Pembrolizumab

Registered South African indications:

• Melanoma 
  - Unresectable or metastatic melanoma
  - Adjuvant treatment of patients with melanoma with lymph node involvement who have undergone complete resection
• Non-small cell lung carcinoma (NSCLC) 
  - In combination with pemetrexed and platinum chemotherapy, for the first-line treatment of metastatic non-squamous NSCLC, with no EGFR or ALK genomic tumour aberrations
  - In combination with carboplatin and either paclitaxel or nab-paclitaxel, for the first-line treatment of metastatic squamous NSCLC
  - As monotherapy for the first-line treatment of patients with metastatic NSCLC of squamous and non-squamous histology whose tumours express PD-L1 with a ≥50% tumour proportion score (TPS) as determined by a validated test, with no EGFR or ALK genomic tumour aberrations
  - As monotherapy, in second-line treatment or greater for the treatment of patients with advanced NSCLC whose tumours express PD-L1 with a ≥1% TPS as determined by a validated test and who have already been treated with platinum-containing chemotherapy
  (Patients with EGFR or ALK genomic tumour aberrations should have been treated for these aberrations before receiving treatment with pembrolizumab)
• Head and neck cancer 
  - As monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, for the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC)
  - As monotherapy, is indicated for the treatment of patients with metastatic or unresectable recurrent HNSCC with disease progression on or after platinum-containing chemotherapy
• Classical Hodgkin lymphoma (cHL)
  - Treatment of patients with relapsed or refractory classical Hodgkin Lymphoma (cHL) 
• Urothelial carcinoma 
  - Treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD-L1 [combined positive score (CPS) ≥10] as determined by a validated test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status 
  - Treatment of patients with locally advanced or metastatic urothelial carcinoma who have received platinum-containing chemotherapy 
• Renal cell carcinoma
  - In combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC) 
• Colorectal cancer
  - First-line treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC)

Contraindications

• Hypersensitivity to the active ingredient or any of the excipients

Cautions

• Pregnancy
• Breastfeeding
• Severe renal impairment
  - Nephritis 
• Moderate to severe hepatic impairment
• Elderly
  ≥75 years: Adjuvant treatment of patients with melanoma
• Known or suspected pneumonitis
  - Prior pneumonitis requiring systemic corticosteroid therapy
• Pre-existing colitis 
• Hepatitis 
• Pre-existing severe endocrinopathies 
  - Adrenal insufficiency 
  - Hypophysitis (including hypopituitarism) 
  - Type 1 diabetes mellitus 
  - Diabetic ketoacidosis 
• Thyroid disorders 
  - Hypothyroidism 
  - Hyperthyroidism 
• Hyperglycaemia or other signs and symptoms of diabetes 
• Previous experience of a severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anti-cancer agents 
• Solid organ transplant recipients
• Allogeneic haematopoietic stem cell transplant (HSCT) after or prior to treatment with pembrolizumab
• Urothelial carcinoma patients who have received prior platinum-containing chemotherapy
  - Patients with poorer prognostic features and/or aggressive disease
• Urothelial cancer patients ineligible for cisplatin-containing chemotherapy and whose tumours express PD-L1 with CPS ≥10
• First-line treatment of patients with non-small cell lung carcinoma whose tumours express PD-L1
• First-line treatment of patients with head and neck squamous cell carcinoma whose tumours express PD-L1
• First-line treatment of patients with metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer
• Active CNS metastases
• ECOG PS ≥2 (except for urothelial carcinoma and renal cell carcinoma)
• HIV infection
• Hepatitis B or Hepatitis C infection
• Active systemic autoimmune disease
• Interstitial lung disease
• History of severe hypersensitivity to another monoclonal antibody
• Receiving immunosuppressive therapy
• History of severe immune-related adverse reactions from treatment with ipilimumab
• Active infections
• Ocular melanoma
• Re-initiating pembrolizumab therapy in patients previously experiencing immune-related myocarditis 
• Coadministration with axitinib for first-line treatment of patients with renal cell carcinoma 
• May impair ability to drive and operate machinery 

Forms avail. in SA and covered in this monograph: inf

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Melanoma
- As monotherapy for the treatment of advanced (unresectable or metastatic) melanoma
- As monotherapy for the adjuvant treatment of adults with Stage III melanoma and lymph node involvement who have undergone complete resection
Non-small cell lung carcinoma (NSCLC)
- As monotherapy for first-line treatment of metastatic NSCLC in adults whose tumours express PD-L1 with a ≥50% tumour proportion score (TPS) with no EGFR or ALK-positive tumour mutations
-  In combination with pemetrexed and platinum chemotherapy, for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK-positive mutations
-  In combination with carboplatin and either paclitaxel or nab-paclitaxel, for the first-line treatment of metastatic squamous NSCLC in adults
- As monotherapy is indicated for the treatment of locally advanced or metastatic NSCLC in adults whose tumours express PD-L1 with a ≥1% TPS and who have received at least one prior chemotherapy regimen
(Patients with EGFR or ALK-positive tumour mutations should also have received targeted therapy before receiving pembrolizumab)
Classical Hodgkin lymphoma (cHL)
- As monotherapy for the treatment of adults with relapsed or refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option
Urothelial carcinoma
- As monotherapy for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy
- As monotherapy for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD-L1 with a combined positive score (CPS) ≥10
Head and neck squamous cell carcinoma (HNSCC)
- As monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, for the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma in adults whose tumours express PD-L1 with a CPS ≥1
- As monotherapy for the treatment of recurrent or metastatic head and neck squamous cell carcinoma in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing on or after platinum-containing chemotherapy
Renal cell carcinoma (RCC)
- In combination with axitinib, for first-line treatment of advanced renal cell carcinoma in adults
Colorectal cancer (CRC)
- As monotherapy for first-line treatment of metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer in adults
Oesophageal carcinoma
- In combination with platinum and fluoropyrimidine-based chemotherapy, for the first-line treatment of locally advanced unresectable or metastatic carcinoma of the oesophagus or HER-2 negative gastroesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS ≥10

• IV: 200mg, as an infusion over 30mins, every 3 weeks
  OR
• IV: 400mg, as an infusion over 30mins, every 6 weeks

PD-L1 testing, if specified in the indication, patient selection for treatment with pembrolizumab based on the tumour expression of PD-L1 should be confirmed by a validated test

MSI-H/dMMR testing for patients with CRC
For treatment with pembrolizumab as monotherapy, testing for MSI-H/dMMR tumour status using a validated test is recommended to select patients with CRC

Patients should be treated with pembrolizumab until disease progression or unacceptable toxicity. Atypical responses (i.e. an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed

For the adjuvant treatment of melanoma, pembrolizumab should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year

See additional prescribing points for recommended dose modifications in the event of immune-related adverse events

South African manufacturer recommendations

Melanoma
- Unresectable or metastatic melanoma
- Adjuvant treatment of patients with melanoma with lymph node involvement who have undergone complete resection
Non-small cell lung carcinoma (NSCLC)
- In combination with pemetrexed and platinum chemotherapy, for the first-line treatment of metastatic non-squamous NSCLC with no EGFR or ALK genomic tumour aberrations
- In combination with carboplatin and either paclitaxel or nab-paclitaxel, for the first-line treatment of metastatic squamous NSCLC
- As monotherapy for the first-line treatment of patients with metastatic NSCLC of squamous and non-squamous histology whose tumours express PD-L1 with a ≥50% tumour proportion score (TPS) as determined by a validated test, with no EGFR or ALK genomic tumour aberrations
- As monotherapy, in second-line treatment or greater for the treatment of patients with advanced NSCLC whose tumours express PD-L1 with a ≥1% TPS as determined by a validated test and who have already been treated with platinum-containing chemotherapy
(Patients with EGFR or ALK genomic tumour aberrations should have been treated for these aberrations before receiving treatment with pembrolizumab)
Head and neck cancer
- As monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, for the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC)
- As monotherapy, is indicated for the treatment of patients with metastatic or unresectable recurrent HNSCC with disease progression on or after platinum-containing chemotherapy
Classical Hodgkin lymphoma (cHL)
- Treatment of patients with relapsed or refractory classical Hodgkin Lymphoma (cHL)
Urothelial carcinoma
- Treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD-L1 [combined positive score (CPS) ≥10] as determined by a validated test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status
- Treatment of patients with locally advanced or metastatic urothelial carcinoma who have received platinum-containing chemotherapy
Renal cell carcinoma (RCC)
- In combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC)
Colorectal cancer
- First-line treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC)

• IV: 200mg, as an infusion over 30mins, every 3 weeks
  OR
• IV: 400mg, as an infusion over 30mins, every 6 weeks

For use in combination, see the prescribing information for the concomitant therapies. When administering pembrolizumab as part of a combination with intravenous chemotherapy, pembrolizumab should be administered first

For the adjuvant treatment of melanoma, pembrolizumab should be administered for up to one year or until disease recurrence or unacceptable toxicity

For RCC patients treated with pembrolizumab in combination with axitinib, see the prescribing information regarding dosing of axitinib. When used in combination with pembrolizumab, dose escalation of axitinib above the initial 5mg dose may be considered at intervals of six weeks or longer

Select patients for treatment with pembrolizumab based on the presence of positive PD-L1 expression in:
- Advanced NSCLC
- Locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy
- PD-L1 expression should be evaluated using the PD-L1 IHC 22C3 pharmDx^TM kit or equivalent

Select patients for treatment with pembrolizumab based on microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumor status in unresectable or metastatic CRC. MSI or MMR tumor status should be evaluated using a validated test

Patients should be treated with pembrolizumab until disease progression or unacceptable toxicity. Atypical responses (i.e. an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. Clinically stable patients with initial evidence of disease progression should remain on treatment until disease progression is confirmed

Forms avail. in SA and covered in this monograph: inf

Paed. dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Classical Hodgkin lymphoma (cHL)
- As monotherapy for the treatment of patients with relapsed or refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option

Younger than 3 years

• Not established for use

3 years and older

• IV: 2mg/kg, as an infusion over 30mins, every 3 weeks; Max: 200mg/dose

The safety and efficacy of pembrolizumab in children below 18 years of age have not been established except in paediatric patients with cHL

South African manufacturer recommendations

Classical Hodgkin lymphoma (cHL)
- Treatment of patients with relapsed or refractory classical Hodgkin Lymphoma (cHL) 

• IV: 2mg/kg, as an infusion over 30mins, every 3 weeks; Max: 200mg/dose

The safety and efficacy of pembrolizumab in children below 18 years of age have not been established except in paediatric patients with cHL

Pregnancy

• Caution; not recommended
• There are no data on the use of pembrolizumab in pregnant women. Animal reproduction studies have not been conducted with pembrolizumab; however, in murine models of pregnancy blockade of PD-L1 signalling has been shown to disrupt tolerance to the foetus and to result in an increased foetal loss. These results indicate a potential risk, based on its mechanism of action, that administration of pembrolizumab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth
• Human immunoglobulins G4 (IgG4) are known to cross the placental barrier; therefore, being an IgG4, pembrolizumab has the potential to be transmitted from the mother to the developing foetus. Pembrolizumab should not be used during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab
• Women of childbearing potential should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of pembrolizumab 

Breastfeeding

• Caution; not recommended
• It is unknown whether pembrolizumab is secreted in human milk. Since it is known that antibodies can be secreted in human milk, a risk to the newborns/ infants cannot be excluded. A decision should be made whether to discontinue breastfeeding or to discontinue pembrolizumab, taking into account the benefit of breastfeeding for the child and the benefit of pembrolizumab therapy for the woman

Fertility

• No clinical data are available on the possible effects of pembrolizumab on fertility. There were no notable effects in the male and female reproductive organs in monkeys based on 1-month and 6-month repeat-dose toxicity studies

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no information available

Hepatic Impairment

• Mild: No dosage adjustment recommended 
• Moderate to severe: Caution; no information available

Elderly

• Caution; no dose adjustment recommended
  Data from patients ≥65 years are too limited to draw conclusions on Classical Hodgkin lymphoma population
  Data are limited in patients ≥75 years for pembrolizumab monotherapy in patients with resected Stage III melanoma and metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer; for pembrolizumab in combination with axitinib in patients with advanced renal cell carcinoma; for chemotherapy combination in patients with metastatic non-small cell lung carcinoma; and for pembrolizumab (with or without chemotherapy) in patients receiving first-line treatment for metastatic or unresectable recurrent head and neck squamous cell carcinoma 

Porphyria Information

• Not yet classified (NC)

Drugs in Sport

• Permitted - No warnings

Monotherapy
Central Nervous System Disorders

• Insomnia
• Headache
• Dizziness
• Dysgeusia
• Epilepsy
• Lethargy
• Peripheral neuropathy
• Guillain-Barré syndrome
  - Axonal neuropathy and demyelinating polyneuropathy
• Myasthenic syndrome
  - Myasthenia gravis, including exacerbation
• Encephalitis
  - Autoimmune encephalitis
• Myelitis
  - Transverse myelitis
• Meningitis (aseptic)
  - Non-infective meningitis
• Fatigue

Cardiovascular Disorders

• Cardiac arrhythmia
  - Atrial fibrillation
• Myocarditis
• Pericardial effusion
• Pericarditis
• Hypertension
• Vasculitis

Respiratory Disorders

• Pneumonitis
  - Interstitial lung disease
  - Organising pneumonia
• Dyspnoea
• Cough

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Colitis
  - Microscopic colitis
  - Enterocolitis
  - Haemorrhagic enterocolitis
  - Autoimmune colitis
  - Immune-mediated enterocolitis
• Abdominal pain
  - Abdominal discomfort
  - Upper and lower abdominal pain
• Constipation
• Dry mouth
• Pancreatitis
  - Autoimmune pancreatitis
  - Acute pancreatitis
• Gastrointestinal perforation
  - Gastric ulcer
  - Duodenal ulcer
• Small intestinal perforation

Hepatobiliary Disorders

• Hepatitis
  - Autoimmune hepatitis
  - Immune-mediated hepatitis
  - Drug induced liver injury
  - Acute hepatitis
• Increased aspartate aminotransferase
• Increased alanine aminotransferase
• Increased blood bilirubin

Genitourinary Disorders

• Nephritis
  - Autoimmune nephritis
  - Renal failure
  - Acute renal failure or acute kidney injury with evidence of nephritis
  - Nephrotic syndrome
  - Glomerulonephritis
  - Membranous glomerulonephritis
• Increased blood creatinine

Endocrine and Metabolic Disorders

• Hyperthyroidism
• Hypothyroidism (myxoedema)
• Hypophysitis (hypopituitarism)
• Adrenal insufficiency
  - Addison's disease
  - Acute adrenocortical insufficiency
  - Secondary adrenocortical insufficiency
• Thyroiditis
  - Autoimmune thyroiditis
  - Thyroid disorder
• Decreased appetite
• Type 1 diabetes mellitus (diabetic ketoacidosis)
• Hyponatraemia
• Hypokalaemia
• Hypocalcaemia
• Hypercalcaemia
• Increased amylase

Musculoskeletal Disorders

• Arthralgia
• Myositis
  - Myalgia
  - Myopathy
  - Necrotising myositis
  - Polymyalgia rheumatica
  - Rhabdomyolysis
• Musculoskeletal pain
  - Musculoskeletal discomfort
  - Back pain
  - Musculoskeletal stiffness
  - Musculoskeletal chest pain
  - Torticollis
• Arthritis
  - Joint swelling
  - Polyarthritis
  - Joint effusion
• Pain in extremity
• Tenosynovitis
  - Tendonitis
  - Synovitis
  - Tendon pain
• Sjogren's syndrome

Skin and Subcutaneous Tissue Disorders

• Rash
  - Erythematous rash
  - Follicular rash
  - Macular rash
  - Maculopapular rash
  - Papular rash
  - Pruritic rash
  - Vesicular rash
  - Genital rash
• Pruritus
  - Urticaria
  - Papular urticaria
  - Genital pruritus
• Severe skin reactions
  - Bullous dermatitis
  - Exfoliative generalised dermatitis
  - Exfoliative rash
  - Pemphigus
  - Grade ≥3 of the following: acute febrile neutrophilic dermatosis, contusion, decubitus ulcer, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, erythema multiforme, jaundice, lichen planus, oral lichen planus, pemphigoid, pruritus, genital pruritus, rash, erythematous rash, maculopapular rash, pruritic rash, pustular rash, skin lesion, skin necrosis and toxic skin eruption
• Vitiligo
  - Skin depigmentation
  - Skin hypopigmentation
  - Hypopigmentation of the eyelid
• Dry skin
• Erythema
• Lichenoid keratosis
  - Lichen planus
  - Lichen sclerosus
• Psoriasis
• Alopecia
• Dermatitis
• Dermatitis acneiform
• Eczema
• Hair colour changes
• Papule
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome
• Erythema nodosum

Immune, Blood and Lymphatic System Disorders

• Pneumonia
• Anaemia
• Neutropenia
• Thrombocytopenia
• Leukopenia
• Lymphopenia
• Eosinophilia
• Immune thrombocytopenia
• Haemolytic anaemia
• Pure red cell aplasia
• Haemophagocytic lymphohistiocytosis
• Infusion-related reaction
  - Drug hypersensitivity
  - Anaphylactic reaction
  - Anaphylactoid reaction
  - Hypersensitivity
  - Cytokine release syndrome
• Sarcoidosis
• Solid organ transplant rejection
• Oedema
  - Peripheral oedema
  - Generalised oedema
  - Fluid overload
  - Fluid retention
  - Eyelid oedema
  - Lip oedema
  - Face oedema
  - Localised oedema
  - Periorbital oedema
• Pyrexia
• Increased blood alkaline phosphatase

Sensory Disorders

• Uveitis
  - Chorioretinitis
  - Iritis
  - Iridocyclitis
• Dry eye
• Vogt-Koyanagi-Harada syndrome

Others

• Influenza-like illness
• Chills

Combination with chemotherapy
Central Nervous System Disorders

• Insomnia
• Headache
• Dizziness
• Dysgeusia
• Epilepsy
• Lethargy
• Peripheral neuropathy
• Fatigue

Cardiovascular Disorders

• Cardiac arrhythmia
  - Atrial fibrillation
• Myocarditis
  - Autoimmune myocarditis
• Pericardial effusion
• Pericarditis
• Hypertension
• Vasculitis

Respiratory Disorders

• Pneumonitis
  - Interstitial lung disease
  - Organising pneumonia
• Dyspnoea
• Cough

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Colitis
  - Microscopic colitis
  - Enterocolitis
  - Haemorrhagic enterocolitis
  - Autoimmune colitis
  - Immune-mediated enterocolitis
• Abdominal pain
  - Abdominal discomfort
  - Upper and lower abdominal pain
• Constipation
• Dry mouth
• Pancreatitis
  - Autoimmune pancreatitis
  - Acute pancreatitis
• Gastrointestinal perforation
  - Gastric ulcer
  - Duodenal ulcer

Hepatobiliary Disorders

• Hepatitis
  - Autoimmune hepatitis
  - Immune-mediated hepatitis
  - Drug induced liver injury
  - Acute hepatitis
• Increased aspartate aminotransferase
• Increased alanine aminotransferase
• Increased blood bilirubin

Genitourinary Disorders

• Nephritis
  - Autoimmune nephritis
  - Renal failure
  - Acute renal failure or acute kidney injury with evidence of nephritis
  - Nephrotic syndrome
  - Glomerulonephritis
  - Membranous glomerulonephritis
• Increased blood creatinine

Endocrine and Metabolic Disorders

• Hyperthyroidism
• Hypothyroidism (myxoedema)
• Hypophysitis (hypopituitarism)
• Adrenal insufficiency
  - Addison's disease
  - Acute adrenocortical insufficiency
  - Secondary adrenocortical insufficiency
• Thyroiditis
  - Autoimmune thyroiditis
  - Thyroid disorder
• Decreased appetite
• Type 1 diabetes mellitus (diabetic ketoacidosis)
• Hyponatraemia
• Hypokalaemia
• Hypocalcaemia
• Hypercalcaemia
• Increased amylase

Musculoskeletal Disorders

• Arthralgia
• Myositis
  - Myalgia
  - Myopathy
  - Necrotising myositis
  - Polymyalgia rheumatica
  - Rhabdomyolysis
• Musculoskeletal pain
  - Musculoskeletal discomfort
  - Back pain
  - Musculoskeletal stiffness
  - Musculoskeletal chest pain
  - Torticollis
• Arthritis
  - Joint swelling
  - Polyarthritis
  - Joint effusion
• Pain in extremity
• Tenosynovitis
  - Tendonitis
  - Synovitis
  - Tendon pain
• Sjogren's syndrome

Skin and Subcutaneous Tissue Disorders

• Rash
  - Erythematous rash
  - Follicular rash
  - Macular rash
  - Maculopapular rash
  - Papular rash
  - Pruritic rash
  - Vesicular rash
  - Genital rash
• Pruritus
  - Urticaria
  - Papular urticaria
  - Genital pruritus
• Severe skin reactions
  - Bullous dermatitis
  - Exfoliative generalised dermatitis
  - Exfoliative rash
  - Pemphigus
  - Grade ≥3 of the following: acute febrile neutrophilic dermatosis, contusion, decubitus ulcer, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, erythema multiforme, jaundice, lichen planus, oral lichen planus, pemphigoid, pruritus, genital pruritus, rash, erythematous rash, maculopapular rash, pruritic rash, pustular rash, skin lesion, skin necrosis and toxic skin eruption
• Vitiligo
  - Skin depigmentation
  - Skin hypopigmentation
  - Hypopigmentation of the eyelid
• Dry skin
• Erythema
• Lichenoid keratosis
• Psoriasis
• Alopecia
• Dermatitis
• Dermatitis acneiform
• Eczema
• Hair colour changes
• Papule

Immune, Blood and Lymphatic System Disorders

• Pneumonia
• Anaemia
• Neutropenia
• Febrile neutropenia
• Thrombocytopenia
• Leukopenia
• Lymphopenia
• Eosinophilia
• Infusion-related reaction
  - Drug hypersensitivity
  - Anaphylactic reaction
  - Anaphylactoid reaction
  - Hypersensitivity
  - Cytokine release syndrome
• Sarcoidosis
• Solid organ transplant rejection
• Oedema
  - Peripheral oedema
  - Generalised oedema
  - Fluid overload
  - Fluid retention
  - Eyelid oedema
  - Lip oedema
  - Face oedema
  - Localised oedema
  - Periorbital oedema
• Pyrexia
• Increased blood alkaline phosphatase

Sensory Disorders

• Dry eye

Others

• Influenza-like illness
• Chills

Combination with axitinib
Central Nervous System Disorders

• Insomnia
• Headache
• Dizziness
• Dysgeusia
• Lethargy
• Peripheral neuropathy
• Myasthenic syndrome
  - Myasthenia gravis, including exacerbation
• Fatigue

Cardiovascular Disorders

• Cardiac arrhythmia
  - Atrial fibrillation
• Myocarditis
• Hypertension

Respiratory Disorders

• Pneumonitis
  - Interstitial lung disease
  - Organising pneumonia
• Dyspnoea
• Cough
• Dysphonia

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Colitis
  - Microscopic colitis
  - Enterocolitis
  - Haemorrhagic enterocolitis
  - Autoimmune colitis
  - Immune-mediated enterocolitis
• Abdominal pain
  - Abdominal discomfort
  - Upper and lower abdominal pain
• Constipation
• Dry mouth
• Pancreatitis
  - Autoimmune pancreatitis
  - Acute pancreatitis
• Gastrointestinal perforation
  - Gastric ulcer
  - Duodenal ulcer

Hepatobiliary Disorders

• Hepatitis
  - Autoimmune hepatitis
  - Immune-mediated hepatitis
  - Drug induced liver injury
  - Acute hepatitis
• Increased aspartate aminotransferase
• Increased alanine aminotransferase
• Increased blood bilirubin

Genitourinary Disorders

• Nephritis
  - Autoimmune nephritis
  - Renal failure
  - Acute renal failure or acute kidney injury with evidence of nephritis
  - Nephrotic syndrome
  - Glomerulonephritis
  - Membranous glomerulonephritis
• Increased blood creatinine

Endocrine and Metabolic Disorders

• Hyperthyroidism
• Hypothyroidism (myxoedema)
• Hypophysitis (hypopituitarism)
• Adrenal insufficiency
  - Addison's disease
  - Acute adrenocortical insufficiency
  - Secondary adrenocortical insufficiency
• Thyroiditis
  - Autoimmune thyroiditis
  - Thyroid disorder
• Decreased appetite
• Type 1 diabetes mellitus (diabetic ketoacidosis)
• Hyponatraemia
• Hypokalaemia
• Hypocalcaemia
• Hypercalcaemia
• Increased amylase

Musculoskeletal Disorders

• Arthralgia
• Myositis
  - Myalgia
  - Myopathy
  - Necrotising myositis
  - Polymyalgia rheumatica
  - Rhabdomyolysis
• Musculoskeletal pain
  - Musculoskeletal discomfort
  - Back pain
  - Musculoskeletal stiffness
  - Musculoskeletal chest pain
  - Torticollis
• Arthritis
  - Joint swelling
  - Polyarthritis
  - Joint effusion
• Pain in extremity
• Tenosynovitis
  - Tendonitis
  - Synovitis
  - Tendon pain
• Sjogren's syndrome

Skin and Subcutaneous Tissue Disorders

• Palmar-plantar erythrodysaesthesia syndrome
• Rash
  - Erythematous rash
  - Follicular rash
  - Macular rash
  - Maculopapular rash
  - Papular rash
  - Pruritic rash
  - Vesicular rash
  - Genital rash
• Pruritus
  - Urticaria
  - Papular urticaria
  - Genital pruritus
• Severe skin reactions
  - Bullous dermatitis
  - Exfoliative generalised dermatitis
  - Exfoliative rash
  - Pemphigus
  - Grade ≥3 of the following: acute febrile neutrophilic dermatosis, contusion, decubitus ulcer, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, erythema multiforme, jaundice, lichen planus, oral lichen planus, pemphigoid, pruritus, genital pruritus, rash, erythematous rash, maculopapular rash, pruritic rash, pustular rash, skin lesion, skin necrosis and toxic skin eruption
• Vitiligo
  - Skin depigmentation
  - Skin hypopigmentation
  - Hypopigmentation of the eyelid
• Dry skin
• Erythema
• Lichenoid keratosis
  - Lichen planus
  - Lichen sclerosus
• Psoriasis
• Alopecia
• Dermatitis
• Dermatitis acneiform
• Eczema
• Hair colour changes
• Papule

Immune, Blood and Lymphatic System Disorders

• Pneumonia
• Anaemia
• Neutropenia
• Thrombocytopenia
• Leukopenia
• Lymphopenia
• Eosinophilia
• Infusion-related reaction
  - Drug hypersensitivity
  - Anaphylactic reaction
  - Anaphylactoid reaction
  - Hypersensitivity
  - Cytokine release syndrome
• Oedema
  - Peripheral oedema
  - Generalised oedema
  - Fluid overload
  - Fluid retention
  - Eyelid oedema
  - Lip oedema
  - Face oedema
  - Localised oedema
  - Periorbital oedema
• Pyrexia
• Increased blood alkaline phosphatase

Sensory Disorders

• Uveitis
  - Chorioretinitis
  - Iritis
  - Iridocyclitis
• Dry eye

Others

• Influenza-like illness
• Chills

• Systemic corticosteroids
  (See additional prescribing points)
• Immunosuppressants 
  (See additional prescribing points)

• Hepatic function
• Renal function
• Thyroid function
• HBV screening
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to hepatitis B surface antigen

Specific cases may require

• PD-L1 expression status 
• Microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) status
• Tumour mutational burden-high (TMB-H) status
• Blood glucose
• Full blood count with differential
• Pregnancy status
• Pituitary function and hormone levels

Additional observations

• Signs and symptoms of
  - Immune-mediated adverse reactions
  - Adrenal insufficiency
  - Diarrhoea/colitis
  - Dermatologic toxicity
  - Diabetes mellitus
  - Hypophysitis
  - Ocular disorders
  - Thyroid disorders
  - Pneumonitis
  - Other immune-mediated adverse reactions
  - Infusion-related reactions
• Early signs and symptoms of transplant-related complications

Traceability

• In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded

Assessment of PD-L1 status

• When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is chosen to minimise false negative or false positive determinations

Use of systemic corticosteroids or immunosuppressants

• The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab
• However, systemic corticosteroids or other immunosuppressants can be used after starting pembrolizumab to treat immune-related adverse reactions
• Corticosteroids can also be used as premedication when pembrolizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions

Dose delay or discontinuation

• No dose reductions of pembrolizumab are recommended. Pembrolizumab should be withheld or discontinued to manage adverse reactions as described in the table below:

Recommended treatment modifications for pembrolizumab

Additional precautions

• Pembrolizumab, as monotherapy or as combination therapy, should be permanently discontinued for Grade 4 or recurrent Grade 3 immune-related adverse reactions, unless otherwise specified in the table above
• For Grade 4 haematological toxicity, only in patients with cHL, pembrolizumab should be withheld until adverse reactions recover to Grades 0-1

Pembrolizumab in combination with axitinib in renal cell carcinoma (RCC)

• When axitinib is used in combination with pembrolizumab, dose escalation of axitinib above the initial 5mg dose may be considered at intervals of six weeks or longer

For liver enzyme elevations, in patients with RCC being treated with pembrolizumab in combination with axitinib:

• If ALT or AST ≥3 times ULN but <10 times ULN without concurrent total bilirubin ≥2 times ULN, both pembrolizumab and axitinib should be withheld until these adverse reactions recover to Grades 0-1
• Corticosteroid therapy may be considered. Rechallenge with a single medicine or sequential rechallenge with both medicines after recovery may be considered. If rechallenging with axitinib, dose reduction as per the axitinib professional information
• If ALT or AST ≥10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN, both pembrolizumab and axitinib should be permanently discontinued and corticosteroid therapy may be considered
• Patients treated with pembrolizumab must be given the patient alert card and be informed about the risks of pembrolizumab

Pharmacokinetics

• Elimination (terminal) half-life (t_1/2): 22 days

Pembrolizumab is a humanised monoclonal antibody which binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been shown to be involved in the control of T-cell immune responses. Pembrolizumab potentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour microenvironment. 

Injection (per 4ml) 100mg

• Keytruda (MSD)