrolysis develop.1

  • Risk of infusion-related reactions.1 2 Importance of informing clinician immediately if signs and symptoms of such reactions (e.g., dizziness, chills, fever, difficulty breathing, pruritus, flushing, feeling of faintness) occur.1 2

  • Risk of immune-mediated rejection of a solid organ transplant.1 2 Importance of informing clinician immediately if signs and symptoms of solid organ transplant rejection occur.1

  • Risk of immune-mediated complications following allogeneic stem cell transplantation.1 2

  • Importance of laboratory monitoring during therapy.1

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential to use a highly effective method of contraception while receiving the drug and for 4 months after the last dose.1 Importance of women informing clinicians if they are or plan to become pregnant.2 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1

  • Importance of advising women to avoid breast-feeding while receiving pembrolizumab and for 4 months after the last dose.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., autoimmune disorders, history of organ transplantation, liver damage).2

  • Importance of informing patients of other important precautionary information.1 2 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Pembrolizumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use

50 mg

Keytruda

Merck

Concentrate, for injection, for IV use

25 mg/mL (100 mg)

Keytruda

Merck

AHFS DI Essentials™. © Copyright 2018, Selected Revisions October 15, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Merck & Co., Inc. Keytruda (pembrolizumab) for injection prescribing information. Whitehouse Station, NJ; 2017 Nov.

2. Merck & Co., Inc. Keytruda (pembrolizumab) medication guide. Whitehouse Station, NJ; 2017 Sep.

3. Robert C, Ribas A, Wolchok JD et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014; 384:1109-17. http://www.ncbi.nlm.nih.gov/pubmed/25034862?dopt=AbstractPlus

4. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2018 Feb 12. http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

5. Hamid O, Robert C, Daud A et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013; 369:134-44. http://www.ncbi.nlm.nih.gov/pubmed/23724846?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4126516&blobtype=pdf

6. Mandel JJ, Olar A, Aldape KD et al. Lambrolizumab induced central nervous system (CNS) toxicity. J Neurol Sci. 2014; 344:229-31. http://www.ncbi.nlm.nih.gov/pubmed/24980937?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4157634&blobtype=pdf

7. Karimkhani C, Gonzalez R, Dellavalle RP. A review of novel therapies for melanoma. Am J Clin Dermatol. 2014; 15:323-37. http://www.ncbi.nlm.nih.gov/pubmed/24928310?dopt=AbstractPlus

8. Poole RM. Pembrolizumab: first global approval. Drugs. 2014; 74:1973-81. http://www.ncbi.nlm.nih.gov/pubmed/25331768?dopt=AbstractPlus

9. Robert C, Schachter J, Long GV et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015; 372:2521-32. http://www.ncbi.nlm.nih.gov/pubmed/25891173?dopt=AbstractPlus

10. Schachter J, Ribas A, Long GV et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017; 390:1853-1862. http://www.ncbi.nlm.nih.gov/pubmed/28822576?dopt=AbstractPlus

11. Ribas A, Puzanov I, Dummer R et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015; 16:908-18. http://www.ncbi.nlm.nih.gov/pubmed/26115796?dopt=AbstractPlus

12. Hamid O, Puzanov I, Dummer R et al. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017; 86:37-45. http://www.ncbi.nlm.nih.gov/pubmed/28961465?dopt=AbstractPlus

13. Reck M, Rodríguez-Abreu D, Robinson AG et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016; 375:1823-1833. http://www.ncbi.nlm.nih.gov/pubmed/27718847?dopt=AbstractPlus

14. Langer CJ, Gadgeel SM, Borghaei H et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016; 17:1497-1508. http://www.ncbi.nlm.nih.gov/pubmed/27745820?dopt=AbstractPlus

15. Herbst RS, Baas P, Kim DW et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016; 387:1540-50. http://www.ncbi.nlm.nih.gov/pubmed/26712084?dopt=AbstractPlus

16. Seiwert TY, Burtness B, Mehra R et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016; 17:956-965. http://www.ncbi.nlm.nih.gov/pubmed/27247226?dopt=AbstractPlus

17. Chow LQM, Haddad R, Gupta S et al. Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort. J Clin Oncol. 2016; 34:3838-3845. http://www.ncbi.nlm.nih.gov/pubmed/27646946?dopt=AbstractPlus

18. Chen R, Zinzani PL, Fanale MA et al. Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. J Clin Oncol. 2017; 35:2125-2132. http://www.ncbi.nlm.nih.gov/pubmed/28441111?dopt=AbstractPlus

19. Balar AV, Castellano D, O'Donnell PH et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017; 18:1483-1492. http://www.ncbi.nlm.nih.gov/pubmed/28967485?dopt=AbstractPlus

20. Bellmunt J, de Wit R, Vaughn DJ et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017; 376:1015-1026. http://www.ncbi.nlm.nih.gov/pubmed/28212060?dopt=AbstractPlus

21. Food and Drug Administration. FDA drug safety communication: FDA alerts healthcare professionals and oncology clinical investigators about two clinical trials on hold evaluating Keytruda (pembrolizumab) in patients with multiple myeloma. Silver Spring, MD; 2017 Sep 20. From the FDA website. https://www.fda.gov/Drugs/DrugSafety/ucm574305.htm

22. US Food and Drug Administration,.Center for Drug Evaluation and Research. Application number 125514Orig1s024: Summary review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/125514Orig1s024SumR.pdf

23. A study of pembrolizumab (MK-3475) in participants with recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma (MK-3475-059/KEYNOTE-059). From clinicaltrials.gov registry. Accessed 2018 Feb 14. https://clinicaltrials.gov/ct2/show/NCT02335411

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