Pembrolizumab: Difference between revisions

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|authorTag={{AV}}
|authorTag={{AV}}
|genericName=Pembrolizumab
|genericName=Pembrolizumab
|aOrAn=
|aOrAn=an
 
|drugClass=[[monoclonal antibody]]
a
|indicationType=treatment
|drugClass=
|indication=patients with unresectable or [[metastatic melanoma]] and disease progression following [[ipilimumab]] and, if [[BRAF|BRAF V400 mutation positive]], a [[BRAF|BRAF inhibitor]]
|indication=
|adverseReactions=[[pruritus]], [[rash]], [[constipation]], [[anorexia|decrease in appetite]], [[diarrhea]], [[nausea]], [[arthralgia]], [[cough]], [[fatigue]], [[erythroderma]], [[adrenal insufficiency]], [[hypophysitis]], [[anemia]],  [[hemolytic anemia]], [[pneumonitis]]
|hasBlackBoxWarning=
|adverseReactions=


<!--Black Box Warning-->
<!--Black Box Warning-->
|blackBoxWarningTitle=
|blackBoxWarningTitle=Title
Title
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i>
|blackBoxWarningBody=
<i><span style="color:#FF0000;">ConditionName: </span></i>


* Content
* Content
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<!--FDA-Labeled Indications and Dosage (Adult)-->
<!--FDA-Labeled Indications and Dosage (Adult)-->
|fdaLIADAdult=
|fdaLIADAdult======[[metastatic melanoma]]=====
 
*pembrolizumab® is indicated for the treatment of patients with unresectable or [[metastatic melanoma]] and disease progression following ipilimumab and, if [[BRAF|BRAF V400 mutation positive]], a [[BRAF|BRAF inhibitor]] .
=====[[metastatic melanoma]]=====
*pembrolizumab ® is indicated for the treatment of patients with unresectable or [[metastatic melanoma]] and disease progression following ipilimumab and, if [[BRAF]] V600 mutation positive, a [[BRAF]] inhibitor .


*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.
*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.
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:*Grade 3 or 4 [[pneumonitis ]]
:*Grade 3 or 4 [[pneumonitis ]]
:*Grade 3 or 4 [[nephritis]]  
:*Grade 3 or 4 [[nephritis]]  
:*[[AST]] or ALT greater than 5 times ULN or total [[bilirubin]] greater than 3 times ULN
:*[[AST]] or ALT greater than 5 times ULN or [[bilirubin|total bilirubin]] greater than 3 times ULN
:**For patients with liver met[[AST]]asis 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 l[[AST]]s for at le[[AST]] 1 week
:**For patients with [[metastasis|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| infusion-related reactions(infusion reaction)]]
:*Grade 3 or 4 [[infusion reaction| infusion-related reactions]]
:*Inability to reduce [[corticosteroid]] dose to 10 mg or less of [[prednisone]] or equivalent per day within 12 weeks
:*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 l[[AST]] dose of pembrolizumab  
:*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  
:*Any severe or Grade 3 treatment-related adverse reaction that recurs  


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*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.
*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.
*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.
*Withdraw the required volume from the vial(s) of pembrolizumab  and transfer into an intravenous (IV) bag containing [[saline|0.9% Sodium Chloride]] Injection, USP or [[Dextrose|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.
*Discard any unused portion left in the vial.


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<!--Guideline-Supported Use (Adult)-->
<!--Guideline-Supported Use (Adult)-->
|offLabelAdultGuideSupport=
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of pembrolizumab in adult patients.
 
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of pembrolizumab in adult patients.


<!--Non–Guideline-Supported Use (Adult)-->
<!--Non–Guideline-Supported Use (Adult)-->
|offLabelAdultNoGuideSupport=
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of pembrolizumab in adult patients.
 
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of pembrolizumab in adult patients.


<!--Pediatric Indications and Dosage-->
<!--Pediatric Indications and Dosage-->


<!--FDA-Labeled Indications and Dosage (Pediatric)-->
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
|fdaLIADPed=
|fdaLIADPed=There is limited information regarding <i>FDA-Labeled Use</i> of pembrolizumab in pediatric patients.
 
There is limited information regarding <i>FDA-Labeled Use</i> of pembrolizumab in pediatric patients.


<!--Off-Label Use and Dosage (Pediatric)-->
<!--Off-Label Use and Dosage (Pediatric)-->


<!--Guideline-Supported Use (Pediatric)-->
<!--Guideline-Supported Use (Pediatric)-->
|offLabelPedGuideSupport=
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of pembrolizumab in pediatric patients.
 
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of pembrolizumab in pediatric patients.


<!--Non–Guideline-Supported Use (Pediatric)-->
<!--Non–Guideline-Supported Use (Pediatric)-->
|offLabelPedNoGuideSupport=
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of pembrolizumab in pediatric patients.
 
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of pembrolizumab in pediatric patients.


<!--Contraindications-->
<!--Contraindications-->
|contraindications=
|contraindications=*None.
 
*None.


<!--Warnings-->
<!--Warnings-->
|warnings=
|warnings=
======Immune-Mediated Pneumonitis======
======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 [[corticosteroid]]s (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]].
*[[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 [[corticosteroid]]s (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]].


*Monitor patients for signs and symptoms of [[pneumonitis]]. Evaluate patients with suspected [[pneumonitis ]]with radiographic imaging and administer [[corticosteroid]]s for Grade 2 or greater [[pneumonitis]]. Withhold pembrolizumab  for moderate (Grade 2) [[pneumonitis]], and permanently discontinue pembrolizumab  for severe (Grade 3) or life-threatening (Grade 4) [[pneumonitis ]].
*Monitor patients for signs and symptoms of [[pneumonitis]]. Evaluate patients with suspected [[pneumonitis ]]with radiographic imaging and administer [[corticosteroid]]s for Grade 2 or greater [[pneumonitis]]. Withhold pembrolizumab  for moderate (Grade 2) [[pneumonitis]], and permanently discontinue pembrolizumab  for severe (Grade 3) or life-threatening (Grade 4) [[pneumonitis ]].


======Immune-Mediated [[colitis]]======
======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 [[corticosteroid]]s (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.
*[[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 [[corticosteroid]]s (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.
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<!--Clinical Trials Experience-->
<!--Clinical Trials Experience-->
|clinicalTrials=
|clinicalTrials=*The following adverse reactions are discussed in greater detail in other sections of the labeling.
 
*The following adverse reactions are discussed in greater detail in other sections of the labeling.


:*Immune-mediated [[pneumonitis ]]
:*Immune-mediated [[pneumonitis ]]
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*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.
*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 and PRECAUTIONS 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.
*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]].
*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]] V600 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 [[corticosteroid]]s 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 [[corticosteroid]]s 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.
*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 [[corticosteroid]]s 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 [[corticosteroid]]s 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.


*pembrolizumab  was discontinued for adverse reactions in 6% of the 89 patients. The most common adverse reactions (reported in at least 20% of patients) were [[fatigue]], [[cough]], [[nausea]], [[pruritus]], [[rash]], [[decreased appetite]], [[constipation]], [[arthralgia]], and [[diarrhea]].
*pembrolizumab  was discontinued for adverse reactions in 6% of the 89 patients. The most common adverse reactions (reported in at least 20% of patients) were [[fatigue]], [[cough]], [[nausea]], [[pruritus]], [[rash]], [[decreased appetite]], [[constipation]], [[arthralgia]], and [[diarrhea]].


: [[File:pembrolizumab02.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
: [[File:pembrolizumab02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
=====Immunogenicity=====
=====Immunogenicity=====


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*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.
*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-->
<!--Postmarketing Experience-->
|postmarketing=
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of pembrolizumab in the drug label.
 
There is limited information regarding <i>Postmarketing Experience</i> of pembrolizumab in the drug label.


<!--Drug Interactions-->
<!--Drug Interactions-->
|drugInteractions=
|drugInteractions=* No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab .
 
* No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab .
<!--Use in Specific Populations-->
<!--Use in Specific Populations-->
|useInPregnancyFDA=
|FDAPregCat=D
*Pregnancy Category D.
|useInPregnancyFDA======Risk Summary=====
 
=====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.
*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.
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*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.
*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.
|useInPregnancyAUS=
|useInPregnancyAUS=There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of pembrolizumab in women who are pregnant.
 
|useInLaborDelivery=There is no FDA guidance on use of pembrolizumab during labor and delivery.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of pembrolizumab in women who are pregnant.
|useInNursing=*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
|useInLaborDelivery=
|useInPed=*Safety and effectiveness of pembrolizumab  have not been established in pediatric patients.
There is no FDA guidance on use of pembrolizumab during labor and delivery.
|useInGeri=*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.
|useInNursing=
|useInGender=There is no FDA guidance on the use of pembrolizumab with respect to specific gender populations.
*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  
|useInRace=There is no FDA guidance on the use of pembrolizumab with respect to specific racial populations.
|useInPed=
|useInRenalImpair=*Based on a population pharmacokinetic analysis, no dose adjustment is needed for patients with [[renal impairment]]
*Safety and effectiveness of pembrolizumab  have not been established in pediatric patients.
|useInHepaticImpair=*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
|useInGeri=
|useInReproPotential=*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.
*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.
|useInImmunocomp=There is no FDA guidance one the use of pembrolizumab in patients who are [[immunocompromised]].
|useInGender=
There is no FDA guidance on the use of pembrolizumab with respect to specific gender populations.
|useInRace=
There is no FDA guidance on the use of pembrolizumab with respect to specific racial populations.
|useInRenalImpair=
*Based on a population pharmacokinetic analysis, no dose adjustment is needed for patients with [[renal impairment]]
|useInHepaticImpair=
*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  
|useInReproPotential=
*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.
|useInImmunocomp=
There is no FDA guidance one the use of pembrolizumab in patients who are [[immunocompromised]].


<!--Administration and Monitoring-->
<!--Administration and Monitoring-->
|administration
|administration=*Intravenous
 
|monitoring=There is limited information regarding <i>Monitoring</i> of pembrolizumab in the drug label.
* Intravenous
|monitoring=
 
There is limited information regarding <i>Monitoring</i> of pembrolizumab in the drug label.
 
* Description


<!--IV Compatibility-->
<!--IV Compatibility-->
|IVCompat=
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of pembrolizumab in the drug label.
 
There is limited information regarding <i>IV Compatibility</i> of pembrolizumab in the drug label.


<!--Overdosage-->
<!--Overdosage-->
|overdose=
|overdose=*There is no information on overdosage with pembrolizumab .
 
*There is no information on overdosage with pembrolizumab .
<!--Pharmacology-->
<!--Pharmacology-->


<!--Drug box 2-->
<!--Drug box 2-->
|drugBox=: [[File:pembrolizumab00.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
|drugBox=: [[File:pembrolizumab00.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]


<!--Mechanism of Action-->
<!--Mechanism of Action-->
|mechAction=
|mechAction=*Binding of the [[Programmed cell death protein 1 | 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 [[Programmed cell death protein 1 | 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.  
 
*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-->
<!--Structure-->
|structure=
|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 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  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.
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<!--Pharmacodynamics-->
<!--Pharmacodynamics-->
|PD=
|PD=There is limited information regarding <i>Pharmacodynamics</i> of pembrolizumab in the drug label.
 
There is limited information regarding <i>Pharmacodynamics</i> of pembrolizumab in the drug label.


<!--Pharmacokinetics-->
<!--Pharmacokinetics-->
|PK=
|alcohol=Alcohol-Pembrolizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
 
*The pharmacokinetics of pembrolizumab was studied in 479 patients who received doses of 1 to 10 mg/kg every 2 weeks or 2 to 10 mg/kg every 3 weeks. Based on a population pharmacokinetic analysis, the mean [% [[coefficient of variation]] (CV%)] clearance ([[CL]]) is 0.22 L/day (28%) and the mean (CV%) elimination [[half-life]] (t1/2) is 26 days (24%). Steady-state concentrations of pembrolizumab were reached by 18 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was 2.1-fold. The peak concentration ([[Cmax]]), trough concentration ([[Cmin]]), and area under the plasma concentration versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks.
 
*Specific Populations: The effects of various covariates on the pharmacokinetics of pembrolizumab were assessed in population pharmacokinetic analyses. The CL of pembrolizumab increased with increasing body weight; the resulting exposure differences were adequately addressed by the administration of a weight-based dose. The following factors had no clinically important effect on the [[CL]] of pembrolizumab: age (range 18 to 94 years), gender, [[renal impairment]], mild hepatic impairment, and tumor burden. The effect of race could not be assessed due to limited data available in non-White patients.
 
*Renal Impairment: The effect of renal impairment on the CL of pembrolizumab was evaluated by population pharmacokinetic analyses in patients with mild (eGFR 60 to 89 mL/min/1.73 m2; n=210), moderate ([[eGFR]] 30 to 59 mL/min/1.73 m2; n=43), or severe (e[[GFR]] 15 to 29 mL/min/1.73 m2; n=2) [[renal impairment]] compared to patients with normal (e[[GFR]] greater than or equal to 90 mL/min/1.73 m2; n=221) renal function. No clinically important differences in the [[CL]] of pembrolizumab were found between patients with [[renal impairment]] and patients with normal renal function .
 
*[[Hepatic Impairment]]: The effect of hepatic impairment on the [[CL]] of pembrolizumab was evaluated by population pharmacokinetic analyses in patients with mild [[hepatic impairment]] (TB less than or equal to ULN and [[AST]] greater than ULN or TB between 1 and 1.5 times ULN and any [[AST]]; n=59) compared to patients with normal hepatic function (TB and [[AST]] less than or equal to ULN; n=410). No clinically important differences in the CL of pembrolizumab were found between patients with mild hepatic impairment and normal hepatic function. 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 [
<!--Nonclinical Toxicology-->
|nonClinToxic=
 
=====Carcinogenesis, Mutagenesis, Impairment of Fertility=====
 
*No studies have been performed to test the potential of pembrolizumab for carcinogenicity or genotoxicity.
 
*Fertility studies have not been conducted with pembrolizumab. In 1-month and 6-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature.
 
===== Animal Toxicology and/or Pharmacology=====
 
*In animal models, inhibition of PD-1 signaling resulted in an increased severity of some infections and enhanced inflammatory responses. [[M. tuberculosis]]-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 knockout mice have also shown decreased survival following infection with [[lymphocytic choriomeningitis virus]] (LCMV). Administration of pembrolizumab in chimpanzees with naturally occurring chronic [[hepatitis]] B infection resulted in two out of four animals with significantly increased levels of serum [[ALT]], [[AST]], and GGT, which persisted for at least 1 month after discontinuation of pembrolizumab.
 
<!--Clinical Studies-->
|clinicalStudies=
 
*The efficacy of pembrolizumab  was investigated in a multicenter, open-label, randomized (1:1), dose-comparative, activity-estimating cohort of Trial 1. Key eligibility criteria were unresectable or [[metastatic melanoma]] with progression of disease; refractory to two or more doses of [[ipilimumab]] (3 mg/kg or higher) and, if [[BRAF]] V600 mutation-positive, a [[BRAF]] or [[MEK inhibitor]]; and disease progression within 24 weeks following the LAST dose of [[ipilimumab]]. The trial excluded patients with autoimmune disease; a medical condition that required immunosuppression; and a history of severe immune-mediated adverse reactions with [[ipilimumab]], defined as any Grade 4 toxicity requiring treatment with [[corticosteroid]]s or Grade 3 toxicity requiring [[corticosteroid]] treatment (greater than 10 mg/day [[prednisone]] or equivalent dose) for greater than 12 weeks. Patients were randomized to receive 2 mg/kg (n=89) or 10 mg/kg (n=84) of pembrolizumab  every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Assessment of tumor status was performed every 12 weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by blinded independent central review and duration of response.
 
*Among the 173 patients enrolled, the median age was 61 years (36% age 65 or older); 60% male; 97% White; and 66% and 34% with an ECOG performance status 0 and 1, respectively. Disease characteristics were [[BRAF]] V600 mutation (17%), [[elevated lactate dehydrogenase]] (39%), M1c (82%), brain met[[AST]]ases (9%), and two or more prior therapies for advanced or met[[AST]]atic disease (73%).
 
*The ORR was 24% (95% confidence interval: 15, 34) in the 2 mg/kg arm, consisting of 1 complete response and 20 partial responses. Among the 21 patients with an objective response, 3 (14%) had progression of disease 2.8, 2.9, and 8.2 months after initial response. The remaining 18 patients (86%) had ongoing responses with durations ranging from 1.4+ to 8.5+ months, which included 8 patients with ongoing responses of 6 months or longer. One additional patient developed two new asymptomatic lesions at the first tumor assessment concurrent with a 75% decrease in overall tumor burden; pembrolizumab  was continued and this reduction in tumor burden was durable for 5+ months.
 
*There were objective responses in patients with and without [[BRAF]] V600 mutation-positive melanoma. Similar ORR results were observed in the 10 mg/kg arm.
<!--How Supplied-->
|howSupplied=
 
*pembrolizumab  for injection (lyophilized powder): carton containing one 50 mg single-use vial (NDC 0006-3029-02).
 
*Store vials under refrigeration at 2°C to 8°C (36°F to 46°F).
 
*pembrolizumab  injection (solution): carton containing one 100 mg/4 mL (25 mg/mL), single-use vial (NDC 0006-3026-02)
 
*Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.
 
<!--Patient Counseling Information-->
|fdaPatientInfo=
 
*Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE).
*Inform patients of the risk of immune-mediated adverse reactions that may require [[corticosteroid]] treatment and interruption or discontinuation of pembrolizumab , including:
:*[[Pneumonitis]]: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath
:*[[colitis]]: Advise patients to contact their healthcare provider immediately for [[diarrhea]] or severe abdominal pain .
:*[[hepatitis]]: Advise patients to contact their healthcare provider immediately for jaundice, severe [[nausea]] or [[vomiting]], or easy bruising or bleeding
:*[[hypophysitis]]: Advise patients to contact their healthcare provider immediately for persistent or unusual [[headache]], extreme weakness, [[dizziness]] or [[fainting]], or vision changes .
:*[[nephritis]]: Advise patients to contact their healthcare provider immediately for signs or symptoms of [[nephritis]] .
:*[[hyperthyroidism]] and [[Hypothyroidism]]: Advise patients to contact their healthcare provider immediately for signs or symptoms of [[hyperthyroidism]] and [[Hypothyroidism]] .
*Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests .
*Advise women that pembrolizumab  may cause fetal harm. Instruct women of reproductive potential to use highly effective [[contraception]] during and for 4 months after the last dose of pembrolizumab  .
*Advise nursing mothers not to breast feed while taking pembrolizumab
<!--Precautions with Alcohol-->
|alcohol=
 
* Alcohol-pembrolizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
 
<!--Brand Names-->
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* KEYTRUDA®<ref>{{Cite web | title =  | url =  }}</ref>
 
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* A® — B®<ref name="www.ismp.org">{{Cite web  | l[[AST]] =  | first =  | title = http://www.ismp.org | url = http://www.ismp.org | publisher =  | date =  }}</ref>
 
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[[Category:Drug]]
[[Category:Chemotherapeutic agents]]

Latest revision as of 03:24, 6 February 2019

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

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

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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