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This section of the website is for UK healthcare professionals only. If you are not a healthcare professional, please click here.

Pooled Safety

This safety information is aligned to the Northern Ireland summary of product characteristics (SmPC).

Please refer to both the Summary of Product Characteristics (SmPC), and Risk Minimisation Materials (RMM) before prescribing KEYTRUDA.

Prescribing Information

The safety of KEYTRUDA® (pembrolizumab) as monotherapy has been evaluated in 6,185 patients with advanced melanoma, resected Stage III melanoma (adjuvant therapy), NSCLC, cHL, urothelial carcinoma, HNSCC, or CRC across four doses (2 mg/kg bodyweight every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg bodyweight every 2 or 3 weeks) in clinical studies.* The frequencies included below are based on all reported adverse drug reactions, regardless of the investigator assessment of causality. In this patient population, the median observation time was 7.6 months (range: 1 day to 47 months) and the most frequent adverse reactions with KEYTRUDA were fatigue (32%), nausea (21%), and diarrhoea (21%). The majority of adverse reactions reported for monotherapy were of Grade 1 or Grade 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions.1

The safety of KEYTRUDA in combination with chemotherapy has been evaluated in 1,437 patients with NSCLC, HNSCC, or oesophageal carcinoma receiving 200 mg, 2 mg/kg bodyweight or 10 mg/kg bodyweight KEYTRUDA every 3 weeks, in clinical studies. The frequencies included below are based on all reported adverse drug reactions, regardless of the investigator assessment of causality. In this patient population, the most frequent adverse reactions were nausea (55%), anaemia (51%), fatigue (39%), constipation (37%), decreased appetite (34%), diarrhoea (33%), neutropenia (29%), and vomiting (28%). Incidences of Grades 3-5 adverse reactions in patients with NSCLC were 67% for KEYTRUDA combination therapy and 66% for chemotherapy alone, in patients with HNSCC were 85% for KEYTRUDA combination therapy and 84% for chemotherapy plus cetuximab, and in patients with oesophageal carcinoma were 86% for KEYTRUDA combination therapy and 83% for chemotherapy alone.1

The safety of KEYTRUDA in combination with axitinib has been evaluated in a clinical study of 429 patients with advanced RCC receiving 200 mg KEYTRUDA every 3 weeks and 5 mg axitinib twice daily. In this patient population, the most frequent adverse reactions were diarrhoea (54%), hypertension (45%), fatigue (38%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysaesthesia syndrome (28%), nausea (28%), ALT increased (27%), AST increased (26%), dysphonia (25%), cough (21%), and constipation (21%). Incidences of Grades 3-5 adverse reactions were 76% for KEYTRUDA combination therapy and 71% for sunitinib alone.1

KEYTRUDA is most commonly associated with immune-related adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of KEYTRUDA. Most immune-related adverse reactions occurring during treatment with KEYTRUDA were reversible and managed with interruptions of KEYTRUDA, administration of corticosteroids and/or supportive care. Immune-related adverse reactions have also occurred after the last dose of KEYTRUDA. Immune-related adverse reactions, including severe and fatal cases, have occurred in patients receiving KEYTRUDA. Immune-related adverse reactions affecting more than one body system can occur simultaneously.

Please refer to the Summary of Product Characteristics (SmPC) and the Risk Minimisation Materials (RMM) for a complete list of adverse events, special warnings, precautions and patients excluded from clinical trials.

*The licensed dose of KEYTRUDA in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The licensed dose of KEYTRUDA as monotherapy in paediatric patients aged 3 years and older with cHL is 2 mg/kg bodyweight (up to a maximum of 200 mg), every 3 weeks administered as an intravenous infusion over 30 minutes. KEYTRUDA must NOT be administered as an intravenous push or bolus injection.

ALT: alanine aminotransferase; AST: aspartate transaminase; NSCLC: Non Small Cell Lung Cancer; cHL: classical Hodgkin Lymphoma; HNSCC: Head and Neck Squamous Cell Carcinoma.

Adverse events occurring in patients treated with KEYTRUDA1

Adverse events reported in clinical trials and post marketing use with KEYTRUDA as a monotherapy treatment†1

Incidence Event
Infections and infestations
Common Pneumonia
Blood and lymphatic system disorders
Very common Anaemia
Common Thrombocytopenia, neutropenia, lymphopenia
Uncommon Leukopenia, eosinophilia
Rare Immune thrombocytopenia, haemolytic anaemia, pure red cell aplasia, haemophagocytic lymphohistiocytosis
Immune system disorders
Common Infusion-related reaction
Uncommon Sarcoidosis
Not known Solid organ transplant rejection
Endocrine disorders
Very common Hypothyroidism
Common Hyperthyroidism, thyroiditis
Uncommon Adrenal insufficiency, hypophysitis
Metabolism and nutrition disorders
Very common Decreased appetite
Common Hyponatraemia, hypokalaemina, hypocalcaemia
Uncommon Type 1 diabetes mellitus
Psychiatric disorders
Common Insomnia
Nervous system disorders
Very common Headache
Common Dizziness, neuropathy peripheral, lethargy, dysgeusia
Uncommon Epilepsy
Rare Encephalitis, Guillain-Barré syndrome, myelitis, myasthenic syndrome, meningitis (aseptic)
Eye disorders
Common Dry eye
Uncommon Uveitis
Rare Vogt-Koyanagi-Harada syndrome
Cardiac disorders
Common Cardiac arrythmia (including atrial fibrillation)a
Uncommon Myocarditis, pericardial effusion, pericarditis
Vascular disorders
Common Hypertension
Rare Vasculitis
Respiratory, thoracic and mediastinal disorders
Very common Dyspnoea, cough
Common Pneumonitis
Gastrointestinal disorders
Very common Diarrhoea, abdominal pain, nausea, vomiting, constipation
Common Colitis, dry mouth
Uncommon Pancreatitis, gastrointestinal ulceration, gastritis
Rare Small intestinal perforation
Hepatobiliary disorders
Uncommon Hepatitis
Rare Cholangitis sclerosing
Skin and subcutaneous tissue disorders
Very common Rash, pruritus
Common Severe skin reactions, erythema, dermatitis, dry skin, vitiligo, eczema, alopecia, dermatitis acneiform
Uncommon Psoriasis, lichenoid keratosis, papule, hair colour changes
Rare Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema nodosum
Musculoskeletal and connective tissue disorders
Very common Musculoskeletal pain, arthralgia
Common Pain in extremity, myositis, arthritis
Uncommon Tenosynovitis
Rare Sjogren's syndrome
Renal and urinary disorders
Uncommon Nephritis
Rare Cystitis noninfective
General disorders and administration site conditions
Very common Fatigue, asthenia, oedema, pyrexia
Common Influenza-like illness, chills
Investigations
Common Aspartate aminotransferase increased, alanine aminotransferase increased, hypercalcaemia, blood alkaline phosphatase increased, blood bilirubin increased, blood creatinine increased
Uncommon Amylase increased

Adapted and modified from KEYTRUDA Summary of Product Characteristics.1

  • Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); and not known (cannot be estimated from the available data). Adverse events were pooled from clinical trials across four doses; KEYTRUDA 2 mg/kg Q3W, 200 mg Q3W, or 10 mg/kg Q2W or Q3W, as well as post marketing usage. The licensed dose of KEYTRUDA in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The licensed dose of KEYTRUDA as monotherapy in paediatric patients aged 3 years and older with cHL is 2 mg/kg bodyweight (up to a maximum of 200 mg), every 3 weeks administered as an intravenous infusion over 30 minutes
  • Adverse reaction frequencies presented may not be fully attributable to KEYTRUDA alone but may contain contributions from the underlying disease or from other medicinal products used in a combination
  • The following terms represent a group of related events that describe a medical condition rather than a single event: infusion-related reaction (drug hypersensitivity, anaphylactic reaction, anaphylactoid reaction, hypersensitivity, infusion-related hypersensitivity reaction, and cytokine release syndrome); hypothyroidism (myxoedema); thyroiditis (autoimmune thyroiditis and thyroid disorder); adrenal insufficiency (Addison’s disease, adrenocortical insufficiency acute, secondary adrenocortical insufficiency); hypophysitis (hypopituitarism); type 1 diabetes mellitus (diabetic ketoacidosis); encephalitis (autoimmune encephalitis, noninfective encephalitis); Guillain-Barré syndrome (axonal neuropathy and demyelinating polyneuropathy); myelitis (including transverse myelitis); myasthenic syndrome (myasthenia gravis, including exacerbation); meningitis aseptic (meningitis, meningitis non-infective); uveitis (chorioretinitis, iritis and iridocyclitis); myocarditis (autoimmune myocarditis); pneumonitis (interstitial lung disease, organising pneumonia, immune-mediated pneumonitis); abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower); colitis (colitis microscopic, enterocolitis, enterocolitis haemorrhagic, autoimmune colitis, and immune-mediated enterocolitis); pancreatitis (autoimmune pancreatitis, pancreatitis acute and immune-mediated pancreatitis); gastrointestinal ulceration (gastric ulcer and duodenal ulcer); hepatitis (autoimmune hepatitis, immune-mediated hepatitis, drug induced liver injury and acute hepatitis); rash (rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular and genital rash); pruritus (urticaria, urticaria papular and pruritus genital); severe skin reactions (dermatitis bullous, dermatitis exfoliative generalised, exfoliative rash, pemphigus, and Grade ≥3 of the following: acute febrile neutrophilic dermatosis, contusion, decubitus ulcer, dermatitis bullous, dermatitis psoriasiform, drug eruption, erythema multiforme, jaundice, lichen planus, oral lichen planus, pemphigoid, pruritus, pruritus genital, rash, rash erythematous, rash maculo-papular, rash pruritic, rash pustular, skin lesion, skin necrosis and toxic skin eruption); vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid); lichenoid keratosis (lichen planus and lichen sclerosus); musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain and torticollis); myositis (myalgia, myopathy, necrotising myositis, polymyalgia rheumatica and rhabdomyolysis); arthritis (joint swelling, polyarthritis and joint effusion); tenosynovitis (tendonitis, synovitis and tendon pain); nephritis (autoimmune nephritis, tubulointerstitial nephritis and renal failure, renal failure acute, or acute kidney injury with evidence of nephritis, nephrotic syndrome, glomerulonephritis and glomerulonephritis membranous); oedema (oedema peripheral, generalised oedema, fluid overload, fluid retention, eyelid oedema and lip oedema, face oedema, localised oedema and periorbital oedema)
  • a Based upon a standard query including bradyarrhythmias and tachyarrhythmias

Q2W: Every two weeks; Q3W: Every three weeks.

Adverse events reported in clinical trials and post marketing use with KEYTRUDA in combination with Chemotherapy†1

Incidence Event
Infections and infestations
Very Common Pneumonia
Blood and lymphatic system disorders
Very common Neutropenia, anaemia, thrombocytopenia, leukopenia
Common Febrile neutropenia, lymphopenia
Uncommon Eosinophilia
Immune system disorders
Common Infusion-related reaction
Endocrine disorders
Very common Hypothyroidism
Common Hyperthyroidism
Uncommon Hypophysitis, adrenal insufficiency, thyroiditis
Metabolism and nutrition disorders
Very common Hypokalaemia, decreased appetite
Common Hypocalcaemia, hyponatraemia
Uncommon Type 1 diabetes mellitus
Psychiatric disorders
Very common Insomnia
Nervous system disorders
Very common Dizziness, neuropathy peripheral, headache
Common Dysgeusia, lethargy
Uncommon Epilepsy
Rare Guillain-Barré syndrome, encephalitis
Eye disorders
Common Dry eye
Rare Uveitis
Cardiac disorders
Common Cardiac arrythmia (including atrial fibrillation)a
Uncommon Myocarditis, pericardial effusion, pericarditis
Vascular disorders
Common Hypertension
Respiratory, thoracic and mediastinal disorders
Very common Dyspnoea, cough
Common Pneumonitis
Gastrointestinal disorders
Very common Nausea, diarrhoea, vomiting, abdominal pain, constipation
Common Colitis, dry mouth, gastritis
Uncommon Pancreatitis, gastrointestinal ulceration
Hepatobiliary disorders
Common Hepatitis
Rare Cholangitis sclerosing
Skin and subcutaneous tissue disorders
Very common Rash, alopecia, pruritus
Common Severe skin reactions, dry skin, erythema, dermatitis
Uncommon Psoriasis, vitiligo, eczema, dermatitis acneiform, lichenoid keratosis
Rare Erythema nodosum, papule, hair colour changes
Musculoskeletal and connective tissue disorders
Very common Musculoskeletal pain, arthralgia
Common Myositis, pain in extremity, arthritis
Uncommon Tenosynovitis
Rare Sjogren's syndrome
Renal and urinary disorders
Common Acute kidney injury
Uncommon Nephritis
General disorders and administration site conditions
Very common Fatigue, asthenia, pyrexia, odema
Common Influenza-like illness, chills
Investigations
Very common Alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased
Common Hypercalcaemia, blood alkaline phosphatase increased, blood bilirubin increased
Uncommon Amylase increased

Adapted and modified from KEYTRUDA Summary of Product Characteristics.1

  • Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); and not known (cannot be estimated from the available data). Adverse events were pooled from clinical trials across four doses; KEYTRUDA 2 mg/kg Q3W, 200 mg Q3W, or 10 mg/kg Q2W or Q3W, as well as post marketing usage. The licensed dose of KEYTRUDA in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The licensed dose of KEYTRUDA as monotherapy in paediatric patients aged 3 years and older with cHL is 2 mg/kg bodyweight (up to a maximum of 200 mg), every 3 weeks administered as an intravenous infusion over 30 minutes
  • Adverse reaction frequencies presented may not be fully attributable to KEYTRUDA alone but may contain contributions from the underlying disease or from other medicinal products used in a combination
  • The following terms represent a group of related events that describe a medical condition rather than a single event: infusion-related reaction (drug hypersensitivity, anaphylactic reaction, anaphylactoid reaction, hypersensitivity, infusion-related hypersensitivity reaction, and cytokine release syndrome); hypothyroidism (myxoedema); thyroiditis (autoimmune thyroiditis and thyroid disorder); adrenal insufficiency (Addison’s disease, adrenocortical insufficiency acute, secondary adrenocortical insufficiency); hypophysitis (hypopituitarism); type 1 diabetes mellitus (diabetic ketoacidosis); encephalitis (autoimmune encephalitis, noninfective encephalitis); Guillain-Barré syndrome (axonal neuropathy and demyelinating polyneuropathy); myelitis (including transverse myelitis); myasthenic syndrome (myasthenia gravis, including exacerbation); meningitis aseptic (meningitis, meningitis non-infective); uveitis (chorioretinitis, iritis and iridocyclitis); myocarditis (autoimmune myocarditis); pneumonitis (interstitial lung disease, organising pneumonia, immune-mediated pneumonitis); abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower); colitis (colitis microscopic, enterocolitis, enterocolitis haemorrhagic, autoimmune colitis, and immune-mediated enterocolitis); pancreatitis (autoimmune pancreatitis, pancreatitis acute and immune-mediated pancreatitis); gastrointestinal ulceration (gastric ulcer and duodenal ulcer); hepatitis (autoimmune hepatitis, immune-mediated hepatitis, drug induced liver injury and acute hepatitis); rash (rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular and genital rash); pruritus (urticaria, urticaria papular and pruritus genital); severe skin reactions (dermatitis bullous, dermatitis exfoliative generalised, exfoliative rash, pemphigus, and Grade ≥3 of the following: acute febrile neutrophilic dermatosis, contusion, decubitus ulcer, dermatitis bullous, dermatitis psoriasiform, drug eruption, erythema multiforme, jaundice, lichen planus, oral lichen planus, pemphigoid, pruritus, pruritus genital, rash, rash erythematous, rash maculo-papular, rash pruritic, rash pustular, skin lesion, skin necrosis and toxic skin eruption); vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid); lichenoid keratosis (lichen planus and lichen sclerosus); musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain and torticollis); myositis (myalgia, myopathy, necrotising myositis, polymyalgia rheumatica and rhabdomyolysis); arthritis (joint swelling, polyarthritis and joint effusion); tenosynovitis (tendonitis, synovitis and tendon pain); nephritis (autoimmune nephritis, tubulointerstitial nephritis and renal failure, renal failure acute, or acute kidney injury with evidence of nephritis, nephrotic syndrome, glomerulonephritis and glomerulonephritis membranous); oedema (oedema peripheral, generalised oedema, fluid overload, fluid retention, eyelid oedema and lip oedema, face oedema, localised oedema and periorbital oedema)
  • a Based upon a standard query including bradyarrhythmias and tachyarrhythmias

Q2W: Every two weeks; Q3W: Every three weeks.

Adverse events reported in clinical trials and post marketing use with KEYTRUDA in combination with axitinib or lenvatinib†1

Incidence Event
Infections and infestations
Very common Urinary tract infection
Common Pneumonia
Blood and lymphatic system disorders
Very common Anaemia
Common Neutropenia, leukopenia, thrombocytopenia
Uncommon Eosinophilia
Immune system disorders
Common Infusion-related reaction
Endocrine disorders
Very common Hypothyroidism
Common Adrenal insufficiency, hyperthyroidism, thyroiditis
Uncommon Hypophysitis
Metabolism and nutrition disorders
Very common Decreased appetite
Common Hypokalaemia, hyponatraemia, hypocalcaemia
Uncommon Type 1 diabetes mellitus
Psychiatric disorders
Common Insomnia
Nervous system disorders
Very common Headache, dysgeusia
Common Dizziness, lethargy, neuropathy peripheral
Uncommon Myasthenic syndrome, encephalitis
Eye disorders
Common Dry eye
Uncommon Uveitis
Rare Vogt-Koyanagi-Harada syndrome
Cardiac disorders
Common Cardiac arrythmia (including atrial fibrillation)a
Uncommon Myocarditis, pericardial effusion
Vascular disorders
Very common Hypertension
Uncommon Vasculitis
Respiratory, thoracic and mediastinal disorders
Very common Dyspnoea, cough, dysphonia
Common Pneumonitis
Gastrointestinal disorders
Very common Diarrhoea, abdominal pain, nausea, vomiting, constipation
Common Colitis, dry mouth, pancreatitis, gastritis
Uncommon Gastrointestinal ulceration
Hepatobiliary disorders
Common Hepatitis
Skin and subcutaneous tissue disorders
Very common Rash, pruritus
Common Severe skin reactions, dermatitis acneiform, dermatitis, dry skin, alopecia, erythema
Uncommon Hair colour changes, lichenoid keratosis, papule, psoriasis, vitiligo, eczema
Rare Toxic epidermal necrolysis, Stevens-Johnson syndrome
Musculoskeletal and connective tissue disorders
Very common Musculoskeletal pain, arthralgia, pain in extremity, myositis
Common Arthritis
Uncommon Tenosynovitis
Rare Sjogren’s syndrome
Renal and urinary disorders
Common Nephritis
Rare Cystitis noninfective
General disorders and administration site conditions
Very common Fatigue, asthenia, pyrexia, oedema
Common Influenza-like illness, chills
Investigations
Very common Lipase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased
Common Amylase increased, blood bilirubin increased, blood alkaline phosphatase increased, hypercalcaemia

Adapted and modified from KEYTRUDA Summary of Product Characteristics.1

  • Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); and not known (cannot be estimated from the available data). Adverse events were pooled from clinical trials across four doses; KEYTRUDA 2 mg/kg Q3W, 200 mg Q3W, or 10 mg/kg Q2W or Q3W, as well as post marketing usage. The licensed dose of KEYTRUDA in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The licensed dose of KEYTRUDA as monotherapy in paediatric patients aged 3 years and older with cHL is 2 mg/kg bodyweight (up to a maximum of 200 mg), every 3 weeks administered as an intravenous infusion over 30 minutes
  • Adverse reaction frequencies presented may not be fully attributable to KEYTRUDA alone but may contain contributions from the underlying disease or from other medicinal products used in a combination
  • The following terms represent a group of related events that describe a medical condition rather than a single event: infusion-related reaction (drug hypersensitivity, anaphylactic reaction, anaphylactoid reaction, hypersensitivity, infusion-related hypersensitivity reaction, and cytokine release syndrome); hypothyroidism (myxoedema); thyroiditis (autoimmune thyroiditis and thyroid disorder); adrenal insufficiency (Addison’s disease, adrenocortical insufficiency acute, secondary adrenocortical insufficiency); hypophysitis (hypopituitarism); type 1 diabetes mellitus (diabetic ketoacidosis); encephalitis (autoimmune encephalitis, noninfective encephalitis); Guillain-Barré syndrome (axonal neuropathy and demyelinating polyneuropathy); myelitis (including transverse myelitis); myasthenic syndrome (myasthenia gravis, including exacerbation); meningitis aseptic (meningitis, meningitis non-infective); uveitis (chorioretinitis, iritis and iridocyclitis); myocarditis (autoimmune myocarditis); pneumonitis (interstitial lung disease, organising pneumonia, immune-mediated pneumonitis); abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower); colitis (colitis microscopic, enterocolitis, enterocolitis haemorrhagic, autoimmune colitis, and immune-mediated enterocolitis); pancreatitis (autoimmune pancreatitis, pancreatitis acute and immune-mediated pancreatitis); gastrointestinal ulceration (gastric ulcer and duodenal ulcer); hepatitis (autoimmune hepatitis, immune-mediated hepatitis, drug induced liver injury and acute hepatitis); rash (rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular and genital rash); pruritus (urticaria, urticaria papular and pruritus genital); severe skin reactions (dermatitis bullous, dermatitis exfoliative generalised, exfoliative rash, pemphigus, and Grade ≥3 of the following: acute febrile neutrophilic dermatosis, contusion, decubitus ulcer, dermatitis bullous, dermatitis psoriasiform, drug eruption, erythema multiforme, jaundice, lichen planus, oral lichen planus, pemphigoid, pruritus, pruritus genital, rash, rash erythematous, rash maculo-papular, rash pruritic, rash pustular, skin lesion, skin necrosis and toxic skin eruption); vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid); lichenoid keratosis (lichen planus and lichen sclerosus); musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain and torticollis); myositis (myalgia, myopathy, necrotising myositis, polymyalgia rheumatica and rhabdomyolysis); arthritis (joint swelling, polyarthritis and joint effusion); tenosynovitis (tendonitis, synovitis and tendon pain); nephritis (autoimmune nephritis, tubulointerstitial nephritis and renal failure, renal failure acute, or acute kidney injury with evidence of nephritis, nephrotic syndrome, glomerulonephritis and glomerulonephritis membranous); oedema (oedema peripheral, generalised oedema, fluid overload, fluid retention, eyelid oedema and lip oedema, face oedema, localised oedema and periorbital oedema)
  • a Based upon a standard query including bradyarrhythmias and tachyarrhythmias
Additional safety information and special populations

Interactions with other medicinal products and other forms of interaction:

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. Since KEYTRUDA is cleared from the circulation through catabolism, no metabolic drug-drug interactions are expected.1

The use of systemic corticosteroids or immunosuppressants should be avoided before starting KEYTRUDA due to their potential to interfere with the pharmacodynamic activity and efficacy of KEYTRUDA. However, systemic corticosteroids or other immunosuppressants can be used after starting KEYTRUDA to treat immune-related adverse events. Corticosteroids can also be used as premedication, when KEYTRUDA is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions.1

Infusion-related reactions:

Some patients have experienced severe infusion-related reactions including hypersensitivity and anaphylaxis. For Grades 3 or 4 infusion reactions, infusion should be stopped and KEYTRUDA permanently discontinued. Patients with Grades 1 or 2 infusion reactions may continue to receive KEYTRUDA with close monitoring.1 Premedication with antipyretic and antihistamine may be considered.1

Immune-related adverse events:

Immune-related adverse events, including severe and fatal cases, have occurred in patients receiving KEYTRUDA. Most immune-related adverse events occurring during treatment with KEYTRUDA were reversible and managed with interruptions of KEYTRUDA, administration of corticosteroids and/or supportive care. Immune-related adverse events have also occurred after the last dose of KEYTRUDA. Immune-related adverse events affecting more than one body system can occur simultaneously.1

Groups excluded from clinical trials:

Patients with the following conditions were excluded from clinical studies: active CNS metastases; ECOG PS ≥2 (except for urothelial cancer and RCC); HIV, Hep B or C infection; active systemic autoimmune disease; interstitial lung disease; prior pneumonitis requiring systemic corticosteroid therapy; history of severe hypersensitivity to another monoclonal antibody; receiving immunosuppressive therapy; history of severe immune-related adverse events from treatment with ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (>10 mg/day prednisone or equivalent) for greater than 12 weeks. Patients with active infections were excluded from clinical studies and were required to have their infection treated prior to receiving KEYTRUDA. Patients with active infections occurring during treatment with KEYTRUDA were managed with appropriate medical therapy. Patients with clinically significant renal (creatinine >1.5 x ULN) or hepatic (bilirubin >1.5 x ULN, ALT, AST >2.5 x ULN in the absence of liver metastases) abnormalities at baseline were also excluded from clinical trials and therefore information is limited in patients with severe renal and moderate to severe hepatic impairment.

There are limited data on the safety and efficacy of KEYTRUDA in patients with ocular melanoma. After careful consideration of the potential increased risk, KEYTRUDA may be used with appropriate medical management in these patients.1

Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT):

Allogeneic HSCT after treatment with KEYTRUDA
Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been observed in patients with classical Hodgkin lymphoma undergoing allogeneic HSCT after previous exposure to KEYTRUDA. Until further data become available, careful consideration to the potential benefits of HSCT and the possible increased risk of transplant-related complications should be made case by case.1

Allogeneic HSCT prior to treatment with KEYTRUDA
In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at an increased risk for GVHD after treatment with KEYTRUDA. Consider the benefit of treatment with KEYTRUDA versus the risk of possible GVHD in patients with a history of allogeneic HSCT.1

Use of KEYTRUDA in urothelial cancer for patients who have received prior platinum-containing chemotherapy:

Physicians should consider the delayed onset of KEYTRUDA effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In urothelial cancer, a higher number of deaths within 2 months was observed in KEYTRUDA compared to chemotherapy. Factors associated with early deaths were fast progressive disease on prior platinum therapy and liver metastases.1

Use of KEYTRUDA in urothelial cancer for patients who are considered ineligible for cisplatin-containing chemotherapy and whose tumours express PD-L1 with CPS ≥10:

The baseline and prognostic disease characteristics of the study population of KEYNOTE-052 included a proportion of patients eligible for a carboplatin-based combination, for whom the benefit has been assessed in a comparative study (KEYNOTE-361). In KEYNOTE-361, a higher number of deaths within 6 months of treatment initiation followed by a long-term survival benefit was observed with KEYTRUDA monotherapy compared to chemotherapy. No specific factor(s) associated with early deaths could be identified. Physicians should consider the delayed onset of KEYTRUDA effect before initiating treatment in patients with urothelial cancer who are considered eligible for carboplatin-based combination chemotherapy. KEYNOTE-052 also included patients eligible for mono-chemotherapy, for whom no randomised data are available. In addition, no safety and efficacy data are available in frailer patients (e.g. ECOG performance status 3) considered not eligible for chemotherapy. In the absence of these data, KEYTRUDA should be used with caution in this population after careful consideration of the potential risk-benefit on an individual basis.1

Use of KEYTRUDA for first-line treatment of patients with NSCLC:

In general, the frequency of adverse reactions for KEYTRUDA combination therapy is observed to be higher than for KEYTRUDA monotherapy or chemotherapy alone, reflecting the contributions of each of these components. A direct comparison of KEYTRUDA when used in combination with chemotherapy to KEYTRUDA monotherapy is not available.1

Physicians should consider the benefit/risk balance of the available treatment options (KEYTRUDA monotherapy or KEYTRUDA in combination with chemotherapy) before initiating treatment in previously untreated patients with NSCLC whose tumours express PD-L1.1 In KEYNOTE-042, a higher number of deaths within 4 months of treatment initiation followed by a long-term survival benefit was observed with KEYTRUDA monotherapy compared to chemotherapy1

Efficacy and safety data from patients ≥75 years are limited. For patients ≥75 years, KEYTRUDA combination therapy should be used with caution after careful consideration of the potential benefit/risk on an individual basis.1

Use of KEYTRUDA for treatment of patients with HNSCC:

In general, the frequency of adverse reactions for KEYTRUDA combination therapy is observed to be higher than for KEYTRUDA monotherapy or chemotherapy alone, reflecting the contributions of each of these components.1 Physicians should consider the benefit/risk balance of the available treatment options (KEYTRUDA monotherapy or KEYTRUDA in combination with chemotherapy) before initiating treatment in patients with head and neck squamous cell carcinoma whose tumours express PD-L1.1

Use of KEYTRUDA for adjuvant treatment of patients with melanoma:

A trend toward increased frequency of severe and serious adverse reactions in patients ≥75 years was observed. Safety data of KEYTRUDA in the adjuvant melanoma setting in patients ≥75 years are limited.1

Use of KEYTRUDA in combination with axitinib for first-line advanced RCC:

Higher than expected frequencies of Grades 3 and 4 ALT and AST elevations have been reported in patients with advanced RCC. Liver enzymes should be monitored before initiation of and periodically throughout treatment. More frequent monitoring of liver enzymes as compared to when the medicines are used in monotherapy may be considered. Medical management guidelines for both medicines should be followed (refer to the SmPC for axitinib).1

Use of KEYTRUDA first-line treatment of patients with MSI-H/dMMR CRC:

In KEYNOTE-177, the hazard rates for overall survival events were greater for KEYTRUDA compared with chemotherapy for the first 4 months of treatment, followed by a long-term survival benefit for KEYTRUDA.1

Elderly:

No dose adjustment is necessary in patients ≥65 years. Data from patients ≥65 years are too limited to draw conclusions on cHL population. Data are limited in patients ≥75 years for KEYTRUDA monotherapy in patients with resected Stage III melanoma and MSI-H or dMMR CRC; for KEYTRUDA in combination with axitinib in patients with advanced RCC; for chemotherapy combination in patients with metastatic NSCLC and oesophageal carcinoma; and for KEYTRUDA (with or without chemotherapy) in patients receiving first-line treatment for metastatic or unresectable recurrent HNSCC.1

Women of childbearing potential:

Women of childbearing potential should use effective contraception during treatment with KEYTRUDA and for at least 4 months after the last dose of KEYTRUDA.1

Pregnancy:

There are no data on the use of KEYTRUDA in pregnant women. KEYTRUDA should not be used during pregnancy unless the clinical condition of the woman requires treatment with KEYTRUDA.1

Breastfeeding:

It is unknown whether KEYTRUDA 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 KEYTRUDA or to discontinue breastfeeding, taking into account the benefit of breast-feeding for the child and the benefit of KEYTRUDA therapy for the woman.1

Fertility:

No clinical data are available on the possible effect of KEYTRUDA on fertility.1

Renal impairment:

No dose adjustment is needed for patients with mild or moderate renal impairment. KEYTRUDA has not been studied in patients with severe renal impairment.1

Hepatic impairment:

No dose adjustment is needed for patients with mild hepatic impairment. KEYTRUDA has not been studied in patients with moderate or severe hepatic impairment.1

Ocular melanoma:

There are limited data on the safety and efficacy of KEYTRUDA in patients with ocular melanoma. After careful consideration of the potential increased risk, KEYTRUDA may be used with appropriate medical management in these patients.1

Immunogenicity:

There is no evidence of an altered pharmacokinetic or safety profile with anti-KEYTRUDA binding or neutralising antibody development.1

Overdose:

There is no information on overdose with KEYTRUDA.

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.1

Paediatric population:

The safety of KEYTRUDA as monotherapy has been evaluated in 161 paediatric patients aged 9 months to 17 years with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumours at 2 mg/kg every 3 weeks in the Phase I/II study KEYNOTE-051. The cHL population (n=22) included patients 11 to 17 years of age. The safety profile in paediatric patients was generally similar to that seen in adults treated with KEYTRUDA. The most common adverse reactions (reported in at least 20% of paediatric patients) were pyrexia (33%), vomiting (30%), headache (26%), abdominal pain (22%), anaemia (21%), cough (21%) and constipation (20%). The majority of adverse reactions reported for monotherapy were of Grades 1 or 2 severity. Seventy-six (47.2%) patients had 1 or more Grades 3 to 5 adverse reactions of which 5 (3.1%) patients had 1 or more adverse reactions that resulted in death. The frequencies are based on all reported adverse drug reactions, regardless of the investigator assessment of causality.1

Contraindications:

Hypersensitivity to the active substance or to any of the following: L-histidine, L-histidine hydrochloride monohydrate, sucrose, polysorbate 80 (E433) or water for injections.

Effect on ability to drive and use machines:

KEYTRUDA has a minor influence on the ability to drive and use machines. In some patients, dizziness and fatigue have been reported following administration of KEYTRUDA.1

Patients who have previously experienced a severe or life-threatening skin adverse reaction:

Caution should be used when considering the use of KEYTRUDA in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anticancer agents.1

Special warnings and precautions for use:

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.1

Laboratory abnormalities:

In patients treated with KEYTRUDA monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 10.8% for lymphocytes decreased, 8.3% for sodium decreased, 6.4% for haemoglobin decreased, 5.4% for phosphate decreased, 5.0% for glucose increased, 3.1% for AST increased, 3.0% for ALT increased, 2.7% for alkaline phosphatase increased, 2.4% for potassium decreased, 2.1% for neutrophils decreased, 2.0% for platelets decreased, 1.9% for calcium increased, 1.9% for potassium increased, 1.9% for bilirubin increased, 1.6% for albumin decreased, 1.5% for calcium decreased, 1.5% for creatinine increased, 0.9% for leucocytes decreased, 0.7% for magnesium increased, 0.6% for glucose decreased, 0.2% for magnesium decreased, and 0.2% for sodium increased.

In patients treated with KEYTRUDA in combination with chemotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 33.0% for neutrophils decreased, 25.5% for lymphocytes decreased, 20.3% for haemoglobin decreased, 19.3% for leucocytes decreased, 13.9% for sodium decreased, 10.8% for platelets decreased, 9.7% for phosphate decreased, 8.4% for potassium decreased, 7.6% for glucose increased, 3.9% for AST increased, 3.8% for potassium increased, 3.7% for calcium decreased, 3.6% for ALT increased, 3.1% for creatinine increased, 3.0% for albumin decreased, 2.2% for calcium increased, 1.6% for alkaline phosphatase increased, 1.2% for bilirubin increased, 0.8% for glucose decreased, and 0.4% for sodium increased.

In patients treated with KEYTRUDA in combination with axitinib or lenvatinib, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 23.0% for lipase increased (not measured in patients treated with KEYTRUDA and axitinib), 12.0% for lymphocyte decreased, 11.4% for sodium decreased, 11.2% for amylase increased, 11.2% for triglycerides increased, 10.4% for ALT increased, 8.9% for AST increased, 7.8% for glucose increased, 7.3% for phosphorus decreased, 6.8% for phosphate decreased, 6.1% for potassium decreased, 5.1% for potassium increased, 4.5% for cholesterol increased, 4.4% for creatinine increased, 4.2% for haemoglobin decreased, 4.0% for magnesium decreased, 3.5% for neutrophils decreased, 3.1% for alkaline phosphatase increased, 3.0% for platelets decreased, 2.8% for bilirubin increased, 2.2% for calcium decreased, 1.7% for white blood cells decreased, 1.6% for magnesium increased, 1.5% for prothrombin INR increased, 1.4% for glucose decreased, 1.2% for albumin decreased, 1.2% for calcium increased, 0.4% for sodium increased, and 0.1% for haemoglobin increased.

Patients with or undergoing solid organ transplant:

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with KEYTRUDA versus the risk of possible organ rejection should be considered in these patients.1

PD-L1 testing:

If specified in the indication, patient selection for treatment with KEYTRUDA based on the tumour expression of PD-L1 should be confirmed by a validated test.1

MSI-H/dMMR testing for patients with CRC:

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

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.1

Method of administration:

KEYTRUDA must be administered by intravenous infusion over 30 minutes. KEYTRUDA must not be administered as an intravenous push or bolus injection. When administering KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be administered first. See also the prescribing information for the concomitant therapies. For instructions on dilution of the medicinal product before administration, see the KEYTRUDA SmPC.1

Patient Alert Card:

All prescribers of KEYTRUDA must be familiar with the Physician Information and Management Guidelines. The prescriber must discuss the risks of KEYTRUDA therapy with the patient. The patient will be provided with the Patient Alert Card with each prescription.

Duration of treatment:

Patients should be treated with KEYTRUDA 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.1

For the adjuvant treatment of melanoma, KEYTRUDA should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year.1

Selected immune-related adverse events reported in KEYTRUDA clinical trials (n=6,185)*1

  Any grade, (n, %) Grade 2, (n, %) Grade 3, (n, %) Grade 4, (n, %) Grade 5, (n, %)
Adrenal insufficiency 52 (0.8) 23 (0.4) 21 (0.3) 4 (0.1) 0.0
Hypothyroidism 699 (11.3) 510 (8.2) 7 (0.1) 0.0 0.0
Hyperthyroidism 261 (4.2) 64 (1.0) 7 (0.1) 0.0 0.0
Pneumonitis 286 (4.6) 128 (2.1) 73 (1.2) 17 (0.3) 9 (0.1)
Colitis 121 (2.0) 35 (0.6) 67 (1.1) 5 (0.1) 0.0
Hypophysitis 38 (0.6) 15 (0.2) 19 (0.3) 1 (<0.1) 0.0
Hepatitis 61 (1.0) 8 (0.1) 41 (0.7) 8 (0.1) 0.0
Nephritis (monotherapy) 25 (0.4) 5 (0.1) 15 (0.2) 2 (<0.1) 0.0
Immune-related severe skin reactions§ 102 (1.6) 11 (0.2) 77 (1.2) 0.0 1 (<0.1)

Adapted from KEYTRUDA, Summary of Product Characteristics.1

*Selected immune-related adverse events were pooled from KEYTRUDA 200 mg Q3W, 2 mg/kg Q3W, 10 mg/kg Q2W or Q3W.
The licensed dose of KEYTRUDA in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The licensed dose of KEYTRUDA as monotherapy in paediatric patients aged 3 years and older with cHL is 2 mg/kg bodyweight (up to a maximum of 200 mg), every 3 weeks administered as an intravenous infusion over 30 minutes.
Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (8.2%) than in patients who did not receive prior thoracic radiation (4.2%). In patients with NSCLC, pneumonitis occurred in 160 (5.7%), including Grade 2, 3, 4 or 5 cases in 62 (2.2%), 47 (1.7%), 14 (0.5%) and 10 (0.4%), respectively. In patients with NSCLC, pneumonitis occurred in 8.9% with a history of prior thoracic radiation.
In patients with non-squamous NSCLC treated with KEYTRUDA in combination with pemetrexed and platinum chemotherapy (n=488), the incidence of nephritis was 1.4% (all Grades) with 0.8% Grade 3 and 0.4% Grade 4.
§ Rare cases of SJS and TEN, some of them fatal, have been observed.

Other immune-related adverse reactions occurred in patients treated with KEYTRUDA

The following additional clinically significant, immune‑related adverse reactions have been reported in clinical trials or in post-marketing experience. Immune-related adverse reactions affecting more than one body system can occur simultaneously.1

  • Uveitis
  • Arthritis
  • Myositis
  • Myocarditis
  • Pancreatitis
  • Guillain-Barré syndrome
  • Myasthenic syndrome
  • Haemolytic anaemia
  • Sarcoidosis
  • Encephalitis
  • Myelitis
  • Vasculitis
  • Cholangitis sclerosing
  • Gastritis

Monitoring immune-related adverse events

Patients should be monitored for the immune-related adverse events that can occur during treatment with KEYTRUDA.1 Patients should be made aware of the symptoms and signs of potential adverse reactions and that they can occur anytime after the last dose of KEYTRUDA.

Monitoring immune-related adverse events1

Immune-related adverse event Monitoring patients for:
Pneumonitis The signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other causes excluded
Colitis The signs and symptoms of colitis, and exclude other possible causes. The potential risk of gastrointestinal perforation should be taken into consideration.
Hepatitis Changes in liver function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and symptoms of hepatitis, and exclude other possible causes
Nephritis Changes in renal function and exclude other causes of renal dysfunction
Thyroid disorders Changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated by clinical evaluation) and clinical signs and symptoms of thyroid dysfunction. Thyroid function and hormone levels should also be monitored to ensure appropriate hormone replacement
Adrenal insufficiency Patients should be monitored for the signs and symptoms of adrenal insufficiency and exclude other causes.
Hypophysitis Signs and symptoms of hypophysitis (including hypopituitarism) and exclude other causes.
Type 1 diabetes (hyperglycaemia/diabetic ketoacidosis) Hyperglycaemia or other signs and symptoms of diabetes
Other Patients should be monitored for the signs and symptoms of other immune-related adverse events. Other causes should be excluded
Immune-related severe skin reactions Patients should be monitored for severe skin reactions and exclude other causes. Symptoms of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis should be referred to a specialised unit for assessment and KEYTRUDA treatment withheld

Adapted from KEYTRUDA, Summary of Product Characteristics.1

Please refer to the KEYTRUDA Summary of Product Characteristics and Risk Minimisation Materials before prescribing KEYTRUDA.

Monitoring and managing immune-related adverse events

Immune-related adverse events, including severe and fatal cases, have occurred in patients receiving KEYTRUDA.1

Most immune-related adverse events occurring during treatment with KEYTRUDA were reversible and managed with interruptions of KEYTRUDA, administration of corticosteroids and/or supportive care.1

Immune-related adverse events have also occurred after the last dose of KEYTRUDA. Immune-related adverse events affecting more than one body system can occur simultaneously.1

For suspected immune-related adverse events, ensure adequate evaluation to confirm aetiology or exclude other causes. Based on the severity of the adverse event, KEYTRUDA should be withheld and corticosteroids administered. Upon improvement to Grade ≤1, corticosteroid taper should be initiated and continued over at least one month. Based on limited data from clinical studies in patients whose immune-related adverse events could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered.1

KEYTRUDA may be restarted within 12 weeks after the last dose of KEYTRUDA if the adverse event recovers to Grade ≤1 and corticosteroid dose has been reduced to ≤10 mg prednisone or equivalent per day.1

KEYTRUDA must be permanently discontinued for any Grade 3 immune‑related adverse event that recurs and for any Grade 4 immune‑related adverse event toxicity, except for endocrinopathies that are controlled with replacement hormones.1 In addition KEYTRUDA should be discontinued for any grade 3 event of myocarditis, encephalitis or Guillain-Barré syndrome.1

For Grade 4 haematological toxicity, only in patients with cHL, KEYTRUDA should be withheld until adverse events recover to Grade 0-1.1

The safety of re-initiating KEYTRUDA therapy in patients previously experiencing immune-related myocarditis is not known.1

Please refer to the KEYTRUDA Summary of Product Characteristics and Risk Minimisation Materials before prescribing KEYTRUDA.

Immune-related pneumonitis

Pneumonitis has been reported in patients receiving KEYTRUDA. Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other causes excluded. Corticosteroids should be administered for Grade ≥2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper); KEYTRUDA should be withheld for Grade 2 pneumonitis, and permanently discontinued for Grade 3, Grade 4 or recurrent Grade 2 pneumonitis.1

Immune-related colitis

Colitis has been reported in patients receiving KEYTRUDA. Patients should be monitored for signs and symptoms of colitis, and other causes excluded. Corticosteroids should be administered for Grade ≥2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper); KEYTRUDA should be withheld for Grade 2 or Grade 3 colitis, and permanently discontinued for Grade 4 or recurrent Grade 3 colitis. The potential risk of gastrointestinal perforation should be taken into consideration.1

Immune-related hepatitis

Hepatitis has been reported in patients receiving KEYTRUDA. Patients should be monitored for changes in liver function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and symptoms of hepatitis, and other causes excluded. Corticosteroids should be administered (initial dose of 0.5-1 mg/kg/day (for Grade 2 events) and 1-2 mg/kg/day (for Grade ≥3 events) prednisone or equivalent followed by a taper). Based on severity of liver enzyme elevations, KEYTRUDA should be withheld or discontinued.1

Immune-related nephritis

Nephritis has been reported in patients receiving KEYTRUDA. Patients should be monitored for changes in renal function, and other causes of renal dysfunction excluded. Corticosteroids should be administered for Grade ≥2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper). Based on severity of creatinine elevations, KEYTRUDA should be withheld for Grade 2, and permanently discontinued for Grade 3 or Grade 4 nephritis.1

Immune-related endocrinopathies

Severe endocrinopathies, including adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, diabetic ketoacidosis, hypothyroidism, and hyperthyroidism have been observed with KEYTRUDA treatment.1

Long-term hormone replacement therapy may be necessary in cases of immune-related endocrinopathies.1

Adrenal insufficiency (primary and secondary) has been reported in patients receiving KEYTRUDA. Hypophysitis has also been reported in patients receiving KEYTRUDA. Patients should be monitored for signs and symptoms of adrenal insufficiency and hypophysitis (including hypopituitarism) and other causes excluded. Corticosteroids to treat adrenal insufficiency and other hormone replacement should be administered as clinically indicated. KEYTRUDA should be withheld for Grade 2 adrenal insufficiency or hypophysitis until the event is controlled with hormone replacement. KEYTRUDA should be withheld or discontinued for Grades 3 or 4 adrenal insufficiency or symptomatic hypophysitis. Continuation of KEYTRUDA may be considered, after corticosteroid taper, if needed. Pituitary function and hormone levels should be monitored to ensure appropriate hormone replacement.1

Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients receiving KEYTRUDA. Patients should be monitored for hyperglycaemia or other signs and symptoms of diabetes. Insulin should be administered for type 1 diabetes, and KEYTRUDA should be withheld in cases of type 1 diabetes associated with Grade ≥3 hyperglycaemia or ketoacidosis until metabolic control is achieved.1

Thyroid disorders, including hypothyroidism, hyperthyroidism and thyroiditis, have been reported in patients receiving KEYTRUDA and can occur at any time during treatment. Hypothyroidism is more frequently reported in patients with HNSCC with prior radiation therapy. Patients should be monitored for changes in thyroid function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and clinical signs and symptoms of thyroid disorders. Hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids. Hyperthyroidism may be managed symptomatically. KEYTRUDA should be withheld for Grade ≥3 until recovery to Grade ≤1 hyperthyroidism. Thyroid function and hormone levels should be monitored to ensure appropriate hormone replacement.1

For patients with Grade 3 or Grade 4 endocrinopathies that improved to Grade 2 or lower and are controlled with hormone replacement, if indicated, continuation of KEYTRUDA may be considered after corticosteroid taper, if needed. Otherwise treatment should be discontinued.1

Immune-related skin adverse reactions

Immune-related severe skin reactions have been reported in patients receiving KEYTRUDA. Patients should be monitored for suspected severe skin reactions and other causes should be excluded. Based on the severity of the adverse reaction, KEYTRUDA should be withheld for Grade 3 skin reactions until recovery to Grade ≤1 or permanently discontinued for Grade 4 skin reactions, and corticosteroids should be administered.1

Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving KEYTRUDA. For suspected SJS or TEN, KEYTRUDA should be withheld and the patient should be referred to a specialised unit for assessment and treatment. If SJS or TEN is confirmed, KEYTRUDA should be permanently discontinued.1

Caution should be used when considering the use of KEYTRUDA in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anticancer agents.1

Other immune-related adverse reactions

The following additional clinically significant, immune-related adverse reactions have been reported in clinical studies or in post-marketing experience: uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, haemolytic anaemia, sarcoidosis, encephalitis, myelitis, vasculitis, cholangitis sclerosing and gastritis.1

Based on the severity and type of the adverse reaction, KEYTRUDA should be withheld for Grade 2 or Grade 3 events and corticosteroids administered. KEYTRUDA may be restarted within 12 weeks after the last dose of KEYTRUDA if the adverse reaction recovers to Grade ≤1 and corticosteroid dose has been reduced to ≤10 mg prednisone or equivalent per day. KEYTRUDA must be permanently discontinued for any Grade 3 immune-related adverse reaction that recurs and for any Grade 4 immune-related adverse reaction. For Grades 3 or 4 myocarditis, encephalitis or Guillain-Barré syndrome, KEYTRUDA should be permanently discontinued.1

Transplant-related adverse reactions

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with KEYTRUDA versus the risk of possible organ rejection should be considered in these patients.1

When to withhold or discontinue KEYTRUDA1

Patients should be treated with KEYTRUDA 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, KEYTRUDA should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year.

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

Managing immune-related adverse events1

Immune-related adverse event Severity Treatment modification
Pneumonitis Grade 2 Withhold until adverse reactions recover to Grade 0-1*
Grade 3 or 4, or recurrent Grade 2 Permanently discontinue
Colitis Grade 2 or 3 Withhold until adverse reactions recover to Grade 0-1*
Grade 4 or recurrent Grade 3 Permanently discontinue
Nephritis Grade 2 nephritis with creatinine >1.5 to ≤3 times upper limit of normal (ULN) Withhold until adverse reactions recover to Grade 0-1*
Grade ≥3 nephritis with creatinine >3 times ULN Permanently discontinue
Endocrinopathies Grade 2 adrenal insufficiency and hypophysitis Withhold treatment until controlled by hormone replacement
Grades 3 or 4 adrenal insufficiency or symptomatic hypophysitis

Type 1 diabetes associated with Grade ≥3 hyperglycaemia (glucose >250 mg/dL or >13.9 mmol/L) or associated with ketoacidosis

Hyperthyroidism Grade ≥3
Withhold until adverse reactions recover to Grades 0-1*

For patients with Grade 3 or Grade 4 endocrinopathies that improved to Grade 2 or lower and are controlled with hormone replacement, if indicated, continuation of KEYTRUDA may be considered after corticosteroid taper, if needed. Otherwise treatment should be discontinued.
Hypothyroidism Hypothyroidism may be managed with replacement therapy without treatment interruption.
Hepatitis
NOTE: for RCC patients treated with KEYTRUDA in combination with axitinib with liver enzyme elevations, see dosing guidelines following this table.
Grade 2 with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 to 5 ULN or total bilirubin >1.5 to 3 times ULN Withhold until adverse reactions recover to Grade 0-1*
Grade ≥3 with AST or ALT >5 times ULN or total bilirubin >3 times ULN Permanently discontinue
Liver metastasis with baseline Grade 2 elevation of AST or ALT, hepatitis with AST or ALT increases ≥50% and lasts ≥1 week Permanently discontinue
Skin reactions Grade 3 or suspected SJS or TEN Withhold until adverse reactions recover to Grade 0-1*
Grade 4 or confirmed SJS or TEN Permanently discontinue
Other immune-related adverse reactions Based on severity and type of reaction
(Grade 2 or Grade 3)

Grade 3 or 4 myocarditis

Grade 3 or 4 encephalitis

Grade 3 or 4 Guillain-Barré syndrome

Grade 4 or recurrent Grade 3
Withhold until adverse reactions recover to Grade 0-1*


Permanently discontinue

Permanently discontinue

Permanently discontinue


Permanently discontinue
Infusion-related reactions Grade 3 or 4 Permanently discontinue

Adapted from KEYTRUDA, Summary of Product Characteristics.1

*If treatment-related toxicity does not resolve to Grade 0-1 within 12 weeks after last dose of KEYTRUDA, or if corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks, KEYTRUDA should be permanently discontinued. Toxicity Grades are in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4).

KEYTRUDA in combination with axitinib in RCC:

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

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

  • If ALT or AST ≥3 times ULN but <10 times ULN without concurrent total bilirubin ≥2 times ULN, both KEYTRUDA 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 SmPC may be considered
  • If ALT or AST ≥10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN, both KEYTRUDA and axitinib should be permanently discontinued and corticosteroid therapy may be considered
Risk Minimisation Materials

Risk minimisation materials are available for HCPs managing patients who are receiving KEYTRUDA. Risk Minimisation materials are available online, from your MSD representative or from MSD Medical Information. (Email: medicalinformationuk@msd.com, Phone: 0208 154 8000).


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Reference

  1. KEYTRUDA NI Summary of Product Characteristics.

Supporting documentation

Prescribing Information | Summary of Product Characteristics | Patient Information Leaflet

GB-PDO-01562 | Date of Preparation: July 2021