Pembrolizumab, marketed under the brand name Keytruda, is a medication used in cancer treatment. It is an immune checkpoint inhibitor that targets the programmed death receptor-1 (PD-1) protein, which plays a role in suppressing the immune system's response to cancer cells.

Indications of Pembrolizumab (Keytruda):

• Recurrent or metastatic Cervical cancer:
  • It is used for the treatment of recurrent or metastatic cervical cancer in patients whose tumors express PD-L1 (combined positive score [CPS] ≥1), as determined by an approved test, and with disease progression on or after chemotherapy.
• Recurrent locally advanced or metastatic esophageal cancer:
  • It is indicated for the treatment of recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus in patients whose tumors express PD-L1 (CPS ≥10) as determined by an approved test, with disease progression after one or more prior lines of systemic therapy.
• Recurrent locally advanced or metastatic gastric cancer:
  • It is effective for the treatment of recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma in patients whose tumors express PD-L1 (CPS ≥1), as determined by an approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy, and if appropriate, HER2/neu-targeted therapy
• Recurrent or metastatic squamous cell carcinoma of the head and neck:
  • It is prescribed as first-line treatment (in combination with platinum and fluorouracil) of metastatic or unresectable recurrent head and neck squamous cell carcinoma.
  • First-line, monotherapy for metastatic or unresectable recurrent HNSCC in patients whose tumors express PD-L1 (CPS ≥1), as determined by an approved test.
  • Monotherapy for recurrent or metastatic HNSCC in patients with disease progression on or after platinum-containing chemotherapy.
• Advanced Hepatocellular carcinoma:
  • It is used for the treatment of hepatocellular carcinoma in patients who have been previously treated with sorafenib.
• Relapsed or refractory classical Hodgkin lymphoma:
  • Adult and pediatric patients with refractory classical Hodgkin lymphoma or patients who have relapsed after 3 or more prior lines of therapy can be treated with pembrolizumab.
• Melanoma:
  • It is indicated as an adjuvant treatment of melanoma with lymph node involvement following complete resection.
  • Treatment of unresectable or metastatic melanoma
• Recurrent or metastatic Merkel cell carcinoma:
  • Merkel cell carcinoma (recurrent locally advanced or metastatic) in adult and pediatric patients can be treated by pembrolizumab.
• Metastatic or unresectable microsatellite instability-high cancer:
  • Solid tumors: Treatment of unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors in adult and pediatric patients that have progressed following prior treatment and have no satisfactory alternative treatment options
  • Limitation of use: Safety and efficacy in pediatric patients with MSI-H central nervous system cancers have not been established.
• Colorectal cancer:
  • Treatment of unresectable or metastatic, MSI-H or mismatch repair deficient colorectal cancer in adult and pediatric patients that have progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Non-small cell lung cancer:
  • It is prescribed as single-agent first-line treatment of non-small cell lung cancer (NSCLC) in patients with stage III NSCLC (who are not candidates for surgical resection or definitive chemoradiation) or in patients with metastatic NSCLC, and with tumors with PD-L1 expression (tumor proportion score [TPS] ≥1%), as determined by an approved test, and with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations
  • First-line treatment (in combination with pemetrexed and platinum chemotherapy) of metastatic nonsquamous NSCLC in patients with no EGFR or ALK genomic tumor aberrations
  • First-line treatment (in combination with carboplatin and either paclitaxel or paclitaxel [protein bound]) of metastatic squamous NSCLC
  • Monotherapy for metastatic NSCLC in patients with tumors with PD-L1 expression (TPS ≥1%), as determined by an approved test, and with disease progression on or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression (on approved EGFR- or ALK-directed therapy) prior to receiving pembrolizumab.
• Relapsed or refractory primary mediastinal large B-cell lymphoma:
  • Primary mediastinal large B-cell lymphoma (PMBCL) in adult and pediatric patients with refractory disease or who have relapsed after 2 or more prior lines of therapy can be treated by this drug.
  • Limitation of use: Not recommended for treatment of PMBCL in patients who require urgent cytoreductive therapy.
• Advanced Renal cell carcinoma:
  • First-line treatment of advanced renal cell carcinoma (in combination with axitinib).
• Metastatic Small cell lung cancer:
  • Treatment of metastatic small cell lung cancer in patients with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy
• Metastatic or locally advanced Urothelial carcinoma:
  • Treatment of locally advanced or metastatic urothelial cancer in patients who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS ≥10) as determined by an approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status
  • Treatment of locally advanced or metastatic urothelial cancer in patients with disease progression during or after platinum-containing chemotherapy or within 1 year of neoadjuvant or adjuvant platinum-containing chemotherapy.

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Pembrolizumab (Keytruda) dose in Adults

Pembrolizumab (Keytruda) dose in the treatment of recurrent or metastatic Cervical cancer:

• In the treatment of recurrent or metastatic cervical cancer, Pembrolizumab is given through an intravenous (IV) injection.
• The recommended dose is 200 mg, which is administered once every three weeks.
• The treatment continues until there is evidence of disease progression, the patient experiences unacceptable side effects, or, if there is no disease progression, for a maximum of up to 24 months.

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Pembrolizumab (Keytruda) dose in the treatment of recurrent locally advanced or metastatic esophageal cancer:

• In the treatment of recurrent locally advanced or metastatic esophageal cancer, the recommended dose of Pembrolizumab is 200 mg, given through an intravenous (IV) injection.
• This dose is administered once every three weeks.
• The treatment continues until there is evidence of disease progression, the patient experiences unacceptable side effects, or, if there is no disease progression, for a maximum of up to 24 months.

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Pembrolizumab (Keytruda) dose in the treatment of recurrent locally advanced or metastatic Gastric cancer:

• In the treatment of recurrent locally advanced or metastatic gastric cancer, the recommended dose of Pembrolizumab is 200 mg, administered through an intravenous (IV) injection.
• This dose is given once every three weeks.
• The treatment continues until there is evidence of disease progression, the patient experiences unacceptable side effects, or, if there is no disease progression, for a maximum of up to 24 months.

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Pembrolizumab (Keytruda) dose in the treatment of unresectable, recurrent or metastatic squamous cell carcinoma of the head and neck (monotherapy):

• In the treatment of unresectable, recurrent, or metastatic head and neck squamous cell cancer using Pembrolizumab as a single agent therapy, the recommended dose is 200 mg administered through an intravenous (IV) injection.
• This dose is given once every three weeks.
• The treatment continues until there is evidence of disease progression, the patient experiences unacceptable side effects, or, if there is no disease progression, for a maximum of up to 24 months.

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Pembrolizumab (Keytruda) dose in the treatment of unresectable, recurrent or metastatic squamous cell carcinoma of the head and neck (combination therapy):

• In the treatment of unresectable, recurrent, or metastatic head and neck squamous cell cancer using Pembrolizumab in combination therapy, the recommended dose is 200 mg administered through an intravenous (IV) injection.
• This dose is given once every three weeks.
• The treatment continues until there is evidence of disease progression, the patient experiences unacceptable side effects, or, if there is no disease progression, for a maximum of up to 24 months.
• In combination therapy, Pembrolizumab is initially used together with 6 cycles of fluorouracil and either carboplatin or cisplatin.
• This combination therapy is given for a defined period of time according to the patient condition.

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Pembrolizumab (Keytruda) dose in the treatment of advanced hepatocellular carcinoma:

• In the treatment of advanced hepatocellular carcinoma, the recommended dose of Pembrolizumab is 200 mg administered through an intravenous (IV) injection.
• This dose is given once every three weeks.
• The treatment continues until there is evidence of disease progression, the patient experiences unacceptable side effects, or, if there is no disease progression, for a maximum of up to 24 months.

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Pembrolizumab (Keytruda) dose in the treatment of relapsed or refractory classical Hodgkin lymphoma:

• In the treatment of relapsed or refractory classical Hodgkin lymphoma, the recommended dose of Pembrolizumab is 200 mg administered through an intravenous (IV) injection.
• This dose is given once every three weeks.
• The treatment continues until there is evidence of disease progression, the patient experiences unacceptable side effects, or, if there is no disease progression, for a maximum of up to 24 months.

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Pembrolizumab (Keytruda) dose in the treatment of Melanoma (adjuvant treatment):

• In the adjuvant treatment of melanoma, the recommended dose of Pembrolizumab is 200 mg administered through an intravenous (IV) injection.
• This dose is given once every three weeks.
• The treatment continues until there is evidence of disease recurrence, the patient experiences unacceptable side effects, or, if there is no disease recurrence, for a maximum of up to 12 months.

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Pembrolizumab (Keytruda) dose in the treatment of unresectable or metastatic Melanoma:

• In the treatment of unresectable or metastatic melanoma, the recommended dose of Pembrolizumab is 200 mg administered through an intravenous (IV) injection.
• This dose is given once every three weeks.
• The treatment continues until there is evidence of disease progression or the patient experiences unacceptable toxicity.

Off-label dosing:

• It's important to note that in the study conducted by Ribas in 2015, an off-label dosing of Pembrolizumab at 2 mg/kg once every three weeks until disease progression or unacceptable toxicity was also evaluated.
• While this off-label dosing regimen was studied, the recommended dose of 200 mg once every three weeks is typically used in clinical practice.

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Pembrolizumab (Keytruda) dose in the treatment of recurrent or metastatic Merkel cell carcinoma:

• In the treatment of recurrent or metastatic Merkel cell carcinoma, the recommended dose of Pembrolizumab is 200 mg administered through an intravenous (IV) injection.
• This dose is given once every three weeks.
• The treatment continues until there is evidence of disease progression, the patient experiences unacceptable toxicity, or, if there is no disease progression, for a maximum of up to 24 months.

Off-label dosing:

• An off-label dosing regimen has been studied in the treatment of Merkel cell carcinoma.
• According to Nghiem's study in 2016, the off-label dosing of Pembrolizumab is 2 mg/kg once every three weeks.
• This off-label dosing regimen can be continued for up to 2 years or until a complete response is achieved, or until there is disease progression or unacceptable toxicity.

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Pembrolizumab (Keytruda) dose in the treatment of unresectable or metastatic microsatellite instability-high cancer:

• In the treatment of unresectable or metastatic microsatellite instability-high (MSI-H) cancer, the recommended dose of Pembrolizumab is 200 mg administered through an intravenous (IV) injection.
• This dose is given once every three weeks.
• The treatment continues until there is evidence of disease progression, the patient experiences unacceptable toxicity, or, if there is no disease progression, for a maximum of up to 24 months.

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Pembrolizumab (Keytruda) dose in the treatment of stage III or metastatic non-small cell lung cancer (monotherapy):

• In the treatment of non-small cell lung cancer (NSCLC), the recommended dose of Pembrolizumab as a single-agent therapy is 200 mg administered through an intravenous (IV) injection.
• This dose is given once every three weeks.
• The treatment continues until there is evidence of disease progression, the patient experiences unacceptable toxicity, or, if there is no disease progression, for a maximum of up to 24 months.

Off-label dosing:

• An off-label dosing regimen has been studied for patients with metastatic NSCLC who have experienced disease progression following platinum-containing chemotherapy.
• According to Herbst's study in 2016, the off-label dosing of Pembrolizumab is 2 mg/kg once every three weeks.
• This off-label dosing regimen can be continued for 24 months or until there is disease progression or unacceptable toxicity.

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Pembrolizumab (Keytruda) dose in the treatment dose of metastatic, nonsquamous non-small cell lung cancer (combination therapy):

• In the treatment of metastatic, nonsquamous non-small cell lung cancer (NSCLC), Pembrolizumab is used in combination therapy with other drugs.
• The recommended dose of Pembrolizumab is 200 mg administered through an intravenous (IV) injection once every three weeks.
• This combination therapy includes pemetrexed and either cisplatin or carboplatin, which are given for four cycles.
• Following the four cycles of combination therapy, Pembrolizumab is continued as monotherapy at a dose of 200 mg once every three weeks.
• The monotherapy is given until there is disease progression, unacceptable toxicity, or, if there is no disease progression, for a total duration of up to 35 cycles or 24 months.
• Additionally, optional indefinite pemetrexed maintenance therapy may be administered along with Pembrolizumab.

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Pembrolizumab (Keytruda) dose in the treatment of metastatic, squamous, non-small cell lung cancer (combination therapy):

• In the treatment of metastatic squamous non-small cell lung cancer (NSCLC), Pembrolizumab is used in combination therapy with other drugs.
• The recommended dose of Pembrolizumab is 200 mg administered through an intravenous (IV) injection once every three weeks.
• This combination therapy includes carboplatin and either paclitaxel or paclitaxel (protein bound), which are given for four cycles.
• Following the four cycles of combination therapy, Pembrolizumab is continued as monotherapy at a dose of 200 mg once every three weeks.
• The monotherapy is given until there is radiographic disease progression, unacceptable toxicity, or, if there is no disease progression, for a total duration of up to 35 cycles.

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Pembrolizumab (Keytruda) dose in the treatment of relapsed or refractory primary mediastinal large B-cell lymphoma:

• In the treatment of relapsed or refractory primary mediastinal large B-cell lymphoma (PMBCL), the recommended dose of Pembrolizumab is 200 mg administered through an intravenous (IV) injection.
• This dose is given once every three weeks.
• The treatment continues until there is evidence of disease progression, the patient experiences unacceptable toxicity, or, if there is no disease progression, for a maximum of up to 24 months.

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Pembrolizumab (Keytruda) dose in the treatment of advanced Renal cell carcinoma:

• In the treatment of advanced renal cell carcinoma (RCC), Pembrolizumab is used in combination with axitinib.
• The recommended dose of Pembrolizumab is 200 mg administered through an intravenous (IV) injection once every three weeks.
• This combination therapy with axitinib is continued until there is evidence of disease progression, the patient experiences unacceptable toxicity, or, if there is no disease progression, for a maximum of up to 24 months.

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Pembrolizumab (Keytruda) dose in the treatment of metastatic small cell lung cancer:

• In the treatment of metastatic small cell lung cancer (SCLC), the recommended dose of Pembrolizumab is 200 mg administered through an intravenous (IV) injection once every three weeks.
• This dose is continued until there is evidence of disease progression, the patient experiences unacceptable toxicity, or, if there is no disease progression, for a maximum of up to 24 months.

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Pembrolizumab (Keytruda) dose in the treatment of locally advanced or metastatic urothelial carcinoma:

• In the treatment of locally advanced or metastatic urothelial carcinoma, the recommended dose of Pembrolizumab is 200 mg administered through an intravenous (IV) injection once every three weeks.
• This dose is continued until there is evidence of disease progression, the patient experiences unacceptable toxicity, or, if there is no disease progression, for a maximum of up to 24 months.

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Pembrolizumab (Keytruda) dose in Children

Note: Please note that the approval of Pembrolizumab by the U.S. Food and Drug Administration (FDA) was obtained through an accelerated process. There is limited availability of well-controlled trials for the use of Pembrolizumab in pediatric patients. Therefore, the dosing for pediatric patients is based on the effectiveness and safety observed in adult trials, as well as pharmacokinetic and safety data specific to pediatric patients.

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Pembrolizumab (Keytruda) dose in the treatment relapsed or refractory classical Hodgkin lymphoma:

• In the treatment of relapsed or refractory classical Hodgkin lymphoma in children aged 2 years and above, as well as adolescents, the recommended dose of Pembrolizumab is based on body weight.
• The intravenous (IV) dose is calculated as 2 mg per kilogram of body weight, with a maximum dose of 200 mg per dose.
• This dose is administered once every three weeks.
• The treatment with Pembrolizumab is continued until there is evidence of disease progression, the patient experiences unacceptable toxicity, or, if there is no disease progression, for a maximum duration of up to 24 months.

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Pembrolizumab (Keytruda) dose in the treatment of recurrent locally advanced or metastatic Merkel cell carcinoma:

• In the treatment of recurrent locally advanced or metastatic Merkel cell carcinoma (MCC) in children aged 2 years and above, as well as adolescents, the recommended dose of Pembrolizumab is based on body weight.
• The intravenous (IV) dose is calculated as 2 mg per kilogram of body weight, with a maximum dose of 200 mg per dose.
• This dose is administered once every three weeks.
• The treatment with Pembrolizumab is continued until there is evidence of disease progression, the patient experiences unacceptable toxicity, or, if there is no disease progression, for a maximum duration of up to 24 months.

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Pembrolizumab (Keytruda) dose of unresectable or metastatic microsatellite instability-high cancer (MSI-H); non-CNS solid tumors progression after treatment without satisfactory alternative treatment options:

• In the treatment of unresectable or metastatic microsatellite instability-high cancer (MSI-H) in children aged 2 years and above, as well as adolescents, the recommended dose of Pembrolizumab is based on body weight.
• The intravenous (IV) dose is calculated as 2 mg per kilogram of body weight, with a maximum dose of 200 mg per dose.
• This dose is administered once every three weeks.
• The treatment with Pembrolizumab is continued until there is evidence of disease progression, the patient experiences unacceptable toxicity, or, if there is no disease progression, for a maximum duration of up to 24 months.

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Pembrolizumab (Keytruda) dose in the treatment of relapsed or refractory primary mediastinal large B-cell lymphoma (PMBCL):

• In the treatment of relapsed or refractory primary mediastinal large B-cell lymphoma (PMBCL) in children aged 2 years and above, as well as adolescents, the recommended dose of Pembrolizumab is based on body weight.
• The intravenous (IV) dose is calculated as 2 mg per kilogram of body weight, with a maximum dose of 200 mg per dose.
• This dose is administered once every three weeks.
• The treatment with Pembrolizumab is continued until there is evidence of disease progression, the patient experiences unacceptable toxicity, or, if there is no disease progression, for a maximum duration of up to 24 months.

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Pembrolizumab (Keytruda) dose adjustment for toxicity:

Children ≥2 years and Adolescents:

• In general, no dosage reductions of pembrolizumab are recommended and depending on the severity of identified toxicity, pembrolizumab therapy is either withheld or discontinued to manage toxicities.

Toxicity	Grade	Action
Colitis (immune-mediated)	2 or 3	Stop Pembrolizumab, administer corticosteroids, resume after recovery
	4	Discontinue Pembrolizumab, administer corticosteroids
Dermatologic toxicity (immune-mediated)	3	Pause Pembrolizumab, seek specialized care
	4	Stop Pembrolizumab, seek specialized care
Endocrinopathies (immune-mediated)	3 or 4	Suspend Pembrolizumab until stable
Hyperglycemia, severe	-	Administer antihyperglycemics
Hyperthyroidism, severe	3	Manage with appropriate medication, resume after recovery or
life-threatening	4	discontinue
Hypophysitis	2	Administer corticosteroids and hormone-replacement therapy if necessary
	3 or 4	Withhold or discontinue Pembrolizumab, administer corticosteroids and hormone-replacement therapy
Hematologic toxicity (in patients with classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma)	4	Suspend Pembrolizumab until resolution
Pneumonitis (immune-mediated)	2	Pause Pembrolizumab, administer corticosteroids
	3 or 4 or recurrent grade 2	Discontinue Pembrolizumab, administer corticosteroids
Other immune-mediated toxicities	2 or 3	Pause Pembrolizumab, corticosteroids may be necessary, resume after improvement
	3 or 4	Discontinue Pembrolizumab, administer corticosteroids
Recurrent immune-mediated adverse reactions	3 or 4	Discontinue Pembrolizumab, administer corticosteroids
Inability to taper corticosteroids	-	Discontinue Pembrolizumab if unable to reduce corticosteroid dose within 12 weeks
Persistent grade 2 or 3 adverse reaction	-	Discontinue Pembrolizumab, administer corticosteroids
Infusion-related reaction	1 or 2	Pause or slow down the infusion
	3 or 4	Stop Pembrolizumab permanently

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Pregnancy Risk Category: D

• Pembrolizumab is a type of medicine that belongs to a group called monoclonal antibodies.
• When used in pregnant women, there is a possibility that it may cross the placenta and reach the developing baby.
• The amount of pembrolizumab transferred to the baby can vary depending on the type of antibodies and the stage of pregnancy.
• The lowest exposure is expected during the period when the baby's organs are forming.
• Since pembrolizumab works by affecting the immune system, it has the potential to harm the developing baby if used during pregnancy.
• It may lead to changes in the baby's immune response or cause immune-related problems later in life if the baby is exposed to the medication in the womb.
• Therefore, it is important to confirm the pregnancy status before starting pembrolizumab treatment in women who can become pregnant.
• If a woman is at risk of pregnancy, she should use effective contraception while receiving the treatment and continue using it for at least 4 months after completing the pembrolizumab treatment.
• This helps to prevent pregnancy and reduce the risk of potential harm to the baby.

Use of Pembrolizumab while breastfeeding

• It is unclear whether pembrolizumab is present in breast milk.
• Since there is a possibility of serious side effects in the nursing infant, it is advised to stop breastfeeding during pembrolizumab therapy and for at least 4 months after the last dose.
• Immunoglobulins, which pembrolizumab belongs to, can be found in breast milk, so it is possible that pembrolizumab may also be present.
• To ensure the safety of the nursing infant, it is recommended to avoid breastfeeding while undergoing pembrolizumab treatment and for the specified period afterwards.

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Pembrolizumab (Keytruda) dose adjustment in renal disease:

• No need to adjust the dosage of pembrolizumab based on renal function.
• A study on the drug's pharmacokinetics showed that there was no significant difference in clearance between patients with an estimated glomerular filtration rate (eGFR) of 15 mL/minute/1.73 m² or higher.
• Therefore, renal function does not appear to have an impact on the clearance of pembrolizumab, and no dosage adjustment is necessary in patients with varying levels of kidney function.

Pembrolizumab (Keytruda) dose adjustment in liver disease:

Hepatic impairment prior to treatment initiation:

Liver Impairment	Dosage Adjustment
Mild	No adjustment
Moderate to severe	No adjustments provided in the labelling

Hepatotoxicity during treatment (in patients without hepatocellular carcinoma):

Liver Enzyme/Bilirubin Levels	Action
AST or ALT >3 to 5 × ULN or total bilirubin >1.5 to 3 × ULN	Withhold treatment; may resume after recovery
AST or ALT >5 × ULN or total bilirubin >3 × ULN (in patients without liver metastases)	Permanently discontinue
Baseline grade 2 ALT or AST abnormalities and liver metastases, with ≥50% increase in AST or ALT persisting for at least 1 week	Permanently discontinue

Renal cell carcinoma (in combination with axitinib):

ALT or AST Levels	Action
ALT or AST ≥3 to <10 × ULN without concurrent total bilirubin ≥2 × ULN	Withhold treatment until recovery; consider corticosteroids
ALT or AST ≥10 × ULN or ALT or AST >3 ULN with concurrent total bilirubin ≥2 × ULN	Permanently discontinue both pembrolizumab and axitinib; consider corticosteroids

Patients with hepatocellular carcinoma (HCC):

Liver Enzyme/Bilirubin Levels	Action
AST or ALT ≥5 × ULN (if baseline is <2 × ULN) or AST or ALT >3 × baseline (if baseline is ≥2 × ULN) or total bilirubin >2 mg/dL (if baseline is <1.5 mg/dL) or total bilirubin >3 mg/dL (regardless of baseline levels)	Withhold treatment; may resume after recovery
AST or ALT >10 × ULN (or Child-Pugh score is ≥ 9) or GI bleeding suggestive of portal hypertension or new onset of clinically detectable ascites or encephalopathy	Permanently discontinue

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Common Side Effects of Pembrolizumab (Keytruda):

• Cardiovascular:
  • Peripheral Edema
  • Cardiac Arrhythmia
• Central Nervous System:
  • Fatigue
  • Pain
  • Headache
• Dermatologic:
  • Pruritus
  • Skin Rash
  • Vitiligo
• Endocrine & Metabolic:
  • Hyperglycemia
  • Hyponatremia
  • Hypoalbuminemia
  • Hypertriglyceridemia
  • Hypophosphatemia
  • Hypocalcemia
  • Hyperkalemia
  • Decreased Serum Bicarbonate
  • Hypercalcemia
  • Hypercholesterolemia
  • Hypokalemia
  • Hypoglycemia
  • Hypothyroidism
  • Hypomagnesemia
  • Weight Loss
• Gastrointestinal:
  • Diarrhea
  • Decreased Appetite
  • Constipation
  • Abdominal Pain
  • Nausea
  • Vomiting
• Genitourinary:
  • Urinary Tract Infection
  • Hematuria
• Hematologic & Oncologic:
  • Lymphocytopenia
  • Anemia
  • Leukopenia
  • Neutropenia
  • Thrombocytopenia
  • Increased INR
  • Hemorrhage
  • Prolonged Partial Thromboplastin Time
• Hepatic:
  • Increased Serum Alkaline Phosphatase
  • Increased Serum Transaminases
  • Increased Serum Aspartate Aminotransferase
  • Increased Serum Alanine Aminotransferase
  • Increased Liver Enzymes
• Immunologic:
  • Graft Versus Host Disease
• Infection:
  • Infection
• Neuromuscular & Skeletal:
  • Musculoskeletal Pain
  • Arthralgia
  • Myalgia
  • Back Pain
  • Asthenia
• Renal:
  • Increased Serum Creatinine
• Respiratory:
  • Upper Respiratory Tract Infection
  • Cough
  • Dyspnea
  • Pneumonia
  • Flu-Like Symptoms
• Miscellaneous:
  • Fever

Rare Side Effects Of Pembrolizumab (Keytruda):

• Cardiovascular:
  • Facial Edema
  • Pericarditis
  • Pericardial Effusion
• Central Nervous System:
  • Peripheral Neuropathy
  • Insomnia
  • Dizziness
  • Peripheral Sensory Neuropathy
• Endocrine & Metabolic:
  • Hyperthyroidism
  • Thyroiditis
• Gastrointestinal:
  • Dysphagia
  • Stomatitis
  • Colitis
• Hepatic:
  • Hyperbilirubinemia
  • Hepatic Sinusoidal Obstruction Syndrome
  • Ascites
  • Hepatitis
• Immunologic:
  • Antibody Development
• Neuromuscular & Skeletal:
  • Neck Pain
  • Arthritis
  • Myositis
• Ophthalmic:
  • Uveitis
• Renal:
  • Acute Renal Failure
• Respiratory:
  • Pneumonitis
• Miscellaneous:
  • Infusion Related Reaction

Pembrolizumab (Keytruda) side effects (frequency not known):

• Cardiovascular:
  • Acute Myocardial Infarction
  • Cardiac Failure
  • Cardiac Tamponade
  • Edema
  • Pulmonary Embolism
  • Septic Shock
• Central Nervous System:
  • Confusion
  • Polyneuropathy
• Dermatologic:
  • Cellulitis
  • Dermatitis
  • Erythematous Rash
  • Follicular Rash
  • Maculopapular Rash
• Genitourinary:
  • Uterine Hemorrhage
• Hematologic & Oncologic:
  • Rectal Hemorrhage
• Infection:
  • Candidiasis
  • Clostridioides Difficile Associated Diarrhea
  • Herpes Zoster Infection
  • Sepsis
• Neuromuscular & Skeletal:
  • Osteomyelitis
• Respiratory:
  • Epistaxis
  • Hemoptysis
  • Pleural Effusion
  • Respiratory Failure
• Miscellaneous:
  • Fistula
  • Physical Health Deterioration

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Contraindications to Pembrolizumab (Keytruda):

• US Labeling: There are no contraindications listed.
• Canadian Labeling: Hypersensitivity to pembrolizumab or any component of the formulation.

Warnings and precautions

Dermatologic toxicities:

• Pembrolizumab can cause skin problems, such as rashes and severe conditions like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening.
• It's important to monitor for any signs of severe skin reactions and rule out other possible causes.
• Depending on the severity of the skin problem, pembrolizumab may need to be temporarily stopped or permanently discontinued, and corticosteroids may be prescribed.
• If there are signs or symptoms of SJS or TEN, pembrolizumab should be stopped and the person should be referred to specialized care for evaluation and treatment.
• If SJS or TEN is confirmed, pembrolizumab should be permanently discontinued.

Diabetes mellitus:

• Pembrolizumab can lead to the development of type 1 diabetes mellitus, including a serious condition called diabetic ketoacidosis.
• It's important to closely monitor for high blood sugar levels (hyperglycemia) and watch out for any signs or symptoms of diabetes.
• In some cases, insulin therapy may be necessary to manage the blood sugar levels.
• If severe hyperglycemia occurs, antihyperglycemic medications may be given, and pembrolizumab treatment should be paused until the blood sugar is under control.

Gastrointestinal toxicities:

• Pembrolizumab can cause immune-mediated colitis, which is inflammation in the gastrointestinal tract.
• Colitis can range from mild to severe (grade 2 to 4).
• The onset of colitis can occur at various times, with a median time of 3.5 months, and the duration can vary as well.
• In many cases, colitis can be managed by using high-dose systemic corticosteroids for a certain period, usually around 7 days, followed by gradually reducing the corticosteroid dosage.
• Most patients experience improvement and resolution of colitis symptoms.
• However, in some cases, treatment interruption, more systemic corticosteroid therapy, or permanent discontinuation of pembrolizumab may be necessary.
• It's important to monitor for signs and symptoms of colitis and promptly administer systemic corticosteroids for colitis of grade 2 or higher severity.

Hepatotoxicity:

• Pembrolizumab can cause immune-mediated hepatitis, which is inflammation of the liver.
• Hepatitis can range from grades 2 to 4 in severity.
• The onset of hepatitis can occur at different times, with a median onset of 1.3 months.
• The duration of hepatitis can also vary, with a median duration of 1.8 months.
• In most cases, hepatitis resolves on its own.
• To manage immune-mediated hepatitis, corticosteroids are administered, with the dosage depending on the severity of hepatitis.
• Typically, high-dose corticosteroids are given for a period of time, around 5 days, followed by a gradual reduction in dosage.
• It's important to monitor liver function and watch for any changes.
• Treatment may require interruption, the use of systemic corticosteroids (for grades 2 and higher hepatitis), or even permanent discontinuation of pembrolizumab.
• When pembrolizumab is used in combination with axitinib, there may be higher frequencies of ALT and AST elevations, especially in grades 3 and 4.
• Monitoring liver enzymes is crucial, both at the start of treatment and periodically during the course.
• If liver enzymes become elevated, pembrolizumab and axitinib may need to be withheld, and corticosteroids can be considered.

Hypersensitivity:

• Rare cases of hypersensitivity and anaphylaxis have been reported with the use of pembrolizumab.
• Hypersensitivity refers to an exaggerated immune response to the medication, which can cause allergic reactions.
• Anaphylaxis is a severe and potentially life-threatening allergic reaction that requires immediate medical attention.
• While these reactions are uncommon, it is important to be aware of the possibility and seek medical help if any signs or symptoms of hypersensitivity or anaphylaxis occur during treatment with pembrolizumab.

Hypophysitis:

• Cases of immune-mediated hypophysitis have been reported with the use of pembrolizumab.
• Hypophysitis refers to inflammation of the pituitary gland, which can lead to hormonal imbalances and symptoms such as hypopituitarism and adrenal insufficiency.
• The onset of hypophysitis can occur within a range of time, with the median onset being around 3.7 months after starting pembrolizumab.
• The duration of hypophysitis can also vary.
• Most cases of hypophysitis were managed using systemic corticosteroids, and nearly half of the patient’s experienced resolution of their symptoms.
• It is important to monitor for signs and symptoms of hypophysitis and, if detected, appropriate measures such as treatment interruption, systemic corticosteroids, and hormone replacement therapy may be required.
• In some cases, permanent discontinuation of pembrolizumab may be necessary.

Reactions that are related to infusion:

• Infusion-related reactions, which can range from mild to severe or even life-threatening, have been observed with the administration of pembrolizumab.
• These reactions can manifest as various signs and symptoms, including rigors, chills, wheezing, itching, flushing, rash, low blood pressure, low oxygen levels, and fever.
• It is important to closely monitor patients during the infusion for any indications of a reaction.
• In the event of a severe (grade 3) or life-threatening (grade 4) infusion-related reaction, the infusion should be interrupted immediately and permanently discontinued.
• This is done to ensure the safety and well-being of the patient.

Nephrotoxicity:

• Nephrotoxicity, specifically immune-mediated nephritis, has been reported with pembrolizumab treatment.
• The onset of autoimmune nephritis typically occurs between 3.2 to 5.1 months after starting treatment, although it can occur earlier or later.
• The duration of nephritis varies but has a median duration of 3.3 months.
• Management of grade 2 or higher nephritis involves the use of systemic corticosteroids.
• Patients often require these corticosteroids, with a median duration of use ranging from 3 to 15 days, followed by a gradual tapering.
• Resolution of nephritis is observed in approximately one-third to one-half of affected patients.
• It is important to monitor renal function for any changes.
• In some cases, treatment interruption, systemic corticosteroids (for moderate to severe toxicity), and/or permanent discontinuation of pembrolizumab may be necessary depending on the severity of the nephritis.
• This approach ensures appropriate management and patient safety.

Toxicity in the lungs:

• Pulmonary toxicity, specifically immune-mediated pneumonitis, has been observed with the use of pembrolizumab.
• This condition can range from grade 3 to grade 4 severity and can even be fatal in some cases.
• Patients with non-small cell lung cancer (NSCLC) who have previously undergone thoracic radiation may have a higher risk of developing pneumonitis.
• The onset of pneumonitis typically occurs around 3.3 months after starting treatment, although it can happen earlier or later.
• The duration of pneumonitis varies, with a median duration of 1.5 months.
• Initial management often involves the use of high-dose systemic corticosteroids, with a median duration of 5 to 16 days, followed by a gradual tapering of the corticosteroid dose.
• Resolution of pneumonitis is observed in over half of the affected patients.
• Monitoring for signs and symptoms of pneumonitis is crucial, and if suspected, radiographic imaging should be performed.
• For grade 2 or higher pneumonitis, systemic corticosteroids should be administered.
• Treatment interruption, corticosteroid therapy (prednisone or equivalent) followed by tapering, and/or permanent discontinuation of pembrolizumab may be necessary depending on the severity of the pneumonitis.
• It is important to note that pneumonitis occurs more frequently in patients with a history of prior thoracic radiation.

Thyroid disorders:

• Thyroid disorders, including immune-mediated hyperthyroidism, hypothyroidism, and thyroiditis, have been observed in patients receiving pembrolizumab.
• The onset of hyperthyroidism typically occurs around 1.4 months after starting treatment, with a median duration of 2.1 months.
• In the majority of cases, hyperthyroidism resolves on its own.
• Hypothyroidism, on the other hand, usually develops around 3.5 months after starting treatment, but the duration can vary widely.
• Only a small portion of patients with hypothyroidism experience resolution of the condition.
• Patients with squamous cell cancer of the head and neck, either as a single agent or in combination with chemotherapy, have a higher incidence of new or worsening hypothyroidism.
• Monitoring thyroid function is important, with baseline assessment, periodic checks during treatment, and evaluation based on clinical indications.
• Signs and symptoms of thyroid disorders should be monitored as well.
• Treatment options for hyperthyroidism may include thionamides and beta-blockers, and treatment interruption or permanent discontinuation of pembrolizumab may be necessary.
• Isolated hypothyroidism can be managed with replacement therapy.
• Thyroiditis typically develops around 1.2 months after starting treatment.

Other immune-mediated toxicities:

• Other immune-mediated toxicities have been observed with pembrolizumab, affecting various organ systems and tissues.
• These toxicities can be severe or even fatal.
• Examples include rashes, dermatitis, uveitis, arthritis, vasculitis, pancreatitis, anemia, sarcoidosis, and many others.
• These adverse events can occur during treatment with pembrolizumab or even after discontinuation.
• If there is suspicion of an immune-mediated adverse event, appropriate evaluation should be done to confirm the cause.
• Treatment should be withheld, and systemic corticosteroids may be administered based on the severity of the reaction.
• Once the adverse event resolves to a mild level, a corticosteroid taper can be initiated, continuing for at least one month.
• If the reaction remains mild during the taper, pembrolizumab treatment may be resumed.
• If immune-mediated adverse reactions do not respond to corticosteroids, other systemic immunosuppressants may be considered, although data is limited.
• Severe or recurring life-threatening immune-mediated adverse events warrant permanent discontinuation of pembrolizumab.

Autoimmune disorders:

• Anti-PD-1 monoclonal antibodies like pembrolizumab and nivolumab can trigger an immune response that may worsen existing autoimmune disorders or previous immune-related adverse events.
• However, a retrospective study conducted on melanoma patients with preexisting autoimmune conditions or prior significant immune reactions to ipilimumab (another immunotherapy) showed that while immune-related side effects did occur, most of them were mild and easily manageable without the need to permanently stop the treatment.
• Interestingly, a significant number of patients still achieved positive treatment responses with anti-PD-1 monoclonal antibody therapy, even in the presence of preexisting autoimmune conditions or prior adverse events caused by ipilimumab.

Hematopoietic stem cells transplant:

• Patients who undergo allogeneic hematopoietic stem cell transplant (HSCT) after being treated with pembrolizumab may experience immune-related complications, some of which can be fatal.
• These complications include graft versus host disease (GVHD) and severe sinusoidal obstructive syndrome (SOS).
• There have been reports of fatal hyperacute GVHD in lymphoma patients who received an anti PD-1 antibody before the transplant.
• These complications can occur even if there was a gap between pembrolizumab treatment and HSCT.
• It is important to closely monitor patients for early signs and symptoms of transplant-related complications such as hyperacute GVHD, severe acute GVHD, steroid-requiring febrile syndrome, SOS, and other immune-related adverse reactions.
• Prompt management is crucial.
• In patients who received allogeneic HSCT before pembrolizumab treatment, there have been reports of acute GVHD, including fatal cases, after receiving pembrolizumab.
• Patients who have experienced GVHD after transplant may have an increased risk of developing GVHD after pembrolizumab treatment.
• It is important to carefully assess the risks of GVHD versus the benefits of pembrolizumab treatment in patients with a history of allogeneic HSCT.

Multiple myeloma:

• In clinical studies involving patients with multiple myeloma, the use of pembrolizumab in combination with a thalidomide analogue and dexamethasone was associated with an increase in mortality.
• The experimental arm, which received pembrolizumab along with dexamethasone and a thalidomide analogue (pomalidomide or lenalidomide), had cases of death caused by various factors including myocarditis, Stevens-Johnson syndrome, heart attack, pericardial hemorrhage, cardiac failure, respiratory tract infection, sepsis, multiple organ dysfunction, respiratory failure, intestinal ischemia, cardiopulmonary arrest, suicide, pulmonary embolism, pneumonia, sudden death, and large intestine perforation.
• It's important to note that multiple myeloma is not an approved indication for PD-1 or PD-L1 blocking antibodies like pembrolizumab.
• Therefore, pembrolizumab should not be used to treat multiple myeloma in combination with a thalidomide analogue and dexamethasone unless it is part of a clinical trial.

Transplantation of solid-organs:

• After the approval and use of pembrolizumab, cases of solid organ transplant rejection have been reported during post marketing surveillance.
• It is important to be aware that pembrolizumab may increase the risk of organ rejection in patients who have undergone solid organ transplantation.
• When considering pembrolizumab treatment in individuals with a history of solid organ transplantation, it is crucial to carefully weigh the potential benefits against the risks involved.
• This decision should be made in consultation with the patient's healthcare team and transplant specialists to determine the most appropriate course of action.

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Pembrolizumab: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

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

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Monitoring parameters:

PD-L1 expression status in:

• Cervical cancer
• Esophageal cancer
• Gastric cancer
• First-line treatment of head and neck squamous cell carcinoma
• Non-small cell lung cancer (as single-agent therapy)
• Cisplatin-ineligible urothelial cancer

Liver function tests (AST, ALT, and total bilirubin):

• Monitor at baseline and periodically during treatment
• Consider more frequent monitoring if receiving pembrolizumab/axitinib combination therapy

Renal function:

• Regular monitoring of kidney function

Thyroid function:

• Monitor at baseline, periodically during treatment, and as clinically indicated

Glucose:

• Monitor for hyperglycemia and other signs/symptoms of diabetes

CBC with differential:

• In patients with Hodgkin lymphoma or primary mediastinal large B-cell lymphoma

Pregnancy test:

• Prior to initiating pembrolizumab treatment in females of reproductive potential

Signs/symptoms to monitor for:

• Colitis
• Dermatologic toxicity
• Hypophysitis
• Thyroid disorders
• Pneumonitis
• Infusion reactions

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How to administer Pembrolizumab (Keytruda)?

Intravenous (IV) Administration:

• Infuse over 30 minutes.
• Use a sterile, nonpyrogenic, low-protein binding inline or add-on filter with a pore size of 0.2 to 5 microns.
• Do not administer other medications through the same infusion line.

Infusion-Related Reactions:

• Grade 1 or 2 reactions: Interrupt or slow down the infusion.
• Grade 3 or 4 reactions: Permanently discontinue the infusion.

Head and Neck Squamous Cell Carcinoma (Unresectable/Recurrent, Metastatic) and Non-Small Cell Lung Cancer (Metastatic):

• When administered in combination with chemotherapy, give pembrolizumab before chemotherapy if both are scheduled for the same day.

Please note that these instructions are a simplified summary.

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Mechanism of action of Pembrolizumab (Keytruda):

• Pembrolizumab is a type of monoclonal antibody that specifically targets the PD-1 receptor.
• PD-1 is a protein found on T-cells (a type of immune cell) that plays a role in regulating immune responses.
• By binding to the PD-1 receptor, pembrolizumab prevents PD-1 ligands (PD-L1 and PD-L2) from attaching to the receptor.
• This binding action blocks the PD-1 signaling pathway, which normally suppresses T-cell activity.
• Inhibiting the PD-1 pathway helps to reverse T-cell suppression and enhances the immune system's ability to fight against tumors.
• Pembrolizumab and other anti-PD-1 antibodies have shown the ability to stimulate antitumor responses in patients.

Notice:

• When using pembrolizumab, it's important to note that the clearance of the drug is approximately 23% lower at steady state (when the drug has reached a consistent level in the body) compared to the first dose.
• In pediatric patients, when the dosing is based on their weight (2 mg/kg), the concentrations of pembrolizumab in their bodies are similar to those seen in adults who receive the same dose.

Distrubition:

• The volume of distribution (V) for pembrolizumab is 6 L.
• This refers to the apparent space in the body where the drug is distributed after administration.

Half-life elimination:

• The half-life of elimination for pembrolizumab is 22 days.
• This indicates the time it takes for half of the drug concentration to decrease in the body through processes such as metabolism and excretion.

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International Brands of Pembrolizumab:

• Keytruda

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Pembrolizumab Brand Names in Pakistan:

No Brands Available in Pakistan.