Pembrolizumab

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Pembrolizumab
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]

Disclaimer

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Overview

Pembrolizumab is an monoclonal antibody that is FDA approved for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V400 mutation positive, a BRAF inhibitor. Common adverse reactions include pruritus, rash, constipation, decrease in appetite, diarrhea, nausea, arthralgia, cough, fatigue, erythroderma, adrenal insufficiency, hypophysitis, anemia, hemolytic anemia, pneumonitis.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

metastatic melanoma
  • This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Recommended Dosing
  • The recommended dose of pembrolizumab is 2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.
Dose Modifications
  • Withhold pembrolizumab for any of the following:
  • Resume pembrolizumab in patients whose adverse reactions recover to Grade 0-1.
  • Permanently discontinue pembrolizumab for any of the following:
  • Any life-threatening adverse reaction
  • Grade 3 or 4 pneumonitis
  • Grade 3 or 4 nephritis
  • AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN
    • For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week
  • Grade 3 or 4 infusion-related reactions
  • Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks
  • Persistent Grade 2 or 3 adverse reactions that do not recover to Grade 0-1 within 12 weeks after last dose of pembrolizumab
  • Any severe or Grade 3 treatment-related adverse reaction that recurs
Preparation and Administration
Reconstitution of pembrolizumab for Injection (Lyophilized Powder)
  • Add 2.3 mL of Sterile Water for Injection, USP by injecting the water along the walls of the vial and not directly on the lyophilized powder (resulting concentration 25 mg/mL).
  • Slowly swirl the vial. Allow up to 5 minutes for the bubbles to clear. Do not shake the vial.
Preparation for Intravenous Infusion
  • Visually inspect the solution for particulate matter and discoloration prior to administration. The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible particles are observed.
  • Dilute pembrolizumab injection (solution) or reconstituted lyophilized powder prior to intravenous administration.
  • Withdraw the required volume from the vial(s) of pembrolizumab and transfer into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. The final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL.
  • Discard any unused portion left in the vial.
Storage of Reconstituted and Diluted Solutions
  • The product does not contain a preservative.
  • Store the reconstituted and diluted solution from the pembrolizumab 50 mg vial either:
  • At room temperature for no more than 6 hours from the time of reconstitution. This includes room temperature storage of reconstituted vials, storage of the infusion solution in the IV bag, and the duration of infusion.
  • Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of reconstitution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.
  • Store the diluted solution from the pembrolizumab 100 mg/4 mL vial either:
  • At room temperature for no more than 6 hours from the time of dilution. This includes room temperature storage of the infusion solution in the IV bag, and the duration of infusion.
  • Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.
  • Do not freeze.
Administration
  • Administer infusion solution intravenously over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter.
  • Do not co-administer other drugs through the same infusion line.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of pembrolizumab in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of pembrolizumab in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of pembrolizumab in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of pembrolizumab in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of pembrolizumab in pediatric patients.

Contraindications

  • None.

Warnings

Immune-Mediated Pneumonitis
  • pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving pembrolizumab in Trial 1. The median time to development of pneumonitis was 5 months (range 0.3 weeks to 9.9 months). The median duration was 4.9 months (range 1 week to 14.4 months). Five of eight patients with Grade 2 and the one patient with Grade 3 pneumonitis required initial treatment with high-dose systemic corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. The median initial dose of high-dose corticosteroid treatment was 63.4 mg/day of prednisone or equivalent with a median duration of treatment of 3 days (range 1 to 34) followed by a corticosteroid taper. pneumonitis led to discontinuation of pembrolizumab in 3 (0.7%) patients. pneumonitis completely resolved in seven of the nine patients with Grade 2-3 pneumonitis.
Immune-Mediated colitis
  • colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving pembrolizumab in Trial 1. The median time to onset of colitis was 6.5 months (range 2.3 to 9.8). The median duration was 2.6 months (range 0.6 weeks to 3.6 months). All three patients with Grade 2 or 3 colitis were treated with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) with a median initial dose of 70 mg/day of prednisone or equivalent; the median duration of initial treatment was 7 days (range 4 to 41), followed by a corticosteroid taper. One patient (0.2%) required permanent discontinuation of pembrolizumab due to colitis. All four patients with colitis experienced complete resolution of the event.
  • Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold pembrolizumab for moderate (Grade 2) or severe (Grade 3) colitis, and permanently discontinue pembrolizumab for life-threatening (Grade 4) colitis
Immune-Mediated hepatitis
  • hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving pembrolizumab in Trial 1. The time to onset was 22 days for the case of Grade 4 hepatitis which lASTed 1.1 months. The patient with Grade 4 hepatitis permanently discontinued pembrolizumab and was treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day) systemic corticosteroids followed by a corticosteroid taper. Both patients with hepatitis experienced complete resolution of the event.
  • Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue pembrolizumab .
Immune-Mediated hypophysitis
  • hypophysitis occurred in 2 (0.5%) of 411 patients, consisting of one Grade 2 and one Grade 4 case (0.2% each), in patients receiving pembrolizumab in Trial 1. The time to onset was 1.7 months for the patient with Grade 4 hypophysitis and 1.3 months for the patient with Grade 2 hypophysitis. Both patients were treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day) corticosteroids followed by a corticosteroid taper and remained on a physiologic replacement dose.
Renal Failure and Immune-Mediated nephritis
  • Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold pembrolizumab for moderate (Grade 2) nephritis, and permanently discontinue pembrolizumab for severe (Grade 3), or life-threatening (Grade 4) nephritis .
Immune-Mediated hyperthyroidism and Hypothyroidism
  • hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving pembrolizumab in Trial 1. The median time to onset was 1.5 months (range 0.5 to 2.1). The median duration was 2.8 months (range 0.9 to 6.1). One of two patients with Grade 2 and the one patient with Grade 3 hyperthyroidism required initial treatment with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. One patient (0.2%) required permanent discontinuation of pembrolizumab due to hyperthyroidism. All five patients with hyperthyroidism experienced complete resolution of the event.
  • Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
Other Immune-Mediated Adverse Reactions
  • Other clinically important immune-mediated adverse reactions can occur.
  • Across clinical studies with pembrolizumab in approximately 2000 patients, the following additional clinically significant, immune-mediated adverse reactions were reported in less than 1% of patients: myasthenic syndrome, optic neuritis, and rhabdomyolysis.
  • For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold pembrolizumab and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart pembrolizumab if the adverse reaction remains at Grade 1 or less. Permanently discontinue pembrolizumab for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction .
Embryofetal Toxicity
  • Based on its mechanism of action, pembrolizumab may cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment with pembrolizumab and for 4 months after the last dose of pembrolizumab

Adverse Reactions

Clinical Trials Experience

  • The following adverse reactions are discussed in greater detail in other sections of the labeling.
Clinical Trials Experience
  • Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
  • The data described in the WARNINGS section reflect exposure to pembrolizumab in Trial 1, an uncontrolled, open-label, multiple cohort trial in which 411 patients with unresectable or metastatic melanoma received pembrolizumab at either 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. The median duration of exposure to pembrolizumab was 6.2 months (range 1 day to 24.6 months) with a median of 10 doses (range 1 to 51). The study population characteristics were: median age of 61 years (range 18 to 94), 39% age 65 years or older, 60% male, 97% white, 73% with M1c disease, 8% with brain metastases, 35% with elevated LDH, 54% with prior exposure to ipilimumab, and 47% with two or more prior systemic therapies for advanced or metastatic disease.
  • pembrolizumab was discontinued for adverse reactions in 9% of the 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of pembrolizumab were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients receiving pembrolizumab . The most frequent serious adverse drug reactions reported in 2% or more of patients in Trial 1 were renal failure, dyspnea, pneumonia, and cellulitis.
  • Table 1 presents adverse reactions identified from analyses of the 89 patients with unresectable or metastatic melanoma who received pembrolizumab 2 mg/kg every three weeks in one cohort of Trial 1. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V400 mutation positive, a BRAF inhibitor. This cohort of Trial 1 excluded patients with severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity requiring treatment with corticosteroids or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of pneumonitis or interstitial lung disease; or any active infection requiring therapy, including HIV or hepatitis B or C. Of the 89 patients in this cohort, the median age was 59 years (range 18 to 88), 33% were age 65 years or older, 53% were male, 98% were white, 44% had an elevated LDH, 84% had Stage M1c disease, 8% had brain metastases, and 70% received two or more prior therapies for advanced or metastatic disease. The median duration of exposure to pembrolizumab was 6.2 months (range 1 day to 15.3 months) with a median of nine doses (range 1 to 23). Fifty-one percent of patients were exposed to pembrolizumab for greater than 6 months and 21% for greater than 1 year.
This image is provided by the National Library of Medicine.
Immunogenicity
  • As with all therapeutic proteins, there is the potential for immunogenicity. Because trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) assay results, a subset analysis was performed in the patients with a concentration of pembrolizumab below the drug tolerance level of the anti-product antibody assay. In this analysis, none of the 97 patients who were treated with 2 mg/kg every 3 weeks tested positive for treatment-emergent anti-pembrolizumab antibodies.
  • The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to pembrolizumab with the incidences of antibodies to other products may be misleading.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of pembrolizumab in the drug label.

Drug Interactions

  • No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab .

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D

Risk Summary
  • Based on its mechanism of action, pembrolizumab may cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.
Animal Data
  • Animal reproduction studies have not been conducted with pembrolizumab to evaluate its effect on reproduction and fetal development, but an assessment of the effects on reproduction was provided. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering pembrolizumab during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 knockout mice.
  • Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab has the potential to be transmitted from the mother to the developing fetus. Based on its mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing immune-mediated disorders or of altering the normal immune response.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of pembrolizumab in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of pembrolizumab during labor and delivery.

Nursing Mothers

  • It is not known whether pembrolizumab is excreted in human milk. No studies have been conducted to assess the impact of pembrolizumab on milk production or its presence in breast milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with pembrolizumab

Pediatric Use

  • Safety and effectiveness of pembrolizumab have not been established in pediatric patients.

Geriatic Use

  • Of the 411 patients treated with pembrolizumab , 39% were 65 years and over. No overall differences in safety or efficacy were reported between elderly patients and younger patients.

Gender

There is no FDA guidance on the use of pembrolizumab with respect to specific gender populations.

Race

There is no FDA guidance on the use of pembrolizumab with respect to specific racial populations.

Renal Impairment

  • Based on a population pharmacokinetic analysis, no dose adjustment is needed for patients with renal impairment

Hepatic Impairment

  • Based on a population pharmacokinetic analysis, no dose adjustment is needed for patients with mild hepatic impairment [total bilirubin (TB) less than or equal to ULN and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST]. pembrolizumab has not been studied in patients with moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe (TB greater than 3 times ULN and any AST) hepatic impairment

Females of Reproductive Potential and Males

  • Based on its mechanism of action, pembrolizumab may cause fetal harm when administered to a pregnant woman . Advise females of reproductive potential to use highly effective contraception during treatment with pembrolizumab and for at least 4 months following the last dose of pembrolizumab.

Immunocompromised Patients

There is no FDA guidance one the use of pembrolizumab in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Intravenous

Monitoring

There is limited information regarding Monitoring of pembrolizumab in the drug label.

IV Compatibility

There is limited information regarding IV Compatibility of pembrolizumab in the drug label.

Overdosage

  • There is no information on overdosage with pembrolizumab .

Pharmacology

This image is provided by the National Library of Medicine.

Mechanism of Action

  • Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.

Structure

  • Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa immunoglobulin with an approximate molecular weight of 149 kDa.
  • pembrolizumab for injection is a sterile, preservative-free, white to off-white lyophilized powder in single-use vials. Each vial is reconstituted and diluted for intravenous infusion. Each 2 mL of reconstituted solution contains 50 mg of pembrolizumab and is formulated in L-histidine (3.1 mg), polysorbate 80 (0.4 mg), and sucrose (140 mg). May contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5.

pembrolizumab injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution that requires dilution for intravenous infusion. Each vial contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of pembrolizumab in the drug label.

Pharmacokinetics

There is limited information regarding Pembrolizumab Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Pembrolizumab Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Pembrolizumab Clinical Studies in the drug label.

How Supplied

There is limited information regarding Pembrolizumab How Supplied in the drug label.

Storage

There is limited information regarding Pembrolizumab Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Pembrolizumab Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Pembrolizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Pembrolizumab Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Pembrolizumab Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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