KEYTRUDA Powder for solution for infusion Ref.[7435] Active ingredients: Pembrolizumab

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

Assessment of PD-L1 status

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

Immune-related adverse reactions

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

For suspected immune-related 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-related 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 remains at 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-related adverse reaction that recurs and for any Grade 4 immune-related adverse reaction toxicity, except for endocrinopathies that are controlled with replacement hormones (see sections 4.2 and 4.8).

Immune-related pneumonitis

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).

Immune-related colitis

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 colitis (see section 4.2). The potential risk of gastrointestinal perforation should be taken into consideration.

Immune-related hepatitis

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).

Immune-related nephritis

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).

Immune-related endocrinopathies

Severe endocrinopathies, including 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-related endocrinopathies.

Hypophysitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for signs and symptoms of hypophysitis (including hypopituitarism and secondary adrenal insufficiency) and other causes excluded. Corticosteroids to treat secondary adrenal insufficiency and other hormone replacement should be administered as clinically indicated, and pembrolizumab should be withheld for symptomatic hypophysitis until the event is controlled with hormone replacement. Continuation of pembrolizumab may be considered, 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 receiving 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 Grade 3 hyperglycaemia 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 replacement 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. For patients with Grade 3 or Grade 4 hyperthyroidism that improved to Grade 2 or lower, continuation of pembrolizumab may be considered, after corticosteroid taper, if needed (see sections 4.2 and 4.8). Thyroid function and hormone levels should be monitored to ensure appropriate hormone replacement.

Immune-related skin adverse reactions

Immune-related 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 or permanently discontinued, 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 signs or symptoms of 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 anticancer agents.

Other immune-related adverse reactions

The following additional clinically significant, immune-related adverse reactions have been reported in clinical trials or in post-marketing experience: uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, haemolytic anaemia, sarcoidosis and encephalitis (see sections 4.2 and 4.8).

Based on the severity of the adverse reaction, pembrolizumab should be withheld and corticosteroids administered.

Pembrolizumab may be restarted within 12 weeks after last dose of KEYTRUDA if the adverse reaction remains at 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-related adverse reaction that recurs and for any Grade 4 immune-related adverse reaction (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.

Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT)

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 classical Hodgkin lymphoma 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.

Infusion-related reactions

Severe infusion-related reactions, including hypersensitivity and anaphylaxis, have been reported in patients receiving pembrolizumab (see section 4.8). For severe infusion reactions, infusion should be stopped and pembrolizumab permanently discontinued (see section 4.2). Patients with mild or moderate infusion reaction may continue to receive pembrolizumab with close monitoring; premedication with antipyretic and antihistamine may be considered.

Disease-specific precautions

Use of pembrolizumab in urothelial carcinoma patients who have received prior platinum-containing chemotherapy

Physicians should consider the delayed onset of pembrolizumab 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 pembrolizumab compared to chemotherapy (see section 5.1). Factors associated with early deaths were fast progressive disease on prior platinum therapy and liver metastases.

Use of pembrolizumab 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, pembrolizumab should be used with caution in this population after careful consideration of the potential risk-benefit on an individual basis.

Use of pembrolizumab for first-line treatment of patients with NSCLC

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 non-small cell lung cancer whose tumours express PD-L1.

Efficacy and safety data from patients ≥75 years are limited. For patients ≥75 years, pembrolizumab combination therapy should be used with caution after careful consideration of the potential benefit/risk on an individual basis (see section 5.1).

Use of pembrolizumab 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 pembrolizumab in the adjuvant melanoma setting in patients ≥75 years are limited.

Patients excluded from clinical trials

Patients with the following conditions were excluded from clinical trials: active CNS metastases; ECOG PS ≥2 (except for urothelial carcinoma); HIV, hepatitis B or hepatitis C infection; 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-related 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 active infections were excluded from clinical trials 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 trials, therefore information is limited in patients with severe renal and moderate to severe hepatic impairment.

For subjects with relapsed or refractory classical Hodgkin lymphoma, clinical data for the use of pembrolizumab in patients ineligible to ASCT due to reasons other than failure to salvage chemotherapy are limited (see section 5.1).

After careful consideration of the potential increased risk, pembrolizumab may be used with appropriate medical management in these patients.

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.

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 immunosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. However, systemic corticosteroids or other immunosuppressants can be used after starting pembrolizumab to treat immune-related adverse reactions (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

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

Pregnancy

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 signaling 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.

Breast-feeding

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 pembrolizumab, taking into account the benefit of breast-feeding for the child and the benefit of pembrolizumab therapy for the woman.

Fertility

No clinical data are available on the possible effects of pembrolizumab on fertility. There were no notable effects in the male and female reproductive organs in monkeys based on 1-month and 6-month repeat dose toxicity studies (see section 5.3).

Pembrolizumab may have a minor influence on the ability to drive and use machines. Fatigue has been reported following administration of pembrolizumab (see section 4.8).

Summary of the safety profile

Pembrolizumab 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 pembrolizumab (see “Description of selected adverse reactions” below).

The safety of pembrolizumab as monotherapy has been evaluated in 4,948 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 and in Table 2 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 pembrolizumab were fatigue (34.1%), rash (22.7%), nausea (21.7%), diarrhoea (21.5%), and pruritus (20.2%). The majority of adverse reactions reported for monotherapy were of Grade 1 or 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions (see section 4.4).

The safety of pembrolizumab in combination with chemotherapy has been evaluated in 791 patients with NSCLC receiving 200 mg, 2 mg/kg or 10 mg/kg pembrolizumab every 3 weeks, in clinical studies. The frequencies included below and in Table 2 are based on all reported adverse drug reactions, regardless of the investigator assessment of causality. In this patient population, the most frequent adverse reactions were nausea (49%), anaemia (48%), fatigue (38%), constipation (34%), diarrhoea (31%), neutropaenia (29%), and decreased appetite (28%). Incidences of Grade 3-5 adverse reactions were 67% for pembrolizumab combination therapy and 66% for chemotherapy alone.

Tabulated list of adverse reactions

Adverse reactions observed in clinical studies of pembrolizumab as monotherapy or in combination with chemotherapy, or reported from post-marketing use of pembrolizumab are listed in Table 2. Adverse reactions known to occur with pembrolizumab or chemotherapies given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical trials with combination therapy. 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.

Table 2. Adverse reactions in patients treated with pembrolizumab^*:

Monotherapy:

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^a

Uncommon: sarcoidosis

Not known: solid organ transplant rejection

Endocrine disorders

Very common: hypothyroidism^b

Common: hyperthyroidism

Uncommon: hypophysitis^c, thyroiditis^d, adrenal insufficiency

Metabolism and nutrition disorders

Very common: decreased appetite

Common: hyponatraemia, hypokalaemia, hypocalcaemia

Uncommon: type 1 diabetes mellitus^e

Psychiatric disorders

Common: insomnia

Nervous system disorders

Very common: headache

Common: dizziness, neuropathy peripheral, lethargy, dysgeusia

Uncommon: epilepsy

Rare: Guillain-Barré syndrome^f, myasthenic syndrome^g, meningitis (aseptic), encephalitis

Eye disorders

Common: dry eye

Uncommon: uveitis^h

Rare: Vogt-Koyanagi-Harada syndrome

Cardiac disorders

Uncommon: pericardial effusion, pericarditis

Rare: myocarditis

Vascular disorders

Common: hypertension

Respiratory, thoracic and mediastinal disorders

Very common: dyspnoea, cough

Common: pneumonitisⁱ

Gastrointestinal disorders

Very common: diarrhoea, abdominal pain^j, nausea, vomiting, constipation

Common: colitis^k, dry mouth

Uncommon: pancreatitis^l

Rare: small intestinal perforation

Hepatobiliary disorders

Uncommon: hepatitis^m

Skin and subcutaneous tissue disorders

Very common: rashⁿ, pruritus^o

Common: severe skin reactions^p, erythema, vitiligo^q, dry skin, alopecia, eczema, dermatitis acneiform

Uncommon: lichenoid keratosis^r, psoriasis, dermatitis, papule, hair colour changes

Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema nodosum

Musculoskeletal and connective tissue disorders

Very common: musculoskeletal pain^s, arthralgia

Common: pain in extremity, myositis^t, arthritis^u

Uncommon: tenosynovitis^v

Renal and urinary disorders

Uncommon: nephritis^w

General disorders and administration site conditions

Very common: fatigue, asthenia, oedema^x, 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

Combination with chemotherapy:

Infections and infestations

Common: pneumonia

Blood and lymphatic system disorders

Very common: neutropaenia, anaemia, thrombocytopaenia

Common: febrile neutropaenia, leukopaenia, lymphopaenia

Uncommon: eosinophilia

Immune system disorders

Common: infusion related reaction^a

Endocrine disorders

Common: hypothyroidism, hyperthyroidism

Uncommon: hypophysitis^c, thyroiditis, adrenal insufficiency

Metabolism and nutrition disorders

Very common: decreased appetite

Common: hyponatraemia, hypokalaemia, hypocalcaemia

Uncommon: type 1 diabetes mellitus

Psychiatric disorders

Common: insomnia

Nervous system disorders

Very common: dizziness, neuropathy peripheral, dysgeusia, headache

Common: lethargy

Uncommon: epilepsy

Eye disorders

Common: dry eye

Cardiac disorders

Uncommon: pericardial effusion, pericarditis

Vascular disorders

Common: hypertension

Respiratory, thoracic and mediastinal disorders

Very common: dyspnoea, cough

Common: pneumonitisⁱ

Gastrointestinal disorders

__Very common:__diarrhoea, nausea, vomiting, constipation, abdominal pain^j

Common: colitis^k, dry mouth

Uncommon: pancreatitis^l

Hepatobiliary disorders

Common: hepatitis^m

Skin and subcutaneous tissue disorders

Very common: rashⁿ, alopecia, pruritus^o

Common: severe skin reactions^p, erythema, dermatitis acneiform, dry skin

Uncommon: psoriasis, dermatitis, eczema, hair colour changes, lichenoid keratosis, papule, vitiligo^q

Musculoskeletal and connective tissue disorders

Very common: musculoskeletal pain^s, arthralgia

Common: myositis^t, pain in extremity, arthritis^u

Uncommon: tenosynovitis^v

Renal and urinary disorders

Common: nephritis^w, acute kidney injury

General disorders and administration site conditions

Very common: fatigue, asthenia, oedema^x, pyrexia

Common: chills, influenza-like illness

Investigations

Very common: alanine aminotransferase increased, blood creatinine increased

Common: aspartate aminotransferase increased, hypercalcaemia, blood alkaline phosphatase increased

Uncommon: amylase increased, blood bilirubin 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. The following terms represent a group of related events that describe a medical condition rather than a single event.
^a infusion-related reaction (drug hypersensitivity, anaphylactic reaction, anaphylactoid reaction, hypersensitivity and cytokine release syndrome)
^b hypothyroidism (myxoedema)
^c hypophysitis (hypopituitarism)
^d thyroiditis (autoimmune thyroiditis and thyroid disorder)
^e type 1 diabetes mellitus (diabetic ketoacidosis)
^f Guillain-Barré syndrome (axonal neuropathy and demyelinating polyneuropathy)
^g myasthenic syndrome (myasthenia gravis, including exacerbation)
^h uveitis (iritis and iridocyclitis)
ⁱ pneumonitis (interstitial lung disease)
^j abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower)
^k colitis (colitis microscopic, enterocolitis, and autoimmune colitis)
^l pancreatitis (autoimmune pancreatitis and pancreatitis acute)
^m hepatitis (autoimmune hepatitis and drug induced liver injury)
ⁿ rash (rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular and genital rash)
^o pruritus (urticaria, urticaria papular, pruritus generalised and pruritus genital)
^p severe skin reactions (dermatitis bullous, dermatitis exfoliative, erythema multiforme, exfoliative rash, pemphigus, skin necrosis, toxic skin eruption and Grade ≥3 of the following: acute febrile neutropaenic 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)
^q vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid)
^r lichenoid keratosis (lichen planus and lichen sclerosus)
^s musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain and torticollis)
^t myositis (myalgia, myopathy, polymyalgia rheumatica and rhabdomyolysis)
^u arthritis (joint swelling, polyarthritis and joint effusion)
^v tenosynovitis (tendonitis, synovitis and tendon pain)
^w nephritis (nephritis autoimmune, tubulointerstitial nephritis and renal failure, renal failure acute, or acute kidney injury with evidence of nephritis, nephrotic syndrome)
^x oedema (oedema peripheral, generalised oedema, fluid overload, fluid retention, eyelid oedema and lip oedema, face oedema, localised oedema and periorbital oedema)

Description of selected adverse reactions

Data for the following immune-related adverse reactions are based on patients who received pembrolizumab across four doses (2 mg/kg every 3 weeks, 10 mg/kg 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.

Immune-related adverse reactions (see section 4.4)

Immune-related pneumonitis

Pneumonitis occurred in 182 (3.7%) patients, including Grade 2, 3, 4 or 5 cases in 78 (1.6%), 48 (1.0%), 9 (0.2%) and 7 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of pneumonitis was 3.7 months (range 2 days to 21.3 months). The median duration was 1.9 months (range 1 day to 17.2+ 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 (3.3%). Pneumonitis led to discontinuation of pembrolizumab in 75 (1.5%) patients. Pneumonitis resolved in 101 patients, 2 with sequelae.

In patients with NSCLC, pneumonitis occurred in 107 (4.9%), including Grade 2, 3, 4 or 5 cases in 39 (1.8%), 30 (1.4%), 10 (0.5%) and 9 (0.4%), respectively. In patients with NSCLC, pneumonitis occurred in 8.1% with a history of prior thoracic radiation.

Immune-related colitis

Colitis occurred in 97 (2.0%) patients, including Grade 2, 3 or 4 cases in 28 (0.6%), 56 (1.1%) and 3 (<0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of colitis was 3.8 months (range 7 days to 20.2 months). The median duration was 1.2 months (range 1 day to 8.7+ months). Colitis led to discontinuation of pembrolizumab in 28 (0.6%) patients. Colitis resolved in 75 patients, 1 with sequelae.

Immune-related hepatitis

Hepatitis occurred in 39 (0.8%) patients, including Grade 2, 3 or 4 cases in 7 (0.1%), 26 (0.5%) and 4 (<0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hepatitis was 2.8 months (range 8 days to 21.4 months). The median duration was 1.1 months (range 1 day to 20.9+ months). Hepatitis led to discontinuation of pembrolizumab in 14 (0.3%) patients. Hepatitis resolved in 27 patients.

Immune-related nephritis

Nephritis occurred in 17 (0.3%) patients, including Grade 2, 3 or 4 cases in 3 (0.1%), 12 (0.2%) and 1 (<0.1%) patients, respectively, receiving pembrolizumab as monotherapy. The median time to onset of nephritis was 5.1 months (range 12 days to 12.8 months). The median duration was 1.8 months (range 6 days to 10.5+ months). Nephritis led to discontinuation of pembrolizumab in 7 (0.1%) patients. Nephritis resolved in 9 patients, 1 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.

Immune-related endocrinopathies

Hypophysitis occurred in 32 (0.6%) patients, including Grade 2, 3 or 4 cases in 13 (0.3%), 15 (0.3%) and 1 (<0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypophysitis was 5.3 months (range 1 day to 17.7 months). The median duration was 1.7 months (range 3 days to 18.1+ months). Hypophysitis led to discontinuation of pembrolizumab in 8 (0.2%) patients. Hypophysitis resolved in 9 patients, 7 with sequelae.

Hyperthyroidism occurred in 197 (4.0%) patients, including Grade 2 or 3 cases in 52 (1.1%) and 5 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hyperthyroidism was 1.4 months (range 1 day to 21.9 months). The median duration was 1.7 months (range 4 days to 15.5+ months). Hyperthyroidism led to discontinuation of pembrolizumab in 3 (0.1%) patients. Hyperthyroidism resolved in 152 (77.2%) patients, 1 with sequelae.

Hypothyroidism occurred in 514 (10.4%) patients, including Grade 2 or 3 cases in 377 (7.6%) and 7 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypothyroidism was 3.5 months (range 1 day to 18.9 months). The median duration was not reached (range 2 days to 29.9+ months). Two patients (<0.1%) discontinued pembrolizumab due to hypothyroidism. Hypothyroidism resolved in 107 (20.8%) patients, 9 with sequelae. In patients with cHL (n=241) the incidence of hypothyroidism was 14.1% (all Grades) with 0.4% Grade 3. In patients with HNSCC (n=609), the incidence of hypothyroidism was 15.1% (all Grades) with 0.5% Grade 3.

Immune-related skin adverse reactions

Immune-related severe skin reactions occurred in 66 (1.3%) patients, including Grade 2, 3 or 5 cases in 6 (0.1%), 48 (1.0%) and 1 (<0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of severe skin reactions was 3.2 months (range 4 days to 19.4 months). The median duration was 1.6 months (range 1 day to 16.1+ months). Severe skin reactions led to discontinuation of pembrolizumab in 5 (0.2%) patients. Severe skin reactions resolved in 46 patients.

Rare cases of SJS and TEN, some of them with fatal outcome, have been observed (see sections 4.2 and 4.4).

Complications of allogeneic HSCT in classical Hodgkin lymphoma

Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with pembrolizumab, 6 patients (26%) developed GVHD, one of which was fatal, and 2 patients (9%) developed severe hepatic VOD after reduced-intensity conditioning, one of which was fatal. The 23 patients had a median follow-up from subsequent allogeneic HSCT of 5.1 months (range: 0-26.2 months).

Laboratory abnormalities

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: 10.8% for lymphocytes decreased, 7.6% for sodium decreased, 6.5% for haemoglobin decreased, 5.2% for phosphate decreased, 5.2% for glucose increased, 2.9% for alkaline phosphatase increased, 2.6% for AST increased, 2.3% for ALT increased, 2% for potassium decreased, 1.8% for bilirubin increased, 1.6% for potassium increased, 1.5% for albumin decreased, 1.5% for calcium increased, 1.4% for creatinine increased, 1.4% for platelets decreased, 1.4% for neutrophils decreased, 1.2% for calcium decreased, 0.8% for magnesium increased, 0.6% for leucocytes decreased, 0.5% for glucose decreased, 0.2% for magnesium decreased, and 0.2% for sodium increased.

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: 23.8% for neutrophils decreased, 20.2% for lymphocytes decreased, 16.2% for haemoglobin decreased, 14.6% for leucocytes decreased, 10.3% for platelets decreased, 7.9% for glucose increased, 7.8% for phosphate decreased, 7.4% for sodium decreased, 4.6% for potassium decreased, 3.7% for ALT increased, 3.6% for creatinine increased, 3.5% for AST increased, 2.9% for calcium decreased, 2.6% for potassium increased, 2.5% for albumin decreased, 1.7% for calcium increased, 1.2% for alkaline phosphatase increased, 0.9% for glucose decreased, 0.7% for bilirubin increased, and 0.1% for sodium increased.

Immunogenicity

In clinical studies in patients treated with pembrolizumab 2 mg/kg every three weeks, 200 mg every three weeks, or 10 mg/kg 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 antibodies against pembrolizumab. There was no evidence of an altered pharmacokinetic or safety profile with anti-pembrolizumab binding or neutralising antibody development.

Paediatric population

The safety of pembrolizumab 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 pembrolizumab. 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 Grade 1 or 2 severity. Sixty-nine (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.

Reporting of suspected adverse reactions

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.