pembrolizumab (Rx)

Brand and Other Names:Keytruda
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 50mg/vial

injectable solution

  • 100mg/4mL (25mg/mL)

Melanoma

Indicated for unresectable or metastatic melanoma

200 mg IV q3Weeks until disease progression or unacceptable toxicity

Non-Small Cell Lung Cancer

Single-agent

  • First-line treatment of metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%)], with no EGFR or ALK genomic tumor aberrations
  • Tumors with PD-L1 expression (TPS ≥1%), with disease progression on or after platinum-containing chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab
  • 200 mg IV q3Weeks until disease progression or unacceptable toxicity, or up to 24 months without disease progression

Combination therapy

  • Nonsquamous NSCLC: First-line treatment in combination with pemetrexed and platinum chemotherapy with no EGFR or ALK genomic tumor aberrations
  • Squamous NSCLC: First-line treatment in combination with carboplatin and either paclitaxel or paclitaxel protein bound
  • 200 mg IV q3Weeks until disease progression, unacceptable toxicity, or up to 24 months without disease progression
  • See prescribing information for chemotherapy agents doses administered in combination with pembrolizumab

Also see Administration

Head & Neck Squamous Cell Carcinoma

Indicated for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy

200 mg IV q3Weeks until disease progression, unacceptable toxicity, or up to 24 months without disease progression

Classical Hodgkin Lymphoma

Indicated for refractory classical Hodgkin lymphoma (cHL) or patients who have relapsed after ≥3 prior lines of therapy

200 mg IV q3Weeks until disease progression, unacceptable toxicity, or up to 24 months without disease progression

Also see Administration

Urothelial Carcinoma

Indicated for patients with locally advanced or metastatic urothelial carcinoma who:

  • Are ineligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (Combined Positive Score (CPS) ≥10) OR
  • Are ineligible for any platinum-containing chemotherapy regardless of PD-L1 status OR
  • Have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

200 mg IV q3Weeks until disease progression, unacceptable toxicity, or up to 24 months without disease progression

Microsatellite Instability-High Cancer

Indicated for unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) who have:

  • Solid tumors that have progressed following prior treatment and in patients who have no satisfactory alternative treatment options, OR
  • Colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan

200 mg IV q3Weeks ntil disease progression, unacceptable toxicity, or up to 24 months without disease progression

Gastric Cancer

Indicated for recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma tumors expressing PD-L1 (combined positive score [CPS] ≥1) with disease progression on or after ≥2 prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy

200 mg IV q3Weeks until disease progression, unacceptable toxicity, or up to 24 months without disease progression

Cervical Cancer

Indicated for recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1)

200 mg IV q3Weeks until disease progression, unacceptable toxicity, or up to 24 months without disease progression

Primary Mediastinal Large B-Cell Lymphoma

Indicated for refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after ≥2 prior lines of therapy

200 mg IV q3Weeks until disease progression, unacceptable toxicity, or up to 24 months without disease progression

Hepatocellular Carcinoma

Indicated for treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

200 mg IV q3Weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression

Dosage Modifications

Renal impairment: No dosage adjustment required

Hepatic impairment

  • Mild: No dosage adjustment required
  • Moderate or severe: Not studied

Interrupt or slow infusion rate

  • Grades 1 or 2 infusion-related reactions

Withhold dose (resume when recover to Grade <1)

  • Grade 3 or 4 endocrinopathies (eg, hypophysitis, hypo- or hyperthyroidism)
  • Grade 4 hematological toxicity in cHL or PMBCL
  • Grade 3 severe skin reactions or suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)
  • Immune-mediated hepatitis in patients without HCC: AST/ALT>3 and up to 5x upper limit of normal (ULN) or total bilirubin >1.5 and up to 3x ULN

Withhold (resume when recover to Grade <1 after corticosteroid taper)

  • Grade 2 immune-mediated pneumonitis
  • Grades 2 or 3 immune-mediated colitis
  • Grade 2 immune-mediated nephritis
  • Any other Grade 2 or 3 immune-mediated adverse reaction, based on the severity and type of reaction

Withhold dose (resume when AST/ALT and total bilirubin recover to Grades <1 or to baseline)

  • Immune-mediated hepatitis in patients with HCC
    • AST/ALT ≥5x ULN if baseline <2x ULN
    • AST/ALT >3x baseline if baseline ≥2x ULN
    • Total bilirubin >2 mg/dL if baseline <1.5 mg/dL
    • Total bilirubin >3 mg/dL, regardless of baseline levels

Permanently discontinue for any of the following

  • Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy)
  • Grades 3 or 4 pneumonitis or recurrent Grade 2 pneumonitis
  • Grades 3 or 4 nephritis
  • Grades 4 severe skin reactions or confirmed SJS or TEN
  • Grades 3 or 4 infusion-related reactions
  • Grades 2 or 3 adverse reaction (excluding endocrinopathy) lasting ≥12 week after last dose
  • Grade 3 (based on severity) or Grade 4 other immune-mediated adverse reactions
  • Grade 4 immune-mediated colitis
  • Immune-mediated hepatitis in patients with HCC
    • ALT/AST >10x ULN; or Child-Pugh score ≥9 points
    • Gastrointestinal bleeding suggestive of portal hypertension
    • New onset of ascites or encephalopathy
  • Immune-mediated hepatitis in patients without HCC
    • Patients without liver metastases: AST/ALT >5x ULN or total bilirubin >3x ULN
    • Patients with liver metastasis and Grade 2 AST/ALT at baseline: With an increase in AST/ALT ≥50% relative to baseline that persists for ≥1 week

Dosing Considerations

cHL, PMBCL, HNSCC, urothelial carcinoma, MSI-H, gastric cancer, HCC, and cervical cancer

  • Indications are approved under accelerated approval based on tumor response rate and durability of response
  • Continued approval may be contingent upon verification and description of clinical benefit in the confirmatory trials
  • PMBCL
    • Limitation of use: Not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy

Patient selection for treatment of NSCLC, gastric cancer, cervical cancer, or urothelial carcinoma

  • Select patients for treatment as a single agent based on the presence of positive PD-L1 expression
    • Metastatic NSCLC
    • Metastatic urothelial carcinoma
    • Metastatic gastric cancer; if PD-L1 expression is undetected in an archival gastric cancer specimen, evaluate the feasibility of obtaining a tumor biopsy for PD-L1 testing
    • Recurrent or metastatic cervical cancer
  • Information on FDA-approved tests for the detection of PD-L1 expression in NSCLC, gastric cancer, cervical cancer, or urothelial carcinoma is available at: http://www.fda.gov/CompanionDiagnostics

Orphan Designations

Multiple myeloma

Nasopharyngeal carcinoma

Merkel cell carcinoma

Esophageal carcinoma

Follicular lymphoma

Small Cell Lung Cancer (excluding those identified as MSI-H or dMMR)

Sponsor

  • Merck, Sharp & Dohme a subsidiary of Merck & Co, Inc; One Merck Drive, Whitehouse Station, NJ 08889

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 50mg/vial

injectable solution

  • 100mg/4mL (25mg/mL)

Classical Hodgkin Lymphoma

Indicated for refractory classical Hodgkin lymphoma (cHL) or relapse after ≥3 prior lines of therapy

2 mg/kg IV q3Weeks; not to exceed 200 mg/dose

Continue until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression

Also see Administration

Microsatellite Instability-High Cancer

Indicated for unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) who have:

  • Solid tumors that have progressed following prior treatment and in patients who have no satisfactory alternative treatment options, OR
  • Colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan

2 mg/kg IV q3Weeks; not to exceed 200 mg/dose

Continue until disease progression, unacceptable toxicity, or up to 24 months without disease progression

Also see Administration

Primary Mediastinal Large B-Cell Lymphoma

Indicated for refractory primary mediastinal large B-cell lymphoma (PMBCL), or relapse after ≥2 prior lines of therapy

2 mg/kg IV q3Weeks; not to exceed 200 mg/day

Dosing Considerations

Limitation of use

  • Safety and effectiveness in pediatric patients with MSI-H CNS cancers not established
  • Not recommended for treatment of PMBCL who require urgent cytoreductive therapy

cHL, PMBCL, and MSI-H

  • Indications are approved under accelerated approval based on tumor response rate and durability of response
  • Continued approval may be contingent upon verification and description of clinical benefit in the confirmatory trials
  • Efficacy for pediatric patients with cHL, PMBCL, or MSI-H cancers was extrapolated from the results in the respective adult population
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Adverse Effects

All grades of severity are listed unless indicated otherwise

>10% (NSCLC)

Decreased appetite (25%)

Nausea (20%)

Thrombocytopenia (20%)

Constipation (15%)

Vomiting (13%)

Dyspnea (23%)

Cough (19%)

Rash (17%)

Arthralgia (11%)

Back pain (11%)

Pruritus (11%)

Neutropenia (11%)

>10% (Urothelial Cancer)

Glucose increased (52%)

Hemoglobin decreased (52%)

Lymphocytes decreased (45%)

Albumin decreased (43%)

Sodium decreased (37%)

Alkaline phosphatase increased (37%)

Creatinine increased (35%)

Phosphate decreased (29%)

AST increased (28%)

Potassium increased (28%)

Calcium decreased (26%)

Nausea (21%)

Constipation (19%)

Diarrhea (18%)

Vomiting (15%)

Lymphocytes decreased, Grade 3 or 4 (15%)

Hemoglobin decreased, Grade 3 or 4 (13%)

Abdominal pain (13%)

>10% (Cervical Cancer)

Anemia (54%)

Lymphocyte count decreased (47%)

Hypoalbuminemia (44%)

Fatigue (43%)

Alkaline phosphatase increased (42%)

Hyponatremia (38%)

Hyperglycemia (38%)

AST increased (34%)

Increased creatinine (32%)

Musculoskeletal pain (27%)

Hypocalcemia (27%)

Anemia, Grade 3 or 4 (24%)

Diarrhea (23%)

Abdominal pain (22%)

Pain (22%)

ALT increased (21%)

Decreased appetite (21%)

Hypokalemia (20%)

Hemorrhage (19%)

Pain (19%)

Nausea (19%)

Vomiting (19%)

Urinary tract infection (UTI) (18%)

Rash (17%)

Infection (16%)

Peripheral edema (15%)

Constipation (14%)

Hyponatremia, Grade 3 or 4 (13%)

Hypothyroidism (11%)

1-10% (Cervical Cancer)

Lymphocyte count decreased, Grade 3 or 4 (9%)

Hypokalemia, Grade 3 or 4 (6%)

UTI, Grade 3 or 4 (5%)

Hypoalbuminemia, Grade 3 or 4 (5%)

Increased creatinine, Grade 3 or 4 (5%)

Musculoskeletal pain, Grade 3 or 4 (5%)

Fatigue, Grade 3 or 4 (5%)

Hemorrhage, Grade 3 or 4 (5%)

Infection, Grade 3 or 4 (4.1%)

AST increased, Grade 3 or 4 (3.9%)

ALT increased, Grade 3 or 4 (3.9%)

Abdominal pain, Grade 3 or 4 (3.1%)

Peripheral edema, Grade 3 or 4 (3%)

Alkaline phosphatase increased, Grade 3 or 4 (2.6%)

Pain, Grade 3 or 4 (2%)

Rash, Grade 3 or 4 (2%)

Diarrhea, Grade 3 or 4 (2%)

Hyperglycemia, Grade 3 or 4 (1.3%)

Hypokalemia, Grade 3 or 4 (1%)

Vomiting, Grade 3 or 4 (1%)

1-10% (Urothelial Carcinoma)

Sodium decreased, Grade 3 or 4 (9%)

Glucose increased, Grade 3 or 4 (8%)

Phosphate decreased, Grade 3 or 4 (8%)

Alkaline phosphatase increased, Grade 3 or 4 (7%)

Urinary tract infection, Grade 3 or 4 (4.9%)

Fatigue, Grade 3 or 4 (4.5%)

Creatinine increased, Grade 3 or 4 (4.4%)

AST increased, Grade 3 or 4 (4.1%)

Decreased appetite, Grade 3 or 4 (3.8%)

Musculoskeletal pain, Grade 3 or 4 (3%)

Hematuria, Grade 3 or 4 (2.3%)

Dyspnea, Grade 3 or 4 (1.9%)

Albumin decreased, Grade 3 or 4 (1.7%)

Calcium decreased, Grade 3 or 4 (1.6%)

Nausea, Grade 3 or 4 (1.1%)

Constipation, Grade 3 or 4 (1.1%)

Abdominal pain, Grade 3 or 4 (1.1%)

1-10% (NSCLC)

Anemia (6%)

Pneumonia (6%)

Dyspnea, Grade 3 or 4 (3.7%)

Urinary tract infection (3%)

Asthenia (2%)

Diarrhea (2%)

Decreased appetite< Grade 3 or 4 (1.5%)

Back pain, Grade 3 or 4 (1.5%)

Nausea, Grade 3 or 4 (1.3%)

Arthralgia, Grade 3 or 4 (1%)

<1%

Urothelial cancer

  • Vomiting, Grade 3 or 4
  • Potassium increased, Grade 3 or 4

NSCLC

  • Rash, Grade 3 or 4
  • Cough, Grade 3 or 4
  • Constipation, Grade 3 or 4
  • Vomiting, Grade 3 or 4

Postmarketing reports

Infusion-related reactions

Exfoliative dermatitis

Bullous pemphigoid

Asthenia

Lymphopenia

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Warnings

Contraindications

None

Cautions

Clinical trials reported immune-mediated pneumonitis, colitis, hepatitis, nephritis and other immune-mediated adverse reactions (eg, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, myasthenic syndrome, optic neuritis, and rhabdomyolysis)

Immune-mediated rashes, including SJS, TEN, exfoliative dermatitis, and bullous pemphigoid, reported; monitor for suspected severe skin reactions and exclude other causes

Solid organ transplant rejection reported in postmarketing setting; treatment increases risk of rejection in solid organ transplant recipients; consider benefit of treatment versus risk of possible organ rejection

Immune-mediated endocrinopathies (eg, adrenal insufficiency, changes in thyroid function, type 1 diabetes mellitus including diabetic ketoacidosis) reported

Infusion-related reactions, including severe and life-threatening reactions, reported; monitor for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever

Hypophysitis reported; monitor for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency)

Thyroid disorders can occur; monitor for changes in thyroid function (at the start of treatment, periodically during treatment, and as clinically indicated) and for clinical signs and symptoms of thyroid disorders

Based on its mechanism of action, fetal harm may occur when administered to a pregnant woman (see Pregnancy)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with pembrolizumab

In two randomized clinical trials in patients with multiple myeloma, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality; treatment of patients with multiple myeloma with a PD-1 or PDL1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials

Also see Dosage Modifications

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Pregnancy & Lactation

Pregnancy

Based on its mechanism of action, fetal harm may occur when administered to a pregnant woman

No human data available informing the risk of embryo-fetal toxicity

Animal data

  • In animal models, the PD-1/PD-L1 signaling pathway is important in the maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue
  • Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab can potentially be transmitted from the mother to the developing fetus

Contraception

  • Advise females of reproductive potential to use effective contraception during treatment and for at least 4 months following final dose

Lactation

Unknown if distributed in human breast milk

No studies conducted to assess impact of pembrolizumab on milk production or its presence in breast milk

Instruct women to discontinue nursing during treatment and for 4 months after final dose

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

more...
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Pharmacology

Mechanism of Action

Monoclonal antibody to programmed cell death-1 protein (PD-1); blocks interaction between PD-1 and its ligands, PD-L1 and PD-L2

PD-1 and PD-L1

  • PD-1 and related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions; PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound
  • This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation
  • Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells

Absorption

Steady-state concentrations were reached by 16 weeks of repeated every 3-week regimen

Systemic accumulation: 2.1-fold

Distribution

Vd: 6 L

Excretion

Half-life: 22 days

Clearance: 193 mL/day (steady-state); 252 mL/day (first-dose)

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Administration

IV Compatibilities

0.9% NaCl

Dextrose 5%

IV Preparation

Reconstitute vial by adding 2.3 mL of Sterile Water for Injection (resulting concentration 25 mg/mL)

Slowly swirl vial; allow up to 5 minutes for bubbles to clear

Do NOT shake vial

Visually inspect reconstituted solution for particulate matter and discoloration prior to administration

Reconstituted solution should appeared clear to slightly opalescent, colorless to slightly yellow solution; discard if extraneous particulate matter other than translucent to white proteinaceous particles is observed

IV infusion preparation

  • Withdraw required volume from vial(s) and transfer into IV bag containing 0.9% NaCl or D5W; mix diluted solution by gentle inversion
  • Final concentration of diluted solution: 1-10 mg/mL
  • Discard any unused portion left in vial

IV Administration

Infuse over 30 minutes through an IV line containing a sterile, nonpyrogenic, low-protein binding 0.2-5 micron in-line or add-on filter

NSCLC (combination therapy): Administer prior to chemotherapy

Do not coadminister other drugs through the same infusion line

Storage

Unopened vials

  • Refrigerate between 2-8°C (36-46°F)
  • Does not contain preservatives
  • Do not freeze

Reconstituted vials/diluted solution

  • Room temperature: Not to exceed 6 hr from time of reconstitution; includes room temperature storage of reconstituted vials and/or dilution, and duration of infusion
  • Refrigerate at 2-8°C (36-46°F): Not to exceed 24 hr from time of reconstitution/dilution
  • If refrigerated, allow diluted solution to come to room temperature prior to administration
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Formulary

FormularyPatient Discounts

Adding plans allows you to compare formulary status to other drugs in the same class.

To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

Adding plans allows you to:

  • View the formulary and any restrictions for each plan.
  • Manage and view all your plans together – even plans in different states.
  • Compare formulary status to other drugs in the same class.
  • Access your plan list on any device – mobile or desktop.

The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

Tier Description
1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
NC NOT COVERED – Drugs that are not covered by the plan.
Code Definition
PA Prior Authorization
Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
QL Quantity Limits
Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
ST Step Therapy
Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
OR Other Restrictions
Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.