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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

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

Prescribing Information

The safety of KEYTRUDA (pembrolizumab) as monotherapy has been evaluated in 5,884 patients with advanced melanoma, resected Stage III melanoma (adjuvant therapy), NSCLC, cHL, urothelial carcinoma, or HNSCC across four doses (2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg 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 7.3 months (range: 1 day to 31 months) and the most frequent adverse reactions with KEYTRUDA were fatigue (32%), nausea (20%), and diarrhoea (20%). 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 1,067 patients with NSCLC or HNSCC receiving 200 mg, 2 mg/kg or 10 mg/kg 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 anaemia (50%), nausea (50%), fatigue (37%), constipation (35%), diarrhoea (30%), neutropaenia (30%), decreased appetite (28%) and vomiting (25%). Incidences of Grades 3-5 adverse reactions in patients with NSCLC were 67% for KEYTRUDA combination therapy and 66% for chemotherapy alone and in patients with HNSCC were 85% for KEYTRUDA combination therapy and 84% for chemotherapy plus cetuximab.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 as monotherapy 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 part of combination therapy is 200 mg every 3 weeks administered as an intravenous infusion over 30 minutes. KEYTRUDA should be administered first when given in combination with chemotherapy. 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 Thrombocytopaenia, lymphopaenia
Uncommon Neutropaenia, leukopaenia, eosinophilia
Rare Immune thrombocytopenic purpura, 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
Uncommon Adrenal insufficiency, hypophysitis, thyroiditis
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 Pericardial effusion, pericarditis
Rare Myocarditis
Vascular disorders
Common Hypertension
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
Rare Small intestinal perforation
Hepatobiliary disorders
Uncommon Hepatitis
Skin and subcutaneous tissue disorders
Very common Rash, pruritus
Common Severe skin reactions, erythema, dry skin, vitiligo, eczema, alopecia, dermatitis acneiform
Uncommon Lichenoid keratosis, psoriasis, dermatitis, 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
Renal and urinary disorders
Uncommon Nephritis
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 2mg/kg Q3W, 200 mg Q3W, or 10 mg/kg Q2W or Q3W, as well as post marketing usage. The licensed dose of KEYTRUDA as monotherapy is either 200 mg every 3 weeks or 400 mg every 6 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 and cytokine release syndrome); hypothyroidism (myxoedema); adrenal insufficiency (Addison’s disease, adrenocortical insufficiency acute, secondary adrenocortical insufficiency); hypophysitis (hypopituitarism); thyroiditis (autoimmune thyroiditis and thyroid disorder); type 1 diabetes mellitus (diabetic ketoacidosis); 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 (iritis and iridocyclitis); myocarditis (autoimmune myocarditis); pneumonitis (interstitial lung disease and organizing pneumonia); abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower); colitis (colitis microscopic, enterocolitis, enterocolitis haemorrhagic, and autoimmune colitis); pancreatitis (autoimmune pancreatitis and pancreatitis acute); 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 generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular and genital rash); pruritus (urticaria, urticaria papular, pruritus generalised and pruritus genital); severe skin reactions (dermatitis bullous, dermatitis exfoliative, dermatitis exfoliative generalised, erythema multiforme, exfoliative rash, pemphigus, skin necrosis, toxic skin eruption and Grade ≥ 3 of the following: acute febrile neutrophilic dermatosis, contusion, decubitus ulcer, dermatitis psoriasiform, drug eruption, jaundice, pemphigoid, pruritus, pruritus generalised, rash, rash erythematous, rash generalised, rash maculo-papular, rash pruritic, rash pustular and skin lesion); 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, polymyalgia rheumatica and rhabdomyolysis); arthritis (joint swelling, polyarthritis and joint effusion); tenosynovitis (tendonitis, synovitis and tendon pain); nephritis (nephritis autoimmune, tubulointerstitial nephritis and renal failure, renal failure acute, or acute kidney injury with evidence of nephritis, nephrotic syndrome 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
Common Pneumonia
Blood and lymphatic system disorders
Very common Anaemia, neutropenia, thrombocytopaenia
Common Febrile neutropaenia, leukopaenia, lymphopaenia
Rare Eosinophilia
Immune system disorders
Common Infusion-related reaction
Endocrine disorders
Common Hypothyroidism, hyperthyroidism
Uncommon Hypophysitis, thyroiditis, adrenal insufficiency
Metabolism and nutrition disorders
Very common Hypokalaemia, decreased appetite
Common Hyponatraemia, hypocalcaemia
Uncommon Type 1 diabetes mellitus
Psychiatric disorders
Common Insomnia
Nervous system disorders
Very common Dizziness, headache, neuropathy peripheral, dysgeusia
Common Lethargy
Uncommon Epilepsy
Eye disorders
Common Dry eye
Cardiac disorders
Common Cardiac arrythmia (including atrial fibrillation)a
Uncommon Pericardial effusion
Rare Myocarditis, pericarditis
Vascular disorders
Common Hypertension
Respiratory, thoracic and mediastinal disorders
Very common Dyspnoea, cough
Common Pneumonitis
Gastrointestinal disorders
Very common Diarrhoea, nausea, vomiting, constipation, abdominal pain
Common Colitis, dry mouth
Uncommon Pancreatitis, gastrointestinal ulceration
Hepatobiliary disorders
Uncommon Hepatitis
Skin and subcutaneous tissue disorders
Very common Rash, alopecia, pruritus
Common Severe skin reactions, erythema, dry skin
Uncommon Psoriasis, dermatitis acneiform, dermatitis, vitiligo, eczema
Rare Hair colour changes, lichenoid keratosis, papule
Musculoskeletal and connective tissue disorders
Very common Musculoskeletal pain, arthralgia
Common Myositis, pain in extremity, arthritis
Uncommon Tenosynovitis
Renal and urinary disorders
Common Nephritis, acute kidney injury
General disorders and administration site conditions
Very common Fatigue, asthenia, pyrexia, oedema
Common Chill, influenza-like illness
Investigations
Very common Blood creatinine increased
Common Hypercalcaemia, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased
Uncommon Blood bilirubin increase, 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 2mg/kg Q3W, 200 mg Q3W, or 10 mg/kg Q2W or Q3W, as well as post marketing usage.The licensed dose of KEYTRUDA as part of combination therapy is 200 mg every 3 weeks administered as an intravenous infusion over 30 minutes. KEYTRUDA should be administered first when given in combination with chemotherapy.
  • 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 and cytokine release syndrome); adrenal insufficiency (Addison’s disease, adrenocortical insufficiency acute, secondary adrenocortical insufficiency); hypophysitis (hypopituitarism); thyroiditis (autoimmune thyroiditis and thyroid disorder); type 1 diabetes mellitus (diabetic ketoacidosis); myocarditis (autoimmune myocarditis); pneumonitis (interstitial lung disease and organizing pneumonia); abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower); colitis (colitis microscopic, enterocolitis, enterocolitis haemorrhagic, and autoimmune colitis); pancreatitis (autoimmune pancreatitis and pancreatitis acute); 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 generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular and genital rash); pruritus (urticaria, urticaria papular, pruritus generalised and pruritus genital); severe skin reactions (dermatitis bullous, dermatitis exfoliative, dermatitis exfoliative generalised, erythema multiforme, exfoliative rash, pemphigus, skin necrosis, toxic skin eruption and Grade ≥ 3 of the following: acute febrile neutrophilic dermatosis, contusion, decubitus ulcer, dermatitis psoriasiform, drug eruption, jaundice, pemphigoid, pruritus, pruritus generalised, rash, rash erythematous, rash generalised, rash maculo-papular, rash pruritic, rash pustular and skin lesion); vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid); musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain and torticollis); myositis (myalgia, myopathy, polymyalgia rheumatica and rhabdomyolysis); arthritis (joint swelling, polyarthritis and joint effusion); tenosynovitis (tendonitis, synovitis and tendon pain); nephritis (nephritis autoimmune, tubulointerstitial nephritis and renal failure, renal failure acute, or acute kidney injury with evidence of nephritis, nephrotic syndrome 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 tachyarrhytmias

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

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

Incidence Event
Infections and infestations
Common Pneumonia
Blood and lymphatic system disorders
Common Anaemia, neutropaenia, leukopaenia, thrombocytopaenia
Uncommon Lymphopaenia, eosinophilia
Immune system disorders
Common Infusion-related reaction
Endocrine disorders
Very common Hyperthyroidism, hypothyroidism
Common Hypophysitis, thyroiditis, adrenal insufficiency
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
Eye disorders
Common Dry eye
Uncommon Uveitis
Cardiac disorders
Common Cardiac arrythmia (including atrial fibrillation)a
Uncommon Myocarditis
Vascular disorders
Very common Hypertension
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
Uncommon Pancreatitis, gastrointestinal ulceration
Hepatobiliary disorders
Common Hepatitis
Skin and subcutaneous tissue disorders
Very common Palmar-Plantar erythrodysaesthesia syndrome, rash, pruritus,
Common Severe skin reactions, dermatitis acneiform, dermatitis, dry skin, alopecia, eczema, erythema
Uncommon Hair colour changes, lichenoid keratosis, papule, psoriasis, vitiligo
Musculoskeletal and connective tissue disorders
Very common Musculoskeletal pain, arthralgia, pain in extremity
Common Myositis, arthritis, tenosynovitis
Renal and urinary disorders
Common Acute kidney injury, nephritis
General disorders and administration site conditions
Very common Fatigue, asthenia, pyrexia
Common Oedema, influenza-like illness, chills
Investigations
Very common Alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased
Common Blood alkaline phosphatase increased, hypercalcaemia, 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 2mg/kg Q3W, 200 mg Q3W, or 10 mg/kg Q2W or Q3W, as well as post marketing usage. The licensed dose of KEYTRUDA as part of combination therapy is 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 and cytokine release syndrome); hypothyroidism (myxoedema); adrenal insufficiency (Addison’s disease, adrenocortical insufficiency acute, secondary adrenocortical insufficiency); hypophysitis (hypopituitarism); thyroiditis (autoimmune thyroiditis and thyroid disorder); type 1 diabetes mellitus (diabetic ketoacidosis); myasthenic syndrome (myasthenia gravis, including exacerbation); uveitis (iritis and iridocyclitis); myocarditis (autoimmune myocarditis); pneumonitis (interstitial lung disease and organizing pneumonia); abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower); colitis (colitis microscopic, enterocolitis, enterocolitis haemorrhagic, and autoimmune colitis); pancreatitis (autoimmune pancreatitis and pancreatitis acute); 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 generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular and genital rash); pruritus (urticaria, urticaria papular, pruritus generalised and pruritus genital); severe skin reactions (dermatitis bullous, dermatitis exfoliative, dermatitis exfoliative generalised, erythema multiforme, exfoliative rash, pemphigus, skin necrosis, toxic skin eruption and Grade ≥ 3 of the following: acute febrile neutrophilic dermatosis, contusion, decubitus ulcer, dermatitis psoriasiform, drug eruption, jaundice, pemphigoid, pruritus, pruritus generalised, rash, rash erythematous, rash generalised, rash maculo-papular, rash pruritic, rash pustular and skin lesion); vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid); musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain and torticollis); myositis (myalgia, myopathy, polymyalgia rheumatica and rhabdomyolysis); arthritis (joint swelling, polyarthritis and joint effusion); tenosynovitis (tendonitis, synovitis and tendon pain); nephritis (nephritis autoimmune, tubulointerstitial nephritis and renal failure, renal failure acute, or acute kidney injury with evidence of nephritis, nephrotic syndrome 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 tachyarrhytmias
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.

For patients with relapsed or refractory cHL, clinical data for the use of KEYTRUDA in patients ineligible to ASCT due to reasons other than failure to salvage chemotherapy are limited. 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:

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 is being assessed in a comparative study, and 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 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

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 from KEYTRUDA monotherapy in patients with resected Stage III melanoma, from KEYTRUDA in combination with axitinib in patients with advanced RCC, from chemotherapy combination in patients with metastatic NSCLC, and from KEYTRUDA (with or without chemotherapy) in patients receiving first-line treatment for metastatic or unresectable recurrent HNSCC ≥ 75 years are limited.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.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 and efficacy of KEYTRUDA in children below 18 years of age have not yet been established.

The safety of KEYTRUDA as monotherapy has been evaluated in 154 paediatric patients 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 safety profile in these 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 (31%), vomiting (26%), headache (22%), abdominal pain (21%), anaemia (21%) and constipation (20%). The majority of adverse reactions reported for monotherapy were of Grades 1 or 2 severity. 69 (44.8%) patients had 1 or more Grades 3 to 5 adverse reactions of which 6 (3.9%) 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 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: 10.9% for lymphocytes decreased, 8.2% for sodium decreased, 6.3% for haemoglobin decreased, 5.2% for phosphate decreased, 4.8% for glucose increased, 2.8% for AST increased, 2.7% for alkaline phosphatase increased, 2.7% for ALT increased, 2.2% for potassium decreased, 1.8% for calcium increased, 1.8% for neutrophils decreased, 1.8% for potassium increased, 1.7% for bilirubin increased, 1.7% for platelets decreased, 1.6% for albumin decreased, 1.5% for calcium decreased,1.3% for creatinine increased, 0.8% 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: 26.7% for neutrophils decreased, 23.9% for lymphocytes decreased, 19.1% for haemoglobin decreased, 17.9% for leukocytes decreased, 12.2% for platelets decreased, 10.2% for sodium decreased, 8.9% for phosphate decreased, 7.4% for glucose increased, 6.5% for potassium decreased, 3.3% for creatinine increased, 3.1% for ALT increased, 3.1% for AST increased, 3.1% for calcium decreased, 3.0% for potassium increased, 2.9% for albumin decreased, 2.3% for calcium increased, 1.2% for alkaline phosphatase increased, 0.8% for glucose decreased, 0.7% for bilirubin increased, and 0.3% for sodium increased.

In patients treated with KEYTRUDA in combination with axitinib, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 20.1% for ALT increased, 13.2% for AST increased, 10.8% for lymphocytes decreased, 8.9% for glucose increased, 7.8% for sodium decreased, 6.4% for phosphate decreased, 6.2% for potassium increased, 4.3% for creatinine increased, 3.6% for potassium decreased, 2.1% for bilirubin increased, 2.1% for haemoglobin decreased, 1.7% for alkaline phosphatase increased, 1.5% for prothrombin INR increased, 1.4% for leukocytes decreased, 1.4% for platelets decreased, 1.2% for activated partial thromboplastin time prolonged, 1.2% for neutrophils decreased, 1.2% for sodium increased, 0.7% for calcium decreased, 0.7% for calcium increased, 0.5% for albumin decreased, and 0.2% for glucose decreased.

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 for patients with NSCLC, urothelial carcinoma or HNSCC:

For treatment with KEYTRUDA as monotherapy, testing for PD-L1 tumour expression using a validated test is recommended to select patients with NSCLC or previously untreated urothelial carcinoma. Patients with HNSCC should be selected for treatment with KEYTRUDA as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy based on the tumour expression of PD-L1 confirmed by a validated test.1

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.

Selected immune-related adverse events reported in KEYTRUDA clinical trials (n=5,884)*1

  Any grade, (n, %) Grade 2, (n, %) Grade 3, (n, %) Grade 4, (n, %) Grade 5, (n, %)
Adrenal insufficiency 46 (0.8) 19 (0.3) 20 (0.3) 3 (0.1) 0.0
Hypothyroidism 645 (11.0) 475 (8.1) 8 (0.1) 0.0 0.0
Hyperthyroidism 244 (4.1) 64 (1.1) 7 (0.1) 0.0 0.0
Pneumonitis 253 (4.3) 106 (1.8) 69 (1.2) 13 (0.2) 9 (0.2)
Colitis 107 (1.8) 31 (0.5) 62 (1.1) 3 (<0.1) 0.0
Hypophysitis 36 (0.6) 13 (0.2) 19 (0.3) 1 (<0.1) 0.0
Hepatitis 50 (0.8) 8 (0.1) 31 (0.5) 8 (0.1) 0.0
Nephritis (monotherapy) 22 (0.4) 5 (0.1) 14 (0.2) 1 (<0.1) 0.0
Immune-related severe skin reactions§ 89 (1.5) 10 (0.2) 65 (1.1) 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 as monotherapy is either 200 mg every 3 weeks or 400 mg every 6 weeks administered intravenously over 30 minutes. The licensed dose of KEYTRUDA as part of combination therapy is 200 mg every 3 weeks administered intravenously over 30 minutes.
Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (8.1%) than those who did not receive it (3.4%). 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
  • Encephalitis
  • Sarcoidosis
  • Myelitis

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
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

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 symptomatic hypophysitis until the event is controlled with hormone replacement. KEYTRUDA should be withheld or discontinued for Grades 3 or 4 adrenal insufficiency or 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, and myelitis.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: 01992 467 272).


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Reference

  1. KEYTRUDA Summary of Product Characteristics.

Supporting documentation

Prescribing Information | Summary of Product Characteristics | Patient Information Leaflet

GB-PDO-00999 | Date of Preparation: September 2020