Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
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.
Immune-mediated adverse reactions, including severe and fatal cases, have occurred in patients receiving pembrolizumab. Most immune-mediated adverse reactions occurring during treatment with pembrolizumab were reversible and managed with interruptions of pembrolizumab, ad ministration of corticosteroids and/or supportive care. Immune-mediated adverse reactions have also occurred after the last dose of pembrolizumab. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously.
For suspected immune-mediated adverse reactions, adequate evaluation to confirm aetiology or exclude other causes should be ensured. Based on the severity of the adverse reaction, pembrolizumab should be withheld and corticosteroids administered. Upon improvement to Grade ≤1, corticosteroid taper should be initiated and continued over at least 1 month. Based on limited data from clinical studies in patients whose immune-mediated adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered.
Pembrolizumab may be restarted within 12 weeks after 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.
Pembrolizumab must be permanently discontinued for any Grade 3 immune-mediated adverse reaction that recurs and for any Grade 4 immune-mediated adverse reacti on toxicity, except for endocrinopathies that are controlled with replacement hormones (see sections 4.2 and 4.8).
Pneumonitis has been reported in patients receiving pembrolizumab (see section 4.8). 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); pembrolizumab should be withheld for Grade 2 pneumonitis, and permanently discontinued for Grade 3, Grade 4 or recurrent Grade 2 pneumonitis (see section 4.2).
Colitis has been reported in patients receiving pembrolizumab (see section 4.8). 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); pembrolizumab should be withheld for Grade 2 or Grade 3 colitis, and permanently discontinued for Grade 4 or recurrent Grade 3 colitis (see section 4.2). The potential risk of gastrointestinal perforation should be taken into consideration.
Hepatitis has been reported in patients receiving pembrolizumab (see section 4.8). 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) and, based on severity of liver enzyme elevations, pembrolizumab should be withheld or discontinued (see section 4.2).
Nephritis has been reported in patients receiving pembrolizumab (see section 4.8). 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) and, based on severity of creatinine elevations, pembrolizumab should be withheld for Grade 2, and permanently discontinued for Grade 3 or Grade 4 nephritis (see section 4.2).
Severe endocrinopathies, including adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, diabetic ketoacidosis, hypothyroidism, and hyperthyroidism have been observed with pembrolizumab treatment.
Long-term hormone replacement therapy may be necessary in cases of immune-mediated endocrinopathies.
Adrenal insufficiency (primary and secondary) has been reported in patients receiving pembrolizumab. Hypophysitis has also been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for signs and symptoms of adrenal i nsufficiency and hypophysitis (including hypopituitarism) and other causes excluded. Corticosteroids to treat adrenal insufficiency and other hormone replacement should be administered as clinically indicated. Pembrolizumab should be withheld for Grade 2 adrenal insufficiency or hypophysitis until the event is controlled with hormone replacement. Pembrolizumab should be withheld or discontinued for Grades 3 or 4 adrenal insufficiency or symptomatic hypophysitis. Continuation of pembrolizumab may be consider ed, after corticosteroid taper, if needed (see section 4.2). Pituitary function and hormone levels should be monitored to ensure appropriate hormone replacement.
Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients rece iving pembrolizumab (see section 4.8). Patients should be monitored for hyperglycaemia or other signs and symptoms of diabetes. Insulin should be administered for type 1 diabetes, and pembrolizumab should be withheld in cases of type 1 diabetes associated with Grade ≥3 hyperglycaemia or ketoacidosis until metabolic control is achieved (see section 4.2).
Thyroid disorders, including hypothyroidism, hyperthyroidism and thyroiditis, have been reported in patients receiving pembrolizumab 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 re placement therapy without treatment interruption and without corticosteroids. Hyperthyroidism may be managed symptomatically. Pembrolizumab 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.
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 pembrolizumab may be considered after corticosteroid taper, if needed. Otherwise treatment should be discontinued (see sections 4.2 and 4.8).
Immune-mediated severe skin reactions have been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for suspected severe skin reactions and other causes should be excluded. Based on the severity of the adverse reaction, pembrolizumab 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 (see section 4.2).
Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving pembrolizumab (see section 4.8). For suspected SJS or TEN, pembrolizumab should be withheld and the patient should be referred to a specialised unit for assessment and treatment. If SJS or TEN is confirmed, pembrolizumab should be permanently discontinued (see section 4.2).
Caution should be used when considering the use of pembrolizumab in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anti-cancer agents.
The following additional clinically significant, immune -mediated 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, gastritis, cystitis noninfective and hypoparathyroidism (see sections 4.2 and 4.8).
Based on the severity and type of the adverse reaction, pembrolizumab should be withheld for Grade 2 or Grade 3 events and corticosteroids administered.
Pembrolizumab may be restarted within 12 weeks after 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.
Pembrolizumab must be permanently discontinued for any Grade 3 immune-mediated adverse reaction that recurs and for any Grade 4 immune-mediated adverse reaction.
For Grades 3 or 4 myocarditis, encephalitis or Guillain-Barré syndrome, pembrolizumab should be permanently discontinued (see sections 4.2 and 4.8).
Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with pembrolizumab may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with pembrolizumab versus the risk of possible organ rejection should be considered in these patients.
Allogeneic HSCT after treatment with pembrolizumab:
Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been observed in patients with cHL undergoing allogeneic HSCT after previous exposure to pembrolizumab. 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 (see section 4.8).
Allogeneic HSCT prior to treatment with pembrolizumab:
In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with pembrolizumab. Patients who experienced GVHD after their transplant procedure may be at an increased risk for GVHD after treatment with pembrolizumab. Consider the benefit of treatment with pembrolizumab versus the risk of possible GVHD in patients with a history of allogeneic HSCT.
Severe infusion-related reactions, including hypersensitivity and anaphylaxis, have been reported in patients receiving pembrolizumab (see section 4.8). For Grades 3 or 4 infusion reactions, infusion should be stopped and pembrolizumab permanently discontinued (see section 4.2). Patients with Grades 1 or 2 infusion reaction may continue to receive pembrolizumab with close monitoring; premedication with antipyretic and antihistamine may be considered.
Pembrolizumab in combination with chemotherapy should be used with caution in patients ≥75 years after careful consideration of the potential benefit/risk on an individual basis (see section 5.1).
Physicians should consider the delayed onset of pembrolizumab effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In urothelial carcinoma, a higher number of deaths within 2 months was observed in pembrolizumab compared to chemotherapy (see section 5.1). Factors associated with early deaths were fast progressive disease on prior platinum therapy and liver metastases.
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 pembrolizumab monotherapy compared to chemotherapy (see section 5.1). No specific factor(s) associated with early deaths could be identified. Physicians should consider the delayed onset of pembrolizumab effect before initiating treatment in patients with urothelial carcinoma 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 avai lable in frailer patients (e.g. ECOG performance status 3) considered not eligible for chemotherapy. In the absence of these data, pembrolizumab should be used with caution in this population after careful consideration of the potential risk-benefit on an individual basis.
In general, the frequency of adverse reactions for pembrolizumab combination therapy is observed to be higher than for pembrolizumab monotherapy or chemotherapy alone, reflecting the contributions of each of these components (see sections 4.2 and 4.8). A direct comparison of pembrolizumab when used in combination with chemotherapy to pembrolizumab monotherapy is not available.
Physicians should consider the benefit/risk balance of the available treatment options (pembrolizumab monotherapy or pembrolizumab in combination with chemotherapy) before initiating treatment in previously untreated patients with NSCLC whose tumours express PD-L1.
In KEYNOTE-042, a higher number of deaths within 4 months of treatment initiation followed by a long-term survival benefit was observed with pembrolizumab monotherapy compared to chemotherapy (see section 5.1).
In general, the frequency of adverse reactions for pembrolizumab combination therapy is observed to be higher than for pembrolizumab monotherapy or chemotherapy alone, reflecting the contributions of each of these components (see section 4.8).
Physicians should consider the benefit/risk balance of the available treatment options (pembrolizumab monotherapy or pembrolizumab in combination with chemotherapy) before initiating treatment in patients with HNSCC whose tumours express PD-L1 (see section 5.1).
A direct comparison of pembrolizumab when used in combination with lenvatinib to pembrolizumab monotherapy is not available. Physicians should consider the benefit/risk balance of the available treatment options (pembrolizumab monotherapy or pembrolizumab in combination with lenvatinib) before initiating treatment in patients with advanced or recurrent MSI-H or dMMR endometrial carcinoma.
A trend toward increased frequency of severe and serious adverse reactions in patients ≥75 years was observed. Safety data of pembrolizumab in the adjuvant melanoma setting in patients ≥75 years are limited.
When pembrolizumab is given with axitinib, higher than expected frequencies of Grades 3 and 4 ALT and AST elevations have been reported in patients with advanced RCC (see section 4.8). 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 (see section 4.2 and refer to the SmPC for axitinib).
In KEYNOTE-177, the hazard rates for overall survival events were greater for pembrolizumab compared with chemotherapy for the first 4 months of treatment, followed by a long-term survival benefit for pembrolizumab (see section 5.1).
Cholangitis and biliary tract infections are not uncommon in patients with BTC. Cholangitis events were reported in KEYNOTE-966 in both treatment groups (11.2% [n=59] of participants in the pembrolizumab plus chemotherapy arm and 10.3% [n=55] of participants in the placebo plus chemotherapy arm). Patients with biliary stents and drains (n=74) were at increased risk of cholangitis and biliary tract infections in KEYNOTE-966 (39.4% [n=13] of participants in the pembrolizumab plus chemotherapy arm vs. 29.3% [n=12] of participants in the placebo plus chemotherapy arm). Patients with BTC (especially those with biliary stents) should be closely monitored for development of cholangitis or biliary tract infections before initiation of treatment and, regularly, thereafter.
Patients with the following conditions were excluded from clinical studies: active CNS metastases; ECOG PS ≥2 (except for urothelial carcinoma and RCC); HIV infection, hepatitis B or hepatitis C infection (except for BTC); active systemic autoimmune disease; interstitial lung disease; prior pneumonitis requiring systemic corticosteroid therapy; a history of severe hypersensitivity to another monoclonal antibody; receiving immunosuppressive therapy and a history of severe immune-mediated adverse reactions 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 ac tive infections were excluded from clinical studies and were required to have their infection treated prior to receiving pembrolizumab. Patients with active infections occurring during treatment with pembrolizumab 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 excluded from clinical studies, therefore information is lim ited 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 (see section 5.1).
After careful consideration of the potential increased risk, pembrolizumab may be used with appropriate medical management in these patients.
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 card with each prescription.
No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. Since pembrolizumab is cleared from the circulation through catabolism, no metabolic drug-drug interactions are expected.
The use of systemic corticosteroids or im munosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. However, systemic corticosteroids or other immunosuppressants can be used after starting pembrolizumab to treat immune -mediated adverse reactions (see section 4.4). Corticosteroids can also be used as premedication, when pembrolizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions.
Women of childbearing potential should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of pembrolizumab.
There are no data on the use of pembrolizumab in pregnant women. Animal reproduction studies have not been conducted with pembrolizumab; however, in murine models of pregnancy blockade of PD-L1 signalling has been shown to disrupt tolerance to the foetus and to result in an increased foetal loss (see section 5.3). These results indicate a potential risk, based on its mechanism of action, that administration of pembrolizumab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth. Human immunoglobulins G4 (IgG4) are known to cross the placental barrier; therefore, being an IgG4, pembrolizumab has the potential to be transmitted from the mother to the developing foetus. Pembrolizumab should not be used during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab.
It is unknown whether pembrolizumab is secreted in human milk. Since it is known that antibodies can be secreted in human milk, a risk to the newborns/infants cannot be excluded. A decision should be made whether to discontinue breast-feeding or to discontinue pembrolizum ab, taking into account the benefit of breast-feeding for the child and the benefit of pembrolizumab therapy for the woman.
No clinical data are available on the possible effects of pembrolizumab on fertility. There were no notable effects in the male and female reproductive organs in monkeys based on 1-month and 6-month repeat-dose toxicity studies (see section 5.3).
Pembrolizumab has a minor influence on the ability to drive and us e machines. In some patients, dizziness and fatigue have been reported following administration of pembrolizumab (see section 4.8).
Pembrolizumab is most commonly associated with immune -mediated adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of pembrolizumab (see “Description of selected adverse reactions” below). The frequencies included below and i n Table 2 are based on all reported adverse drug reactions, regardless of the investigator assessment of causality.
The safety of pembrolizumab as monotherapy has been evaluated in 7 631 patients across tumour types and across four doses (2 mg/kg bw every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg bw every 2 or 3 weeks) in clinical studies. In this patient population, the median observation time was 8.5 months (range: 1 day to 39 months) and the most frequent adverse reactions with pembrolizumab were fatigue (31%), diarrhoea (22%), and nausea (20%). The majority of adverse reactions reported for monotherapy were of Grades 1 or 2 severity. The most serious adverse reactions were immune-mediated adverse reactions and severe infusion-related reactions (see section 4.4). The incidences of immune-mediated adverse reactions were 37% all Grades and 9% for Grades 3-5 for pembrolizumab monotherapy in the adjuvant setting and 25% all Grades and 6% for Grades 3-5 in the metastatic setting. No new immune-mediated adverse reactions were identified in the adjuvant setting.
When pembrolizumab is administered in combination, refer to the SmPC for the resp ective combination therapy components prior to initiation of treatment.
The safety of pembrolizumab in combination with chemotherapy has been evaluate d in 5 183 patients across tumour types receiving 200 mg, 2 mg/kg bw or 10 mg/kg bw pembrolizumab every 3 weeks, in clinical studies. In this patient population, the most frequent adverse reactions were anaemia (52%), nausea (52%), fatigue (35%), diarrhoea (33%), constipation (32%), vomiting (28%), decreased appetite (28%), neutrophil count decreased (27%) and neutropenia (25%). Incidences of Grades 3-5 adverse reactions in patients with NSCLC were 6 9% for pembrolizumab combination therapy and 61% for chemotherapy alone, in patients with HNSCC were 85% for pembrolizumab combination therapy and 84% for chemotherapy plus cetuximab, in patients with oesophageal carcinoma were 86% for pembrolizumab combination therapy and 83% for chemotherapy alone, in patients with TNBC were 80% for pembrolizumab combination therapy and 77% for chemotherapy al one, in patients with cervical cancer were 82% for pembrolizumab combination and 75% for chemotherapy, with or without bevacizumab, in patients with gastric cancer were 74% for pembrolizumab combination therapy (chemotherapy with or without trastuzumab) and 68 % for chemotherapy with or without trastuzumab, and in patients with biliary tract carcinoma were 85% for pembrolizumab combination therapy and 84% for chemotherapy alone.
When pembrolizumab is administered in combination with axitinib or lenvatinib, refer to the SmPC for axitinib or lenvatinib prior to initiation of treatment. For addi tional lenvatinib safety information related to advanced RCC see the SmPC for Kisplyx and for advanced EC see the SmPC for Lenvima. For additional axitinib safety information for elevated liver enzymes see also section 4.4.
The safety of pembrolizumab in combination with axitinib or lenvatinib in advanced RCC, and in combination with lenvatinib in advanced EC has been evaluated in a total of 1 456 patients with advanced RCC or advanced EC receiving 200 mg pembrolizumab every 3 weeks with either axitinib 5 mg twice daily or lenvatinib 20 mg once daily in clinical studies, as appropriate. In these patient populations, the most frequent adverse reactions were diarrhoea (58%), hypertension (54%), hypothyroidism (46%), fatigue (41%), decreased appetite (40%), nausea (40%), arthralgia (30%), vomiting (28%), weight decreased (28%), dysphonia (28%), abdominal pain (28%), proteinuria (27%), palmar-plantar erythrodysaesthesia syndrome (26%), rash (26%), stomatitis (25%), constipation (25%), musculoskeletal pain (23%), headache (23%) and cough (21%). Grades 3-5 adverse reactions in patients with RCC were 80% for pembrolizumab in combination with either axitinib or lenvatinib and 71% for sunitinib alone. In patients with EC, Grades 3-5 adverse reactions were 89% for pemb rolizumab in combination with lenvatinib and 73% for chemotherapy alone.
Adverse reactions observed in clinical studies of pembrolizumab as monotherapy or in combination with chemotherapy or other anti-tumour medici nes or reported from post-marketing use of pembrolizumab are listed in Table 2. These reactions are presented by system organ class and by frequency. 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); very rare (<1/10 000); and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Adverse reactions known to occur with pembrolizumab or combination therapy components given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical studies with combination therapy.
For additional safety information when pembrolizumab is administered in combination, refer to the SmPC for the respective combination therapy components.
Table 2. Adverse reactions in patients treated with pembrolizumab†:
| Monotherapy | In combination with chemotherapy | In combination with axitinib or lenvatinib | |
|---|---|---|---|
| Infections and infestations | |||
| Very common | urinary tract infection | ||
| Common | pneumonia | pneumonia | pneumonia |
| Blood and lymphatic system disorders | |||
| Very common | anaemia | anaemia, neutropenia, thrombocytopenia | anaemia |
| Common | thrombocytopenia, neutropenia, lymphopenia | febrile neutropenia, leukopenia, lymphopenia | neutropenia, thrombocytopenia, lymphopenia, leukopenia |
| Uncommon | leukopenia, immune thrombocytopenia, eosinophilia | eosinophilia | eosinophilia |
| Rare | haemophagocytic lymphohistiocytosis, haemolytic anaemia, pure red cell aplasia | haemolytic anaemia, immune thrombocytopenia | |
| Immune system disorders | |||
| Common | infusion-related reaction* | infusion-related reaction* | infusion-related reaction* |
| Uncommon | sarcoidosis* | ||
| Rare | sarcoidosis | ||
| Not known | solid organ transplant rejection | ||
| Endocrine disorders | |||
| Very common | hypothyroidism* | hypothyroidism* | hypothyroidism |
| Common | hyperthyroidism | adrenal insufficiency*, thyroiditis*, hyperthyroidism* | adrenal insufficiency*, hyperthyroidism, thyroiditis* |
| Uncommon | adrenal insufficiency*, hypophysitis*, thyroiditis* | hypophysitis* | hypophysitis* |
| Rare | hypoparathyroidism | hypoparathyroidism | hypoparathyroidism |
| Metabolism and nutrition disorders | |||
| Very common | decreased appetite | hypokalaemia, decreased appetite | decreased appetite |
| Common | hyponatraemia, hypokalaemia, hypocalcaemia | hyponatraemia, hypocalcaemia | hyponatraemia, hypokalaemia, hypocalcaemia |
| Uncommon | type 1 diabetes mellitus* | type 1 diabetes mellitus* | type 1 diabetes mellitus* |
| Psychiatric disorders | |||
| Very common | insomnia | ||
| Common | insomnia | insomnia | |
| Nervous system disorders | |||
| Very common | headache | neuropathy peripheral, headache | headache, dysgeusia |
| Common | dizziness, neuropathy peripheral, lethargy, dysgeusia | dizziness, dysgeusia, lethargy | dizziness, neuropathy peripheral, lethargy |
| Uncommon | myasthenic syndrome*, epilepsy | encephalitis*, epilepsy | myasthenic syndrome*, encephalitis* |
| Rare | Guillain-Barré syndrome*, encephalitis*, myelitis*, optic neuritis, meningitis (aseptic)* | myasthenic syndrome, Guillain-Barré syndrome*, optic neuritis | optic neuritis |
| Eye disorders | |||
| Common | dry eye | dry eye | dry eye |
| Uncommon | uveitis* | uveitis* | |
| Rare | Vogt-Koyanagi-Harada syndrome | uveitis* | Vogt-Koyanagi-Harada syndrome |
| Cardiac disorders | |||
| Common | cardiac arrhythmia‡ (including atrial fibrillation) | cardiac arrhythmia‡ (including atrial fibrillation) | cardiac arrhythmia‡ (including atrial fibrillation) |
| Uncommon | myocarditis, pericardial effusion, pericarditis | myocarditis*, pericardial effusion, pericarditis | myocarditis, pericardial effusion |
| Vascular disorders | |||
| Very common | hypertension | ||
| Common | hypertension | hypertension | |
| Uncommon | vasculitis* | vasculitis* | |
| Rare | vasculitis* | ||
| Respiratory, thoracic and mediastinal disorders | |||
| Very common | dyspnoea, cough | dyspnoea, cough | dyspnoea, cough |
| Common | pneumonitis* | pneumonitis* | pneumonitis* |
| Gastrointestinal disorders | |||
| Very common | diarrhoea, abdominal pain*, nausea, vomiting, constipation | diarrhoea, vomiting, nausea, abdominal pain*, constipation | diarrhoea, abdominal pain*, nausea, vomiting, constipation |
| Common | colitis*, dry mouth | colitis*, gastritis*, dry mouth | colitis*, pancreatitis*, gastritis*, dry mouth |
| Uncommon | pancreatitis*, gastritis*, gastrointestinal ulceration* | pancreatitis*, gastrointestinal ulceration* | gastrointestinal ulceration* |
| Rare | pancreatic exocrine insufficiency, small intestinal perforation, coeliac disease | pancreatic exocrine insufficiency, small intestinal perforation, coeliac disease | small intestinal perforation |
| Not known | pancreatic exocrine insufficiency, coeliac disease | ||
| Hepatobiliary disorders | |||
| Common | hepatitis* | hepatitis* | hepatitis* |
| Rare | cholangitis sclerosing | cholangitis sclerosing* | |
| Skin and subcutaneous tissue disorders | |||
| Very common | pruritus*, rash* | alopecia, pruritus*, rash* | rash*, pruritus* |
| Common | severe skin reactions*, erythema, dermatitis, dry skin, vitiligo*, eczema, alopecia, dermatitis acneiform | severe skin reactions*, erythema, dermatitis, dry skin, dermatitis acneiform, eczema | severe skin reactions*, dermatitis, dry skin, erythema, dermatitis acneiform, alopecia |
| Uncommon | psoriasis, lichenoid keratosis*, papule, hair colour changes | psoriasis, vitiligo*, papule | eczema, lichenoid keratosis*, psoriasis, vitiligo*, papule, hair colour changes |
| Rare | Stevens-Johnson syndrome, erythema nodosum, toxic epidermal necrolysis | Stevens-Johnson syndrome, lichenoid keratosis*, erythema nodosum, hair colour changes | toxic epidermal necrolysis, Stevens-Johnson syndrome |
| Musculoskeletal and connective tissue disorders | |||
| Very common | musculoskeletal pain*, arthralgia | musculoskeletal pain*, arthralgia | arthralgia, musculoskeletal pain*, myositis*, pain in extremity |
| Common | myositis*, pain in extremity, arthritis* | myositis*, pain in extremity, arthritis* | arthritis* |
| Uncommon | tenosynovitis* | tenosynovitis* | tenosynovitis* |
| Rare | Sjogren’s syndrome | Sjogren’s syndrome | Sjogren’s syndrome |
| Renal and urinary disorders | |||
| Common | acute kidney | injury nephritis* | |
| Uncommon | nephritis* | nephritis*, cystitis noninfective | |
| Rare | cystitis noninfective | cystitis noninfective | |
| General disorders and administration site conditions | |||
| Very common | fatigue, asthenia, oedema*, pyrexia | fatigue, asthenia, pyrexia | fatigue, asthenia, oedema*, pyrexia |
| Common | influenza-like illness, chills | oedema*, influenza-like illness, chills | influenza-like illness, chills |
| Investigations | |||
| Very common | alanine aminotransferase increased, aspartate aminotransferase increased | lipase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased | |
| Common | alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, hypercalcaemia, blood bilirubin increased, blood creatinine increased | vblood bilirubin increased, blood alkaline phosphatase increased, blood creatinine increased, hypercalcaemia | amylase increased, blood bilirubin increased, blood alkaline phosphatase increased, hypercalcaemia |
| Uncommon | amylase increased | amylase increased | |
† Adverse reaction frequencies presented in Table 2 may not be fully attributable to pembrolizumab alone but may contain contributions from the underlying disease or from other medicinal products used in a combination.
‡ Based upon a standard query including bradyarrhythmias and tachyarrhythmias.
* The following terms represent a group of related events that describe a medical condition rather than a single event:
When pembrolizumab is administered in combination with enfortumab vedotin, refer to the SmPC for enfortumab vedotin prior to initiation of treatment.
The safety of pembrolizumab in combination with enfortumab vedotin has been evaluated among 564 patients with unresectable or metastatic urothelial carcinoma receiving 200 mg pembrolizumab on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle. Overall, the incidence of adverse reactions for pembrolizumab in combination with enfortumab vedotin was observed to be higher than for pembrolizumab monotherapy reflecting the contribution of enfortumab vedotin and the longer duration of treatment of the combination therapy. Adverse reactions were generally similar to those observed in patients receiving pembrolizumab or enfortumab vedotin as monotherapy. The incidence of rash maculo-papular was 36% all Grades (10% Grades 3-4), which is higher than observed in pembrolizumab monotherapy.
Generally, adverse event frequencies were higher in patients ≥65 years of age compared to <65 years of age, particularly for serious adverse events (56.3% and 35.3%, respectively) and ≥ Grade 3 events (80.3% and 64.2%, respectively), similar to observations with the chemotherapy comparator.
Data for the following immune-mediated adverse reactions are based on patients who received pembrolizumab across four doses (2 mg/kg bw every 3 weeks, 10 mg/kg bw every 2 or 3 weeks, or 200 mg every 3 weeks) in clinical studies (see section 5.1). The management guidelines for these adverse reactions are described in section 4.4.
Pneumonitis occurred in 324 (4.2%) patients, including Grade 2, 3, 4 or 5 cases in 143 (1.9%), 81 (1.1%), 19 (0.2%) and 9 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of pneumonitis was 3.9 months (range: 2 days to 27.2 months). The median duration was 2.0 months (range: 1 day to 51.0+ months). Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (8.1%) than in patients who did not receive prior thoracic radiation (3.9%). Pneumonitis led to discontinuation of pembrolizumab in 131 (1.7%) patients. Pneumonitis resolved in 196 patients, 6 with sequel ae.
In patients with NSCLC, pneumonitis occurred in 230 (6.1%), including Grade 2, 3, 4 or 5 cases in 103 (2.7%), 63 (1.7%), 17 (0.4%) and 10 (0.3 ), respectively. In patients with locally advanced or metastatic NSCLC, pneumonitis occurred in 8.9 with a history of prior thoracic radiation. In patients with cHL, the incidence of pneumonitis (all Grades) ranged from 5.2% to 10.8% for cHL patients in KEYNOTE-087 (n=210) and KEYNOTE-204 (n=148), respectively.
Colitis occurred in 158 (2.1%) patients, including Grade 2, 3 or 4 cases in 49 (0.6%), 82 (1.1%) and 6 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of colitis was 4.3 months (range: 2 days to 24.3 months). The median duration was 1.1 month (range: 1 day to 45.2 months). Colitis led to discontinuation of pembrolizumab in 48 (0.6%) patients. Colitis resolved in 132 patients, 2 with sequelae. In patients with CRC treated with pembrolizumab as monotherapy (n=153), the incidence of co litis was 6.5% (all Grades) with 2.0% Grade 3 and 1.3% Grade 4.
Hepatitis occurred in 80 (1.0%) patients, including Grade 2, 3 or 4 cases in 12 (0.2%), 55 (0.7%) and 8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hepatitis was 3.5 months (range: 8 days to 26.3 months). The median duration was 1.3 months (range: 1 day to 29.0+ months). Hepatitis led to discontinuation of pembrolizum ab in 37 (0.5%) patients. Hepatitis resolved in 60 patients.
Nephritis occurred in 37 (0.5%) patients, including Grade 2, 3 or 4 cases in 11 (0.1%), 19 (0.2%) and 2 (<0.1%) patients, respectively, receiving pembrolizumab as monotherapy. The median time to onset of nephritis was 4.2 months (range: 12 days to 21.4 months). The median duration was 3.3 months (range: 6 days to 28.2+ months). Nephritis led to discontinuation of pembrolizumab in 17 (0.2%) patients. Nephritis resolved in 25 patients, 5 with sequelae. In patients with non-squamous NSCLC treated with pembrolizumab 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.
Adrenal insufficiency occurred in 74 (1.0%) patients, including Grade 2, 3 or 4 cases in 34 (0.4%), 31 (0.4%) and 4 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of adrenal insufficiency was 5.4 months (range: 1 day to 23.7 months). The median duration was not reached (range: 3 days to 40.1+ months). Adrenal insufficiency led to disco ntinuation of pembrolizumab in 13 (0.2%) patients. Adrenal insufficiency resolved in 28 patients, 11 with sequelae.
Hypophysitis occurred in 52 (0.7%) patients, including Grade 2, 3 or 4 cases in 23 (0.3%), 24 (0.3%) and 1 (<0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypophysitis was 5.9 months (range: 1 day to 17.7 months). The median duration was 3.6 months (range: 3 days to 48.1+ months). Hypophysitis led to discontinuation of pembrolizumab in 14 (0.2%) patients. Hypophysitis resolved in 23 patients, 8 with sequelae.
Hyperthyroidism occurred in 394 (5.2%) patients, including Grade 2 or 3 cases in 108 (1.4%) and 9 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hyperthyroidism was 1.4 months (range: 1 day to 23.2 months). The median duration was 1.6 months (range: 4 days to 43.1+ months). Hyperthyroidism led to discontinuation of pembrolizumab in 4 (0.1%) patients. Hyperthyroidism resolved in 326 (82.7%) patients, 11 with sequelae. In patients with melanoma, NSCLC and RCC treated with pembrolizumab monotherapy in the adjuvant setting (n=2 060), the incidence of hyperthyroidism was 11.0%, the majority of which were Grade 1 or 2.
Hypothyroidism occurred in 939 (12.3%) patients, including Grade 2 or 3 cases in 687 (9.0%) and 8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypothyroidism was 3.4 months (range: 1 day to 25.9 months). The median duration was not reached (range: 2 days to 63.0+ months). Hypothyroidism led to discontinuation of pembrolizumab in 6 (0.1%) patients. Hypothyroidism resolved in 216 (23.0%) patients, 16 with sequelae. In patients with cHL (n=389) the incidence of hypothyroidism was 17%, all of which were Grade 1 or 2. In patients with HNSCC treated with pembrolizumab as monotherapy (n=909), the incidence of hypothyroidism was 16.1% (all Grades) with 0.3% Grade 3. In patients with HNSCC treated with pembrolizumab in combination with platinum and 5-FU chemotherapy (n=276), the inci dence of hypothyroidism was 15.2%, all of which were Grade 1 or 2. In patients treated with pembrolizumab in combination with axitinib or lenvatinib (n=1 456), the incidence of hypothyroidism was 46.2% (all Grades) with 0.8% Grade 3 or 4. In patients with melanoma, NSCLC and RCC treated with pembrolizumab monotherapy in the adjuvant setting (n= 2 060), the incidence of hypothyroidism was 18.5%, the majority of which were Grade 1 or 2.
Immune-mediated severe skin reactions occurred in 130 (1.7%) patients, including Grade 2, 3, 4 or 5 cases in 11 (0.1%), 103 (1.3%), 1 (<0.1%) and 1 (<0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of severe skin reactions was 2.8 months (range: 2 days to 25.5 months). The median duration was 1.9 months (range: 1 day to 47.1+ months). Severe skin reactions led to discontinuation of pembrolizumab in 18 (0.2%) patients. Severe skin reactions
resolved in 95 patients, 2 with sequelae.
Rare cases of SJS and TEN, some of them with fatal outcome, have been observed (see sections 4.2 and 4.4).
Of 14 patients in KEYNOTE-013 who proceeded to allogeneic HSCT after treatment with pembrolizumab, 6 patients reported acute GVHD and 1 patient reported chronic GVHD, none of which were fatal. Two patients experienced hepatic VOD, one of which was fatal. One patient experienced eng raftment syndrome post-transplant.
Of 32 patients in KEYNOTE-087 who proceeded to allogeneic HSCT after treatment with pembrolizumab, 16 patients reported acute GVHD and 7 patients reported chronic GVHD, two of which were fatal. No patients experienced he patic VOD. No patients experienced engraftment syndrome post-transplant.
Of 14 patients in KEYNOTE-204 who proceeded to allogeneic HSCT after treatment with pembrolizumab, 8 patients reported acute GVHD and 3 patients reported chronic GVHD, none of which were fatal. No patients experienced hepatic VOD. One patient experienced engraftment syndrome post-transplant.
In a clinical study of previously untreated patients with RCC receivi ng pembrolizumab in combination with axitinib, a higher than expected incidence of Grades 3 and 4 ALT increased (20%) and AST increased (13%) were observed. The median time to onset of ALT increased was 2.3 months (range: 7 days to 19.8 months). In patients with ALT ≥3 times ULN (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. Of the patients who recovered, 92 (84%) were rechallenged with either pembrolizumab (3%) or axitinib (31%) monotherapy or with both (50%). Of these patients, 55% had no recurrence of ALT >3 times ULN, and of those patients with recurrence of ALT >3 times ULN, all recovered. There were no Grade 5 hepatic events.
In patients treated with pembrolizumab monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 9.4% for lymphocytes decreased, 7.4% for sodium decreased, 5.8% for haemoglobin decreased, 5.3% for phosphate decreased, 5.3% for glucose increased, 3.3% for ALT increased, 3.1% for AST increased, 2.6% for alkaline phosphatase increased, 2.3% for potassium decreased, 2.1% for potassium increased, 1.9% for neutrophils decreased, 1.8% for platelets decreased, 1.8% for calcium increased, 1.7% for bilirubin increased, 1.5% for calcium decreased, 1.4% for albumin decreased, 1.3% for creatinine increased, 1.2% for glucose decreased, 0.8% for leucocytes decreased, 0.7% for magnesium increased, 0.5% for sodium increased, 0.4% for haemoglobin increased, and 0.2% for magnesium decreased.
In patients treated with pembrolizumab 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: 39.9% for neutrophils decreased, 25.5% for lymphocytes decreased, 23.3% for leucocytes decreased, 20.8% for haemoglobin decreased, 13.7% for platelets decreased, 10.4% for sodium decreased, 7.7% for potassium decreased, 7.3% for phosphate decreased, 5.7% for ALT increased, 5.5% for glucose increased, 5.3% for AST increased, 3.6% for bilirubin increased, 3.5% for calcium decreased, 3.4% for potassium increased, 3.1% for creatinine increased, 2.8% for alkaline phosphatase increased, 2.6% for albumin decreased, 1.7% for calcium increased, 1.0% for glucose decreased, 0.5% for sodium increased and 0.1% for haemoglobin increased.
In patients treated with pembrolizumab 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 pembrolizumab 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, 6.8% for ph osphate 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.
In clinical studies in patients treated with pembrolizumab 2 mg/kg bw every three weeks, 200 mg every three weeks, or 10 mg/kg bw every two or three weeks as monotherapy, 36 (1.8%) of 2 034 evaluable patients tested positive for treatment-emergent antibodies to pembrolizumab, of which 9 (0.4%) patients had neutralising antib odies against pembrolizumab. There was no evidence of an
altered pharmacokinetic or safety profile with anti-pembrolizumab binding or neutralising antibody development.
The safety of pembrolizumab 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 bw every 3 weeks in the Phase I/II study KEYNOTE-051. The cHL population (n=22) included patie nts 11 to 17 years of age. The safety profile in paediatric patients was generally similar to that seen in adults treated with pembrolizumab. 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. Long-term safety data of pembrolizumab in adolescents with Stage IIB, IIC and III melanoma treated in the adjuvant setting are currently unavailable.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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