pembrolizumab: prescribing information – dosing, contraindications, interactions, side effects

For healthcare professionals

4.1 Therapeutic indications

Applies to: KEYTRUDA 25 mg/mL concentrate for solution for infusion

Melanoma
KEYTRUDA as monotherapy is indicated for the treatment of adults and adolescents aged 12 years and older with advanced (unresectable or metastatic) melanoma.
KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults and adolescents aged 12 years and older with Stage IIB, IIC or III melanoma and who have undergone complete resection (see section 5.1).
Non-small cell lung carcinoma (NSCLC)
KEYTRUDA, in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment, is indicated for the treatment of resectable non-small cell lung carcinoma at high risk of recurrence in adults (for selection criteria, see section 5.1).
KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with non-small cell lung carcinoma who are at high risk of recurrence following complete resection and platinum-based chemotherapy (for selection criteria, see section 5.1).
KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma in adults whose tumours express PD-L1 with a ≥ 50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations.

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first- line treatment of metastatic non-squamous non-small cell lung carcinoma in adults whose tumours have no EGFR or ALK positive mutations.
KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous non-small cell lung carcinoma in adults.
KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic non-small cell lung carcinoma in adults whose tumours express PD-L1 with a ≥ 1% TPS and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving KEYTRUDA.
Malignant pleural mesothelioma (MPM)
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of adults with unresectable non-epithelioid malignant pleural mesothelioma.
Classical Hodgkin lymphoma (cHL)
KEYTRUDA as monotherapy is indicated for the treatment of adult and paediatric patients aged 3 years and older with relapsed or refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option.
Urothelial carcinoma
KEYTRUDA, in combination with enfortumab vedotin, as neoadjuvant treatment and then continued after radical cystectomy as adjuvant treatment, is indicated for the treatment of adults with resectable muscle invasive bladder cancer (MIBC) who are ineligible for cisplatin-containing chemotherapy.
KEYTRUDA, in combination with enfortumab vedotin, is indicated for the first-line treatment of unresectable or metastatic urothelial carcinoma in adults.
KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy (see section 5.1).
KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD-L1 with a combined positive score (CPS) ≥ 10 (see section 5.1).
Head and neck squamous cell carcinoma (HNSCC)
KEYTRUDA as monotherapy is indicated for the treatment of resectable locally advanced head and neck squamous cell carcinoma as neoadjuvant treatment, continued as adjuvant treatment in combination with radiation therapy with or without concomitant cisplatin and then as monotherapy in adults whose tumours express PD-L1 with a CPS ≥ 1.
KEYTRUDA, as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, is indicated for the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma in adults whose tumours express PD-L1 with a CPS ≥ 1 (see section 5.1).
KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic head and neck squamous cell carcinoma in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing on or after platinum-containing chemotherapy (see section 5.1).

Renal cell carcinoma (RCC)
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of advanced renal cell carcinoma in adults (see section 5.1).
KEYTRUDA, in combination with lenvatinib, is indicated for the first-line treatment of advanced renal cell carcinoma in adults (see section 5.1).
KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with renal cell carcinoma at increased risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions (for selection criteria, see section 5.1).
Microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) cancers Colorectal cancer (CRC) KEYTRUDA as monotherapy is indicated for adults with MSI-H or dMMR colorectal cancer in the following settings:
- first-line treatment of metastatic colorectal cancer;
- treatment of unresectable or metastatic colorectal cancer after previous fluoropyrimidine-based combination therapy.
Non-colorectal cancers
KEYTRUDA as monotherapy is indicated for the treatment of the following MSI-H or dMMR tumours in adults with:
- advanced or recurrent endometrial carcinoma, who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation;
- unresectable or metastatic gastric, small intestine, or biliary cancer, who have disease progression on or following at least one prior therapy.
Oesophageal carcinoma
KEYTRUDA, in combination with platinum and fluoropyrimidine-based chemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic carcinoma of the oesophagus in adults whose tumours express PD-L1 with a CPS ≥ 10 (see section 5.1).
Triple-negative breast cancer (TNBC)
KEYTRUDA, in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery, is indicated for the treatment of adults with locally advanced, or early-stage triple-negative breast cancer at high risk of recurrence (see section 5.1).
KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of locally recurrent unresectable or metastatic triple-negative breast cancer in adults whose tumours express PD-L1 with a CPS ≥ 10 and who have not received prior chemotherapy for metastatic disease (see section 5.1).
Endometrial carcinoma (EC)
KEYTRUDA, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of primary advanced or recurrent endometrial carcinoma in adults who are candidates for systemic therapy.
KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of advanced or recurrent endometrial carcinoma in adults who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation.

Cervical cancer
KEYTRUDA, in combination with chemoradiotherapy (external beam radiation therapy followed by brachytherapy), is indicated for the treatment of FIGO 2014 Stage III - IVA locally advanced cervical cancer in adults who have not received prior definitive therapy.
KEYTRUDA, in combination with chemotherapy with or without bevacizumab, is indicated for the treatment of persistent, recurrent, or metastatic cervical cancer in adults whose tumours express PD-L1 with a CPS ≥ 1.
Gastric or gastro-oesophageal junction (GEJ) adenocarcinoma
KEYTRUDA, in combination with trastuzumab, fluoropyrimidine and platinum-containing chemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic HER2-positive gastric or gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS ≥ 1.
KEYTRUDA, in combination with fluoropyrimidine and platinum-containing chemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic HER2-negative gastric or gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS ≥ 1 (see section 5.1).
Biliary tract carcinoma (BTC)
KEYTRUDA, in combination with gemcitabine and cisplatin, is indicated for the first-line treatment of locally advanced unresectable or metastatic biliary tract carcinoma in adults.
Ovarian Cancer
KEYTRUDA, in combination with paclitaxel, with or without bevacizumab, is indicated for the treatment of platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma in adults whose tumours express PD-L1 with a CPS ≥ 1 and who have received one or two prior systemic treatment regimens.

Applies to: KEYTRUDA 395 mg solution for injection / KEYTRUDA 790 mg solution for injection

KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with non-small cell lung carcinoma who are at high risk of recurrence following complete resection and platinum-based chemotherapy (for selection criteria, see section 5.1).
KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma in adults whose tumours express PD-L1 with a ≥ 50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations.
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first- line treatment of metastatic non-squamous non-small cell lung carcinoma in adults whose tumours have no EGFR or ALK positive mutations.
KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous non-small cell lung carcinoma in adults.
KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic non-small cell lung carcinoma in adults whose tumours express PD-L1 with a ≥ 1% TPS and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving KEYTRUDA.
Malignant pleural mesothelioma (MPM)
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of adults with unresectable non-epithelioid malignant pleural mesothelioma.
Classical Hodgkin lymphoma (cHL)
KEYTRUDA as monotherapy is indicated for the treatment of adults and adolescents aged 12 years and older with relapsed or refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option.
Urothelial carcinoma
KEYTRUDA, in combination with enfortumab vedotin, as neoadjuvant treatment and then continued after radical cystectomy as adjuvant treatment, is indicated for the treatment of adults with resectable muscle invasive bladder cancer (MIBC) who are ineligible for cisplatin-containing chemotherapy.
KEYTRUDA, in combination with enfortumab vedotin, is indicated for the first-line treatment of unresectable or metastatic urothelial carcinoma in adults.
KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy (see section 5.1).
KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD-L1 with a combined positive score (CPS) ≥ 10 (see section 5.1).
Head and neck squamous cell carcinoma (HNSCC)
KEYTRUDA as monotherapy is indicated for the treatment of resectable locally advanced head and neck squamous cell carcinoma as neoadjuvant treatment, continued as adjuvant treatment in combination with radiation therapy with or without concomitant cisplatin and then as monotherapy in adults whose tumours express PD-L1 with a CPS ≥ 1.
KEYTRUDA, as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, is indicated for the first-line treatment of metastatic or unresectable recurrent head and

neck squamous cell carcinoma in adults whose tumours express PD-L1 with a CPS ≥ 1 (see section 5.1).
KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic head and neck squamous cell carcinoma in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing on or after platinum-containing chemotherapy (see section 5.1).
Renal cell carcinoma (RCC)
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of advanced renal cell carcinoma in adults (see section 5.1).
KEYTRUDA, in combination with lenvatinib, is indicated for the first-line treatment of advanced renal cell carcinoma in adults (see section 5.1).
KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with renal cell carcinoma at increased risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions (for selection criteria, see section 5.1).
Microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) cancers Colorectal cancer (CRC) KEYTRUDA as monotherapy is indicated for adults with MSI-H or dMMR colorectal cancer in the following settings:
- first-line treatment of metastatic colorectal cancer;
- treatment of unresectable or metastatic colorectal cancer after previous fluoropyrimidine-based combination therapy.
Non-colorectal cancers
KEYTRUDA as monotherapy is indicated for the treatment of the following MSI-H or dMMR tumours in adults with:
- advanced or recurrent endometrial carcinoma, who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation;
- unresectable or metastatic gastric, small intestine, or biliary cancer, who have disease progression on or following at least one prior therapy.
Oesophageal carcinoma
KEYTRUDA, in combination with platinum and fluoropyrimidine-based chemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic carcinoma of the oesophagus in adults whose tumours express PD-L1 with a CPS ≥ 10 (see section 5.1).
Triple-negative breast cancer (TNBC)
KEYTRUDA, in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery, is indicated for the treatment of adults with locally advanced, or early-stage triple-negative breast cancer at high risk of recurrence (see section 5.1).
KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of locally recurrent unresectable or metastatic triple-negative breast cancer in adults whose tumours express PD-L1 with a CPS ≥ 10 and who have not received prior chemotherapy for metastatic disease (see section 5.1).

Endometrial carcinoma (EC)
KEYTRUDA, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of primary advanced or recurrent endometrial carcinoma in adults who are candidates for systemic therapy.
KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of advanced or recurrent endometrial carcinoma in adults who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation.
Cervical cancer
KEYTRUDA, in combination with chemoradiotherapy (external beam radiation therapy followed by brachytherapy), is indicated for the treatment of FIGO 2014 Stage III - IVA locally advanced cervical cancer in adults who have not received prior definitive therapy.
KEYTRUDA, in combination with chemotherapy with or without bevacizumab, is indicated for the treatment of persistent, recurrent, or metastatic cervical cancer in adults whose tumours express PD-L1 with a CPS ≥ 1.
Gastric or gastro-oesophageal junction (GEJ) adenocarcinoma
KEYTRUDA, in combination with trastuzumab, fluoropyrimidine and platinum-containing chemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic HER2-positive gastric or gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS ≥ 1.
KEYTRUDA, in combination with fluoropyrimidine and platinum-containing chemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic HER2-negative gastric or gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS ≥ 1 (see section 5.1).
Biliary tract carcinoma (BTC)
KEYTRUDA, in combination with gemcitabine and cisplatin, is indicated for the first-line treatment of locally advanced unresectable or metastatic biliary tract carcinoma in adults.
Ovarian Cancer
KEYTRUDA, in combination with paclitaxel, with or without bevacizumab, is indicated for the treatment of platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma in adults whose tumours express PD-L1 with a CPS ≥ 1 and who have received one or two prior systemic treatment regimens.

4.2 Posology and method of administration

Applies to: KEYTRUDA 25 mg/mL concentrate for solution for infusion

Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer.
Patients receiving subcutaneous pembrolizumab can switch to intravenous pembrolizumab at their next scheduled dose. Patients receiving intravenous pembrolizumab can switch to subcutaneous pembrolizumab at their next scheduled dose.
PD-L1 testing
If specified in the indication, patient selection for treatment with KEYTRUDA based on the tumour expression of PD-L1 should be confirmed by a validated test (see sections 4.1, 4.4, 4.8 and 5.1).
MSI/MMR testing
If specified in the indication, patient selection for treatment with KEYTRUDA based on MSI-H/dMMR tumour status should be confirmed by a validated test (see sections 4.1 and 5.1).
Posology
The recommended dose of KEYTRUDA in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes.

The recommended dose of KEYTRUDA as monotherapy in paediatric patients aged 3 years and older with cHL or patients aged 12 years and older with melanoma is 2 mg/kg bodyweight (bw) (up to a maximum of 200 mg), every 3 weeks administered as an intravenous infusion over 30 minutes.
For use in combination, see the Summary of Product Characteristics (SmPC) for the concomitant therapies.
Patients should be treated with KEYTRUDA until disease progression or unacceptable toxicity (and up to maximum duration of therapy if specified for an indication). 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, NSCLC, or RCC, KEYTRUDA should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year.
For the neoadjuvant and adjuvant treatment of resectable NSCLC, patients should be treated with neoadjuvant KEYTRUDA in combination with chemotherapy for 4 doses of 200 mg every 3 weeks or 2 doses of 400 mg every 6 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as monotherapy for 13 doses of 200 mg every 3 weeks or 7 doses of 400 mg every 6 weeks or until disease recurrence or unacceptable toxicity. Patients who experience disease progression that precludes definitive surgery or unacceptable toxicity related to KEYTRUDA as neoadjuvant treatment in combination with chemotherapy should not receive KEYTRUDA monotherapy as adjuvant treatment.
For the neoadjuvant and adjuvant treatment of cisplatin-ineligible MIBC, patients should be treated with neoadjuvant KEYTRUDA in combination with enfortumab vedotin for 3 doses of 200 mg every 3 weeks or until disease progression that precludes radical cystectomy or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA in combination with enfortumab vedotin for 14 doses of 200 mg every 3 weeks or 7 doses of 400 mg every 6 weeks or until disease recurrence or unacceptable toxicity.
For the neoadjuvant and adjuvant treatment of resectable locally advanced HNSCC, patients should be treated with neoadjuvant KEYTRUDA as monotherapy for 2 doses of 200 mg every 3 weeks or 1 dose of 400 mg or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA in combination with radiation with or without concomitant cisplatin for 3 doses of 200 mg every 3 weeks or 2 doses of 400 mg every 6 weeks followed by KEYTRUDA as monotherapy for 12 doses of 200 mg every 3 weeks or 6 doses of 400 mg every 6 weeks or until disease recurrence or unacceptable toxicity. Patients who experience disease progression that precludes definitive surgery or unacceptable toxicity related to KEYTRUDA monotherapy as neoadjuvant treatment should not receive KEYTRUDA in combination with radiation with or without concomitant cisplatin as adjuvant treatment.
For the neoadjuvant and adjuvant treatment of TNBC, patients should be treated with neoadjuvant KEYTRUDA in combination with chemotherapy for 8 doses of 200 mg every 3 weeks or 4 doses of 400 mg every 6 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as monotherapy for 9 doses of 200 mg every 3 weeks or 5 doses of 400 mg every 6 weeks or until disease recurrence or unacceptable toxicity. Patients who experience disease progression that precludes definitive surgery or unacceptable toxicity related to KEYTRUDA as neoadjuvant treatment in combination with chemotherapy should not receive KEYTRUDA monotherapy as adjuvant treatment.
For locally advanced cervical cancer, patients should be treated with KEYTRUDA concurrent with chemoradiotherapy, followed by KEYTRUDA as monotherapy. KEYTRUDA can be administered as either 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity or up to 24 months.

Dose delay or discontinuation (see also section 4.4)
No dose reductions of KEYTRUDA are recommended. KEYTRUDA should be withheld or discontinued to manage adverse reactions as described in Table 1.
Table 1: Recommended treatment modifications for KEYTRUDA
Immune-mediated adverse reactions
Severity
Treatment modification

Pneumonitis
Grade 2
Withhold until adverse reactions recover to
Grades 0-1*
Grades 3 or 4, or recurrent
Grade 2
Permanently discontinue

Colitis
Grades 2 or 3
Withhold until adverse reactions recover to
Grades 0-1*
Grade 4 or recurrent Grade 3
Permanently discontinue

Nephritis
Grade 2 with creatinine > 1.5 to
≤ 3 times upper limit of normal
(ULN)
Withhold until adverse reactions recover to
Grades 0-1*
Grade ≥ 3 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 pembrolizumab 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 pembrolizumab 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 times ULN or total bilirubin > 1.5 to 3 times ULN
Withhold until adverse reactions recover to
Grades 0-1*
Grade ≥ 3 with AST or ALT
> 5 times ULN or total bilirubin
> 3 times ULN
Permanently discontinue

Immune-mediated adverse reactions
Severity
Treatment modification
In case of 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
Stevens-Johnson syndrome
(SJS) or toxic epidermal necrolysis (TEN)
Withhold until adverse reactions recover to
Grades 0-1*
Grade 4 or confirmed SJS or
TEN
Permanently discontinue
Other immune-mediated adverse reactions
Based on severity and type of reaction (Grade 2 or Grade 3)
Withhold until adverse reactions recover to
Grades 0-1*
Grades 3 or 4 myocarditis
Grades 3 or 4 encephalitis
Grades 3 or 4 Guillain-Barré syndrome
Permanently discontinue
Grade 4 or recurrent Grade 3
Permanently discontinue
Myocarditis-myositis-myasthenia gravis overlap syndrome†
Grade 2
Withhold until adverse reactions recover to
Grades 0-1*
Grades 3 or 4
Permanently discontinue
Infusion-related reactions
Grades 3 or 4
Permanently discontinue
Note: toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4).
*
If treatment-related toxicity does not resolve to Grades 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.
†
Presenting as an overlap of either two or all three conditions. The most severe CTCAE grade of the individual events should be considered when assessing the recommended treatment modification for KEYTRUDA.
The safety of re-initiating pembrolizumab therapy in patients previously experiencing immune-mediated myocarditis is not known.
KEYTRUDA, as monotherapy or as combination therapy, should be permanently discontinued for Grade 4 or recurrent Grade 3 immune-mediated adverse reactions, unless otherwise specified in Table 1.
For Grade 4 haematological toxicity, only in patients with cHL, KEYTRUDA should be withheld until adverse reactions recover to Grades 0-1.
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 pembrolizumab, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer (see section 5.1).

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.
KEYTRUDA in combination with lenvatinib
When used in combination with lenvatinib, one or both medicines should be interrupted as appropriate. Lenvatinib should be withheld, dose reduced, or discontinued in accordance with the instructions in the lenvatinib SmPC for combination with pembrolizumab. No dose reductions are recommended for KEYTRUDA.
Patients treated with KEYTRUDA must be given the patient card and be informed about the risks of KEYTRUDA (see also package leaflet).
Special populations
Elderly
No dose adjustment is necessary in patients ≥ 65 years (see sections 4.4 and 5.1).
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 (see sections 4.4 and 5.2).
Hepatic impairment
No dose adjustment is needed for patients with mild or moderate hepatic impairment. KEYTRUDA has not been studied in patients with severe hepatic impairment (see sections 4.4 and 5.2).
Paediatric population
The safety and efficacy of KEYTRUDA in children below 18 years of age have not been established except in paediatric patients with melanoma or cHL. Currently available data are described in sections 4.8, 5.1 and 5.2.
Method of administration
It is important to check the vial label to ensure that the correct formulation (intravenous or subcutaneous) is being prepared and administered to the patient as prescribed, to reduce the risk of medication errors.
KEYTRUDA concentrate for solution for infusion is for intravenous use only. KEYTRUDA concentrate for solution for infusion is not intended for subcutaneous administration.
KEYTRUDA concentrate for solution for infusion must be administered by infusion over 30 minutes.
KEYTRUDA intravenous formulation must not be administered as an intravenous push or bolus injection.
KEYTRUDA concentrate for solution for infusion should not be substituted for or with subcutaneous pembrolizumab because they have different recommended dosages and routes of administration.
When administering KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be administered first.
When administering KEYTRUDA as part of a combination with enfortumab vedotin, KEYTRUDA should be administered after enfortumab vedotin when given on the same day.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Applies to: KEYTRUDA 395 mg solution for injection / KEYTRUDA 790 mg solution for injection

Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer.
Patients receiving intravenous pembrolizumab can switch to subcutaneous pembrolizumab at their next scheduled dose. Patients receiving subcutaneous pembrolizumab can switch to intravenous pembrolizumab at their next scheduled dose.

PD-L1 testing
If specified in the indication, patient selection for treatment with KEYTRUDA based on the tumour expression of PD-L1 should be confirmed by a validated test (see sections 4.1, 4.4, 4.8 and 5.1).
MSI/MMR testing
If specified in the indication, patient selection for treatment with KEYTRUDA based on MSI-H/dMMR tumour status should be confirmed by a validated test (see sections 4.1 and 5.1).
Posology
The recommended dose of KEYTRUDA solution for injection in adults and in adolescents with melanoma or cHL aged 12 years and older who weigh greater than 40 kg is either:
- 395 mg every 3 weeks administered as a subcutaneous injection over 1 minute or - 790 mg every 6 weeks administered as a subcutaneous injection over 2 minutes.
For use in combination, see the Summary of Product Characteristics (SmPC) for the concomitant therapies.
Patients should be treated with KEYTRUDA until disease progression or unacceptable toxicity (and up to maximum duration of therapy if specified for an indication). 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, NSCLC, or RCC, KEYTRUDA should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year.
For the neoadjuvant and adjuvant treatment of resectable NSCLC, patients should be treated with neoadjuvant KEYTRUDA in combination with chemotherapy for 4 doses of 395 mg every 3 weeks or 2 doses of 790 mg every 6 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as monotherapy for 13 doses of 395 mg every 3 weeks or 7 doses of 790 mg every 6 weeks or until disease recurrence or unacceptable toxicity. Patients who experience disease progression that precludes definitive surgery or unacceptable toxicity related to KEYTRUDA as neoadjuvant treatment in combination with chemotherapy should not receive KEYTRUDA monotherapy as adjuvant treatment.
For the neoadjuvant and adjuvant treatment of cisplatin-ineligible MIBC, patients should be treated with neoadjuvant KEYTRUDA in combination with enfortumab vedotin for 3 doses of 395 mg every 3 weeks or until disease progression that precludes radical cystectomy or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA in combination with enfortumab vedotin for 14 doses of 395 mg every 3 weeks or 7 doses of 790 mg every 6 weeks or until disease recurrence or unacceptable toxicity.
For the neoadjuvant and adjuvant treatment of resectable locally advanced HNSCC, patients should be treated with neoadjuvant KEYTRUDA as monotherapy for 2 doses of 395 mg every 3 weeks or 1 dose of 790 mg or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA in combination with radiation with or without concomitant cisplatin for 3 doses of 395 mg every 3 weeks or 2 doses of 790 mg every 6 weeks followed by KEYTRUDA as monotherapy for 12 doses of 395 mg every 3 weeks or 6 doses of 790 mg every 6 weeks or until disease recurrence or unacceptable toxicity. Patients who experience disease progression that precludes definitive surgery or unacceptable toxicity related to KEYTRUDA monotherapy as neoadjuvant treatment should not receive KEYTRUDA in combination with radiation with or without concomitant cisplatin as adjuvant treatment.

For the neoadjuvant and adjuvant treatment of TNBC, patients should be treated with neoadjuvant KEYTRUDA in combination with chemotherapy for 8 doses of 395 mg every 3 weeks or 4 doses of 790 mg every 6 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as monotherapy for 9 doses of 395 mg every 3 weeks or 5 doses of 790 mg every 6 weeks or until disease recurrence or unacceptable toxicity. Patients who experience disease progression that precludes definitive surgery or unacceptable toxicity related to KEYTRUDA as neoadjuvant treatment in combination with chemotherapy should not receive KEYTRUDA monotherapy as adjuvant treatment.
For locally advanced cervical cancer, patients should be treated with KEYTRUDA concurrent with chemoradiotherapy, followed by KEYTRUDA as monotherapy. KEYTRUDA can be administered as either 395 mg every 3 weeks or 790 mg every 6 weeks until disease progression, unacceptable toxicity or up to 24 months.
Dose delay or discontinuation (see also section 4.4)
No dose reductions of KEYTRUDA are recommended. KEYTRUDA should be withheld or discontinued to manage adverse reactions as described in Table 1.
Table 1: Recommended treatment modifications for KEYTRUDA
Immune-mediated adverse reactions
Severity
Treatment modification

Pneumonitis
Grade 2
Withhold until adverse reactions recover to
Grades 0-1*
Grades 3 or 4, or recurrent
Grade 2
Permanently discontinue

Colitis
Grades 2 or 3
Withhold until adverse reactions recover to
Grades 0-1*
Grade 4 or recurrent Grade 3
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

Immune-mediated adverse reactions
Severity
Treatment modification
Hypothyroidism
Hypothyroidism may be managed with replacement therapy without treatment interruption.

For RCC patients treated with KEYTRUDA in combination with axitinib, see the SmPC regarding dosing of axitinib. When used in combination with pembrolizumab, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer (see section 5.1).
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.
KEYTRUDA in combination with lenvatinib
When used in combination with lenvatinib, one or both medicines should be interrupted as appropriate. Lenvatinib should be withheld, dose reduced, or discontinued in accordance with the instructions in the lenvatinib SmPC for combination with pembrolizumab. No dose reductions are recommended for KEYTRUDA.
Patients treated with KEYTRUDA must be given the patient card and be informed about the risks of KEYTRUDA (see also package leaflet).
Special populations
Elderly
No dose adjustment is necessary in patients ≥ 65 years (see sections 4.4 and 5.1).
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 (see sections 4.4 and 5.2).
Hepatic impairment
No dose adjustment is needed for patients with mild or moderate hepatic impairment. KEYTRUDA has not been studied in patients with severe hepatic impairment (see sections 4.4 and 5.2).
Paediatric population
The safety and efficacy of KEYTRUDA solution for injection have not been established in paediatric patients except for adolescents aged 12 years and older with melanoma or cHL. A recommended dose for adolescents aged 12 years and older who weigh 40 kg or less has not been established (see sections 4.8, 5.1 and 5.2).
Method of administration
It is important to check the vial label to ensure that the correct formulation (intravenous or subcutaneous) is being prepared and administered to the patient as prescribed, to reduce the risk of medication errors.
KEYTRUDA solution for injection is for subcutaneous use only. Do not administer
KEYTRUDA solution for injection intravenously.
KEYTRUDA solution for injection should not be substituted for or with intravenous pembrolizumab because they have different recommended dosages and routes of administration.
KEYTRUDA solution for injection is for subcutaneous injection into the thigh or abdomen only.
Prior to administration, remove KEYTRUDA solution for injection from refrigeration and allow the solution to reach room temperature for at least 30 minutes. For instructions on the use and handling of KEYTRUDA solution for injection prior to administration, refer to section 6.6.

Inject KEYTRUDA solution for injection into the subcutaneous tissue of the thigh or abdomen, avoiding the 5 cm area around the navel. Do not inject into skin that is damaged, sore, bruised, scarred, scaly, or has red patches. Rotate injection sites for subsequent injections.
During treatment with KEYTRUDA solution for injection, do not administer other medicinal products for subcutaneous use at the same site as KEYTRUDA solution for injection.
When administering KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be administered first.
When administering KEYTRUDA as part of a combination with enfortumab vedotin, KEYTRUDA should be administered after enfortumab vedotin when given on the same day.

4.3 (1.2+, 31.5+)

Applies to: KEYTRUDA 25 mg/mL concentrate for solution for infusion

% with duration ≥ 6 months
54%
34%
*
Cetuximab, platinum, and 5-FU
†
Based on the stratified Cox proportional hazard model
‡
Based on stratified log-rank test
§
Response: Best objective response as confirmed complete response or partial response ¶ Based on Miettinen and Nurminen method stratified by ECOG (0 vs. 1), HPV status (positive vs.

negative) and PD-L1 status (strongly positive vs. not strongly positive)

Figure 31: Kaplan-Meier curve for overall survival for pembrolizumab plus chemotherapy in KEYNOTE-048 with PD-L1 expression (CPS ≥ 1)

Treatment arm OS rate at 12 months OS rate at 24 months HR (95% CI) p-value Pembrolizumab + Chemo 55% 31% 0.65 (0.53, 0.80) 0.00002 Standard 44% 17% Time in Months Overall Survival (%) Number at Risk Pembrolizumab + Chemo:
Standard:

Table 33: Efficacy results for pembrolizumab as monotherapy in KEYNOTE-048 with PD-L1 expression (CPS ≥ 1) Endpoint Pembrolizumab n=257 Standard Treatment* n=255 OS Number (%) of patients with event 197 (77%) 229 (90%) Median in months (95% CI)

Applies to: KEYTRUDA 395 mg solution for injection / KEYTRUDA 790 mg solution for injection

negative) and PD-L1 status (strongly positive vs. not strongly positive)

Figure 31: Kaplan-Meier curve for overall survival for pembrolizumab plus chemotherapy in KEYNOTE-048 with PD-L1 expression (CPS ≥ 1)

Table 34: Efficacy results for pembrolizumab as monotherapy in KEYNOTE-048 with PD-L1 expression (CPS ≥ 1) Endpoint Pembrolizumab n=257 Standard Treatment* n=255 OS Number (%) of patients with event 197 (77%) 229 (90%) Median in months (95% CI)

4.8 Undesirable effects

Applies to: KEYTRUDA 25 mg/mL concentrate for solution for infusion

Summary of the safety profile
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 in Table 2 are based on all reported adverse drug reactions, regardless of the investigator assessment of causality.
Pembrolizumab in monotherapy (see section 4.2)
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.
Pembrolizumab in combination with chemotherapy, radiation therapy (RT) or chemoradiotherapy (CRT) (see section 4.2) When pembrolizumab is administered in combination, refer to the SmPC for the respective combination therapy components prior to initiation of treatment.
The safety of pembrolizumab in combination with chemotherapy, RT or CRT has been evaluated in 7 015 patients across tumour types receiving 200 mg, 2 mg/kg bw or 10 mg/kg bw pembrolizumab every 3 weeks or 400 mg pembrolizumab every 6 weeks, in clinical studies. In this patient population, the most frequent adverse reactions were anaemia (51%), nausea (50%), fatigue (36%), diarrhoea (35%), constipation (32%), vomiting (27%), and decreased appetite (26%). Incidences of Grades 3-5 adverse reactions in patients with NSCLC were 69% for pembrolizumab combination therapy and 61% for chemotherapy alone, in patients with HNSCC were 80% for pembrolizumab combination therapy (chemotherapy or RT with or without chemotherapy), and 79% for chemotherapy plus cetuximab or RT with or without chemotherapy, 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 alone, in patients with cervical cancer were 77% for pembrolizumab combination therapy (chemotherapy with or without bevacizumab or in combination with CRT) and 71% for chemotherapy with or without bevacizumab or CRT alone, in patients with gastric cancer were 74% for pembrolizumab combination therapy (chemotherapy with or without trastuzumab) and 68% for chemotherapy with or without trastuzumab, in patients with biliary tract carcinoma were 85% for pembrolizumab combination therapy and 84% for chemotherapy alone, in patients with EC were 59% for pembrolizumab combination therapy and 46% for chemotherapy alone, in patients with malignant pleural

mesothelioma were 44% for pembrolizumab combination therapy and 30% for chemotherapy alone and in patients with ovarian cancer were 83% for pembrolizumab combination therapy (chemotherapy with or without bevacizumab) and 71% for chemotherapy with or without bevacizumab.
Pembrolizumab in combination with tyrosine kinase inhibitor (TKI) (see section 4.2) When pembrolizumab is administered in combination with axitinib or lenvatinib, refer to the SmPC for axitinib or lenvatinib prior to initiation of treatment. For additional 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 pembrolizumab in combination with lenvatinib and 73% for chemotherapy alone.
Tabulated summary of adverse reactions
Adverse reactions observed in clinical studies of pembrolizumab as monotherapy or in combination with chemotherapy, RT or CRT or other anti-tumour medicines 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†
MedDRA SOC and frequency category
Monotherapy
In combination with chemotherapy, radiation therapy or chemoradiotherapy
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 haemolytic anaemia⁎, eosinophilia eosinophilia

MedDRA SOC and frequency category
Monotherapy
In combination with chemotherapy, radiation therapy or chemoradiotherapy
In combination with axitinib or lenvatinib
Rare haemolytic anaemia⁎, haemophagocytic lymphohistiocytosis, pure red cell aplasia 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⁎, hyperthyroidism⁎, thyroiditis⁎ 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 dizziness, neuropathy peripheral, lethargy Uncommon myasthenic syndrome⁎¶, epilepsy encephalitis⁎, lethargy myasthenic syndrome⁎¶, encephalitis⁎ Rare Guillain-Barré syndrome⁎, encephalitis⁎, myelitis⁎, optic neuritis, meningitis (aseptic)⁎ myasthenic syndrome⁎¶, Guillain-Barré syndrome⁎, myelitis, optic neuritis, epilepsy, meningitis (aseptic) optic neuritis Eye disorders Common dry eye dry eye dry eye Uncommon uveitis⁎ uveitis⁎ uveitis⁎

MedDRA SOC and frequency category
Monotherapy
In combination with chemotherapy, radiation therapy or chemoradiotherapy
In combination with axitinib or lenvatinib
Rare
Vogt-Koyanagi-Har ada syndrome
Vogt-Koyanagi-Harad a syndrome
Cardiac disorders
Common cardiac arrhythmia‡
(including atrial fibrillation) cardiac arrhythmia‡
(including atrial fibrillation) cardiac arrhythmia‡
(including atrial fibrillation)
Uncommon myocarditis¶, pericarditis⁎, pericardial effusion myocarditis⁎¶, pericarditis⁎, pericardial effusion 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, nausea, vomiting, 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

MedDRA SOC and frequency category
Monotherapy
In combination with chemotherapy, radiation therapy or chemoradiotherapy
In combination with axitinib or lenvatinib
Uncommon psoriasis, lichenoid keratosis⁎, papule, hair colour changes psoriasis, lichenoid keratosis⁎, vitiligo⁎, papule eczema, lichenoid keratosis⁎, psoriasis, vitiligo⁎, papule, hair colour changes Rare Stevens-Johnson syndrome, erythema nodosum, toxic epidermal necrolysis Stevens-Johnson syndrome, erythema nodosum, hair colour changes toxic epidermal necrolysis, Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders Very common musculoskeletal pain⁎, arthralgia arthralgia, musculoskeletal pain⁎ 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, oedema⁎ fatigue, asthenia, oedema⁎, pyrexia Common influenza-like illness, chills 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 blood 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

- haemolytic anaemia (autoimmune haemolytic anaemia and Coombs negative haemolytic anaemia)
- infusion-related reaction (drug hypersensitivity, anaphylactic reaction, anaphylactoid reaction, hypersensitivity, infusion-related hypersensitivity reaction, cytokine release syndrome and serum sickness)
- sarcoidosis (cutaneous sarcoidosis and pulmonary sarcoidosis)
- hypothyroidism (myxoedema, immune-mediated hypothyroidism and autoimmune hypothyroidism)
- adrenal insufficiency (Addison’s disease, adrenocortical insufficiency acute, secondary adrenocortical insufficiency and primary adrenal insufficiency)
- thyroiditis (autoimmune thyroiditis, silent thyroiditis, thyroid disorder, thyroiditis acute and immune-mediated thyroiditis)
- hyperthyroidism (Graves' disease)
- hypophysitis (hypopituitarism and lymphocytic hypophysitis)
- type 1 diabetes mellitus (diabetic ketoacidosis)
- myasthenic syndrome (myasthenia gravis, including exacerbation)
- encephalitis (autoimmune encephalitis and noninfective encephalitis)
- Guillain-Barré syndrome (axonal neuropathy and demyelinating polyneuropathy)
- myelitis (including transverse myelitis)
- meningitis aseptic (meningitis and meningitis noninfective)
- uveitis (chorioretinitis, iritis and iridocyclitis)
- myocarditis (autoimmune myocarditis and immune-mediated myocarditis)
- pericarditis (autoimmune pericarditis, pleuropericarditis and myopericarditis)
- vasculitis (central nervous system vasculitis, aortitis and giant cell arteritis)
- pneumonitis (interstitial lung disease, organising pneumonia, immune-mediated pneumonitis, immune-mediated lung disease and autoimmune lung disease)
- abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower)
- colitis (colitis microscopic, enterocolitis, enterocolitis haemorrhagic, autoimmune colitis and immune-mediated enterocolitis)
- gastritis (gastritis erosive, gastritis haemorrhagic and immune-mediated gastritis)
- pancreatitis (autoimmune pancreatitis, pancreatitis acute and immune-mediated pancreatitis)
- gastrointestinal ulceration (gastric ulcer and duodenal ulcer)
- hepatitis (autoimmune hepatitis, immune-mediated hepatitis, drug induced liver injury and acute hepatitis)
- cholangitis sclerosing (immune-mediated cholangitis)
- pruritus (urticaria, urticaria papular and pruritus genital)
- rash (rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular and genital rash)
- severe skin reactions (exfoliative rash, pemphigus, and Grade ≥ 3 of the following: cutaneous vasculitis, dermatitis bullous, dermatitis exfoliative, dermatitis exfoliative generalised, erythema multiforme, lichen planus, oral lichen planus, pemphigoid, pruritus, pruritus genital, rash, rash erythematous, rash maculo-papular, rash pruritic, rash pustular, skin necrosis and toxic skin eruption)
- vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid)
- lichenoid keratosis (lichen planus and lichen sclerosus)
- musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain and torticollis)
- myositis (myalgia, myopathy, necrotising myositis, polymyalgia rheumatica and rhabdomyolysis)
- arthritis (joint swelling, polyarthritis, joint effusion, autoimmune arthritis and immune-mediated arthritis)
- tenosynovitis (tendonitis, synovitis and tendon pain)
- nephritis (autoimmune nephritis, immune-mediated nephritis, tubulointerstitial nephritis, renal failure, renal failure acute, or acute kidney injury with evidence of nephritis, nephrotic syndrome, glomerulonephritis, glomerulonephritis membranous and glomerulonephritis acute)
- oedema (oedema peripheral, generalised oedema, fluid overload, fluid retention, eyelid oedema, lip oedema, face oedema, localised oedema and periorbital oedema) Pembrolizumab in combination with enfortumab vedotin (see section 4.2) 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.
The safety of pembrolizumab in combination with enfortumab vedotin has been evaluated among 167 patients with MIBC receiving 200 mg pembrolizumab on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle as neoadjuvant treatment and continued after radical cystectomy as adjuvant treatment. 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. Adverse reactions were generally similar to those occurring in patients with unresectable or metastatic urothelial carcinoma treated with pembrolizumab in combination with enfortumab vedotin.
Description of selected adverse reactions
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.
Immune-mediated adverse reactions (see section 4.4)
Immune-mediated pneumonitis
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 sequelae.
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.
Immune-mediated colitis
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 colitis was 6.5% (all Grades) with 2.0% Grade 3 and 1.3% Grade 4.
Immune-mediated hepatitis
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 pembrolizumab in 37 (0.5%) patients. Hepatitis resolved in 60 patients.
Immune-mediated nephritis
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.
Immune-mediated endocrinopathies
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 discontinuation 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 recurrent or metastatic 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 recurrent or metastatic HNSCC treated with pembrolizumab in combination with platinum and 5-FU chemotherapy (n=276), the incidence of hypothyroidism was 15.2%, all of which were Grade 1 or 2. In patients with resectable locally advanced HNSCC treated with pembrolizumab as neoadjuvant treatment and in combination with radiation therapy with or without concomitant cisplatin for adjuvant treatment (n=361), the incidence of hypothyroidism was 24.7%, 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 skin adverse reactions
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).
Complications of allogeneic HSCT in cHL
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 engraftment 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 hepatic 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.
Elevated liver enzymes when pembrolizumab is combined with axitinib in RCC
In a clinical study of previously untreated patients with RCC receiving 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.
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: 9.9% for lymphocytes decreased, 7.3% for sodium decreased, 5.7% for haemoglobin decreased, 4.6% for glucose increased, 4.5% for phosphate decreased, 3.1% for ALT increased, 2.9% for AST increased, 2.6% for alkaline phosphatase increased, 2.2% for potassium decreased, 2.1% for neutrophils decreased, 1.7% for bilirubin increased, 1.7% for platelets decreased, 1.7% for potassium increased, 1.6% for calcium increased, 1.4% for albumin decreased, 1.3% for calcium decreased, 1.2% for creatinine increased, 0.8% for leukocytes decreased, 0.8% for magnesium increased, 0.6% for glucose decreased, 0.2% for magnesium decreased, and 0.2% for sodium increased.
In patients treated with pembrolizumab in combination with chemotherapy, RT or CRT, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 36.4% for neutrophils decreased, 31.7% for lymphocytes decreased, 23.7% for leukocytes decreased, 20.2% for haemoglobin decreased, 11.4% for platelets decreased, 9.5% for sodium decreased, 7.8% for potassium decreased, 7.2% for phosphate decreased, 5.5% for glucose increased, 5.3% for ALT increased, 4.7% for AST increased, 3.4% for calcium decreased, 3.1% for creatinine increased, 3.0% for bilirubin increased, 3.0% for potassium increased, 2.4% for albumin decreased, 2.3% for alkaline phosphatase increased, 1.6% for calcium increased, 0.9% for glucose decreased, 0.4% for sodium increased and 0.2% 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), 12.3% 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 phosphate decreased, 6.1% for potassium decreased, 5.1% for potassium increased, 4.5% for cholesterol increased, 4.4% for creatinine increased, 4.2% for haemoglobin decreased, 4.0% for neutrophils decreased, 3.1% for alkaline phosphatase increased, 3.0% for platelets decreased, 2.8% for bilirubin increased, 2.2% for calcium decreased, 2.2% for magnesium increased, 1.7% for leukocytes decreased, 1.5% for magnesium decreased, 1.5% for prothrombin INR increased, 1.4% for glucose decreased, 1.2% for albumin decreased, 1.0% for calcium increased, 0.4% for sodium increased, and 0.1% for haemoglobin increased.
Immunogenicity
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 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 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 patients 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 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.

Applies to: KEYTRUDA 395 mg solution for injection / KEYTRUDA 790 mg solution for injection

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.
Pembrolizumab in combination with chemotherapy, radiation therapy (RT) or chemoradiotherapy (CRT) (see section 4.2) When pembrolizumab is administered in combination, refer to the SmPC for the respective combination therapy components prior to initiation of treatment.
The safety of intravenous pembrolizumab in combination with chemotherapy, RT or CRT has been evaluated in 7 015 patients across tumour types receiving 200 mg, 2 mg/kg bw or 10 mg/kg bw pembrolizumab every 3 weeks or 400 mg pembrolizumab every 6 weeks, in clinical studies. In this patient population, the most frequent adverse reactions were anaemia (51%), nausea (50%), fatigue (36%), diarrhoea (35%), constipation (32%), vomiting (27%), and decreased appetite (26%).
Incidences of Grades 3-5 adverse reactions in patients with NSCLC were 69% for pembrolizumab combination therapy and 61% for chemotherapy alone, in patients with HNSCC were 80% for pembrolizumab combination therapy (chemotherapy or RT with or without chemotherapy), and 79% for chemotherapy plus cetuximab or RT with or without chemotherapy, 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 alone, in patients with cervical cancer were 77% for pembrolizumab combination therapy (chemotherapy with or without bevacizumab or in combination with CRT) and 71% for chemotherapy with or without bevacizumab or CRT alone, in patients with gastric cancer were 74% for pembrolizumab combination therapy (chemotherapy with or without trastuzumab) and 68% for chemotherapy with or without trastuzumab, in patients with biliary tract carcinoma were 85% for pembrolizumab combination therapy and 84% for chemotherapy alone, in patients with EC were 59% for pembrolizumab combination therapy and 46% for chemotherapy alone, in patients with malignant pleural mesothelioma were 44% for pembrolizumab combination therapy and 30% for chemotherapy alone and in patients with ovarian cancer were 83% for pembrolizumab combination therapy (chemotherapy with or without bevacizumab) and 71% for chemotherapy with or without bevacizumab.
Pembrolizumab in combination with tyrosine kinase inhibitor (TKI) (see section 4.2) When pembrolizumab is administered in combination with axitinib or lenvatinib, refer to the SmPC for axitinib or lenvatinib prior to initiation of treatment. For additional 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 intravenous 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 pembrolizumab in combination with lenvatinib and 73% for chemotherapy alone.

Tabulated summary of adverse reactions
Adverse reactions observed in clinical studies of intravenous pembrolizumab as monotherapy or in combination with chemotherapy, RT or CRT or other anti-tumour medicines 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†
MedDRA SOC and frequency category
Monotherapy
In combination with chemotherapy, radiation therapy or chemoradiotherapy
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 haemolytic anaemia⁎, eosinophilia eosinophilia Rare haemolytic anaemia⁎, haemophagocytic lymphohistiocytosis, pure red cell aplasia 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

MedDRA SOC and frequency category
Monotherapy
In combination with chemotherapy, radiation therapy or chemoradiotherapy
In combination with axitinib or lenvatinib
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 dizziness, neuropathy peripheral, lethargy Uncommon myasthenic syndrome⁎¶, epilepsy encephalitis⁎, lethargy myasthenic syndrome⁎¶, encephalitis⁎ Rare Guillain-Barré syndrome⁎, encephalitis⁎, myelitis⁎, optic neuritis, meningitis (aseptic)⁎ myasthenic syndrome⁎¶, Guillain-Barré syndrome⁎, myelitis, optic neuritis, epilepsy, meningitis (aseptic) optic neuritis Eye disorders Common dry eye dry eye dry eye Uncommon uveitis⁎ uveitis⁎ uveitis⁎ Rare Vogt-Koyanagi-Har ada syndrome Vogt-Koyanagi-Harad a syndrome Cardiac disorders Common cardiac arrhythmia‡ (including atrial fibrillation) cardiac arrhythmia‡ (including atrial fibrillation) cardiac arrhythmia‡ (including atrial fibrillation) Uncommon myocarditis¶, pericarditis⁎, pericardial effusion myocarditis⁎¶, pericarditis⁎, pericardial effusion myocarditis¶, pericardial effusion Vascular disorders Very common

hypertension
Common hypertension hypertension
Uncommon

MedDRA SOC and frequency category
Monotherapy
In combination with chemotherapy, radiation therapy or chemoradiotherapy
In combination with axitinib or lenvatinib
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⁎, dermatitis, erythema, dry skin, dermatitis acneiform, eczema severe skin reactions⁎, dermatitis, dry skin, erythema, dermatitis acneiform, alopecia Uncommon psoriasis, lichenoid keratosis⁎, papule, hair colour changes psoriasis, lichenoid keratosis⁎, vitiligo⁎, papule eczema, lichenoid keratosis⁎, psoriasis, vitiligo⁎, papule, hair colour changes Rare Stevens-Johnson syndrome, erythema nodosum, toxic epidermal necrolysis Stevens-Johnson syndrome, erythema nodosum, hair colour changes toxic epidermal necrolysis, Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders Very common musculoskeletal pain⁎, arthralgia arthralgia, musculoskeletal pain⁎ 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

MedDRA SOC and frequency category
Monotherapy
In combination with chemotherapy, radiation therapy or chemoradiotherapy
In combination with axitinib or lenvatinib
Common influenza-like illness, chills influenza-like illness, chills, injection site reaction§ influenza-like illness, chills Investigations Very common

†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.
¶Myocarditis, myositis, myasthenia gravis can occur simultaneously (as myocarditis-myositis-myasthenia gravis overlap syndrome).
§Reported in a study outside of the pooled dataset (subcutaneous injection related). The frequency is based on exposure to KEYTRUDA solution for injection in MK-3475A-D77 and includes injection site reaction, injection site erythema, injection site haemorrhage, injection site induration and injection site pain.
⁎ The following terms represent a group of related events that describe a medical condition rather than a single event:
- haemolytic anaemia (autoimmune haemolytic anaemia and Coombs negative haemolytic anaemia)
- infusion-related reaction (drug hypersensitivity, anaphylactic reaction, anaphylactoid reaction, hypersensitivity, infusion-related hypersensitivity reaction, cytokine release syndrome and serum sickness)
- sarcoidosis (cutaneous sarcoidosis and pulmonary sarcoidosis)
- hypothyroidism (myxoedema, immune-mediated hypothyroidism and autoimmune hypothyroidism)
- adrenal insufficiency (Addison’s disease, adrenocortical insufficiency acute, secondary adrenocortical insufficiency and primary adrenal insufficiency)
- thyroiditis (autoimmune thyroiditis, silent thyroiditis, thyroid disorder, thyroiditis acute and immune-mediated thyroiditis)
- hyperthyroidism (Graves' disease)
- hypophysitis (hypopituitarism and lymphocytic hypophysitis)
- type 1 diabetes mellitus (diabetic ketoacidosis)
- myasthenic syndrome (myasthenia gravis, including exacerbation)
- encephalitis (autoimmune encephalitis and noninfective encephalitis)
- Guillain-Barré syndrome (axonal neuropathy and demyelinating polyneuropathy)
- myelitis (including transverse myelitis)
- meningitis aseptic (meningitis and meningitis noninfective)
- uveitis (chorioretinitis, iritis and iridocyclitis)
- myocarditis (autoimmune myocarditis and immune-mediated myocarditis)
- pericarditis (autoimmune pericarditis, pleuropericarditis and myopericarditis)
- vasculitis (central nervous system vasculitis, aortitis and giant cell arteritis)
- pneumonitis (interstitial lung disease, organising pneumonia, immune-mediated pneumonitis, immune-mediated lung disease and autoimmune lung disease)
- abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower)
- colitis (colitis microscopic, enterocolitis, enterocolitis haemorrhagic, autoimmune colitis and immune-mediated enterocolitis)

- gastritis (gastritis erosive, gastritis haemorrhagic and immune-mediated gastritis)
- pancreatitis (autoimmune pancreatitis, pancreatitis acute and immune-mediated pancreatitis)
- gastrointestinal ulceration (gastric ulcer and duodenal ulcer)
- hepatitis (autoimmune hepatitis, immune-mediated hepatitis, drug induced liver injury and acute hepatitis)
- cholangitis sclerosing (immune-mediated cholangitis)
- pruritus (urticaria, urticaria papular and pruritus genital)
- rash (rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular and genital rash)
- severe skin reactions (exfoliative rash, pemphigus, and Grade ≥ 3 of the following: cutaneous vasculitis, dermatitis bullous, dermatitis exfoliative, dermatitis exfoliative generalised, erythema multiforme, lichen planus, oral lichen planus, pemphigoid, pruritus, pruritus genital, rash, rash erythematous, rash maculo-papular, rash pruritic, rash pustular, skin necrosis and toxic skin eruption)
- vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid)
- lichenoid keratosis (lichen planus and lichen sclerosus)
- musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain and torticollis)
- myositis (myalgia, myopathy, necrotising myositis, polymyalgia rheumatica and rhabdomyolysis)
- arthritis (joint swelling, polyarthritis, joint effusion, autoimmune arthritis and immune-mediated arthritis)
- tenosynovitis (tendonitis, synovitis and tendon pain)
- nephritis (autoimmune nephritis, immune-mediated nephritis, tubulointerstitial nephritis, renal failure, renal failure acute, or acute kidney injury with evidence of nephritis, nephrotic syndrome, glomerulonephritis, glomerulonephritis membranous and glomerulonephritis acute)
- oedema (oedema peripheral, generalised oedema, fluid overload, fluid retention, eyelid oedema, lip oedema, face oedema, localised oedema and periorbital oedema) Pembrolizumab in combination with enfortumab vedotin (see section 4.2) When pembrolizumab is administered in combination with enfortumab vedotin, refer to the SmPC for enfortumab vedotin prior to initiation of treatment.
The safety of intravenous 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.
The safety of intravenous pembrolizumab in combination with enfortumab vedotin has been evaluated among 167 patients with MIBC receiving 200 mg pembrolizumab on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle as neoadjuvant treatment and continued after radical cystectomy as adjuvant treatment. 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. Adverse reactions were generally similar to those occurring in patients with unresectable or metastatic urothelial carcinoma treated with pembrolizumab in combination with enfortumab vedotin.
Description of selected adverse reactions
Data for the following immune-mediated adverse reactions are based on patients who received intravenous 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.

Immune-mediated adverse reactions (see section 4.4)
Immune-mediated pneumonitis
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 sequelae.
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.
Immune-mediated colitis
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 colitis was 6.5% (all Grades) with 2.0% Grade 3 and 1.3% Grade 4.
Immune-mediated hepatitis
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 pembrolizumab in 37 (0.5%) patients. Hepatitis resolved in 60 patients.
Immune-mediated nephritis
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.
Immune-mediated endocrinopathies
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 discontinuation 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 recurrent or metastatic 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 recurrent or metastatic HNSCC treated with pembrolizumab in combination with platinum and 5-FU chemotherapy (n=276), the incidence of hypothyroidism was 15.2%, all of which were Grade 1 or 2. In patients with resectable locally advanced HNSCC treated with pembrolizumab as neoadjuvant treatment and in combination with radiation therapy with or without concomitant cisplatin for adjuvant treatment (n=361), the incidence of hypothyroidism was 24.7%, 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 skin adverse reactions
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).
Complications of allogeneic HSCT in cHL
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 engraftment 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 hepatic 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.

Elevated liver enzymes when pembrolizumab is combined with axitinib in RCC
In a clinical study of previously untreated patients with RCC receiving 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.
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: 9.9% for lymphocytes decreased, 7.3% for sodium decreased, 5.7% for haemoglobin decreased, 4.6% for glucose increased, 4.5% for phosphate decreased, 3.1% for ALT increased, 2.9% for AST increased, 2.6% for alkaline phosphatase increased, 2.2% for potassium decreased, 2.1% for neutrophils decreased, 1.7% for bilirubin increased, 1.7% for platelets decreased, 1.7% for potassium increased, 1.6% for calcium increased, 1.4% for albumin decreased, 1.3% for calcium decreased, 1.2% for creatinine increased, 0.8% for leukocytes decreased, 0.8% for magnesium increased, 0.6% for glucose decreased, 0.2% for magnesium decreased, and 0.2% for sodium increased.
In patients treated with pembrolizumab in combination with chemotherapy, RT or CRT, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 36.4% for neutrophils decreased, 31.7% for lymphocytes decreased, 23.7% for leukocytes decreased, 20.2% for haemoglobin decreased, 11.4% for platelets decreased, 9.5% for sodium decreased, 7.8% for potassium decreased, 7.2% for phosphate decreased, 5.5% for glucose increased, 5.3% for ALT increased, 4.7% for AST increased, 3.4% for calcium decreased, 3.1% for creatinine increased, 3.0% for bilirubin increased, 3.0% for potassium increased, 2.4% for albumin decreased, 2.3% for alkaline phosphatase increased, 1.6% for calcium increased, 0.9% for glucose decreased, 0.4% for sodium increased and 0.2% 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), 12.3% 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 phosphate decreased, 6.1% for potassium decreased, 5.1% for potassium increased, 4.5% for cholesterol increased, 4.4% for creatinine increased, 4.2% for haemoglobin decreased, 4.0% for neutrophils decreased, 3.1% for alkaline phosphatase increased, 3.0% for platelets decreased, 2.8% for bilirubin increased, 2.2% for calcium decreased, 2.2% for magnesium increased, 1.7% for leukocytes decreased, 1.5% for magnesium decreased, 1.5% for prothrombin INR increased, 1.4% for glucose decreased, 1.2% for albumin decreased, 1.0% for calcium increased, 0.4% for sodium increased, and 0.1% for haemoglobin increased.
Immunogenicity
In a clinical study in patients treated with subcutaneous administration of KEYTRUDA solution for injection 790 mg every 6 weeks or intravenous administration of pembrolizumab 400 mg every 6 weeks, with a median duration of treatment on subcutaneous pembrolizumab exceeding 6 months (range: 1 day to 12.5 months), 1.4% (3/211) of patients developed treatment-emergent anti- pembrolizumab antibodies and 0.5% (1/211) developed neutralising antibodies. In the intravenous pembrolizumab arm, 0.9% (1/114) of patients developed treatment-emergent anti-pembrolizumab antibodies and 0% (0/114) developed neutralising antibodies. There was no evidence of an altered pharmacokinetic or safety profile with anti-pembrolizumab binding or neutralising antibody development. The pembrolizumab immunogenicity profile of subcutaneous pembrolizumab was consistent with the known immunogenicity profile of intravenous pembrolizumab.

The incidence of treatment-emergent anti-recombinant berahyaluronidase alfa antibodies was 1.5% (3/194) with low titer values reported for all three subjects and no detectable systemic concentration of recombinant berahyaluronidase alfa. The clinical relevance of the development of anti-recombinant berahyaluronidase alfa antibodies after treatment with subcutaneous pembrolizumab is unknown.
Paediatric population
Subcutaneous formulation
The safety of pembrolizumab solution for injection for the treatment of melanoma and cHL in adolescents aged 12 years and older who weigh greater than 40 kg is extrapolated from studies of intravenous pembrolizumab in adults. In addition, pharmacokinetic modeling and simulation analyses showed similar pembrolizumab exposures in adolescents aged 12 years and older who weigh greater than 40 kg compared to adults suggesting a similar safety profile to adult patients (see sections 5.1 and 5.2).
Intravenous formulation
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 patients 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 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.

4.4 Special warnings and precautions for use

Applies to: KEYTRUDA 25 mg/mL concentrate for solution for infusion

Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Assessment of PD-L1 status
When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is chosen to minimise false negative or false positive determinations.
Immune-mediated adverse reactions
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, administration 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 reaction toxicity, except for endocrinopathies that are controlled with replacement hormones (see sections 4.2 and 4.8).
In patients with pre-existing autoimmune disease (AID), data from observational studies suggest that the risk of immune-mediated adverse reactions following immune-checkpoint inhibitor therapy may be increased as compared with the risk in patients without pre-existing AID. In addition, flares of the underlying AID were frequent, but the majority were mild and manageable.
Immune-mediated 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-mediated 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 or recurrent Grade 3 colitis (see section 4.2). The potential risk of gastrointestinal perforation should be taken into consideration.
Immune-mediated 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-mediated 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-mediated endocrinopathies
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 insufficiency 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 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 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 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. 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 skin adverse reactions
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.
Other immune-mediated adverse reactions
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, hypoparathyroidism, pericarditis and myocarditis-myositis-myasthenia gravis overlap syndrome (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).
Transplant-related adverse reactions
Solid organ transplant rejection
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 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.
Infusion-related reactions
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.
Use of pembrolizumab in combination with chemotherapy
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).
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 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.
Use of pembrolizumab in urothelial carcinoma for patients who are considered ineligible for cisplatin-containing chemotherapy and whose tumours express PD-L1 with CPS ≥ 10 The baseline and prognostic disease characteristics of the study population of KEYNOTE-052 included a proportion of patients eligible for a carboplatin-based combination, for whom the benefit has been assessed in a comparative study (KEYNOTE-361). In KEYNOTE-361, a higher number of deaths within 6 months of treatment initiation followed by a long-term survival benefit was observed with 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 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 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).
Use of pembrolizumab for first-line treatment of patients with HNSCC
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).
Use of pembrolizumab for treatment of patients with advanced or recurrent MSI-H or dMMR endometrial carcinoma 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.
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.
Use of pembrolizumab in combination with axitinib for first-line treatment of patients with RCC 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).
Use of pembrolizumab for first-line treatment of patients with MSI-H/dMMR CRC
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).
Use of pembrolizumab for first-line treatment of patients with BTC
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 excluded from clinical studies
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 active 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 limited in patients with severe renal and moderate to severe hepatic impairment.
There are limited data on the safety and efficacy of KEYTRUDA in patients with ocular melanoma (see section 5.1).
After careful consideration of the potential increased risk, pembrolizumab may be used with appropriate medical management in these patients.
Excipients with known effect
This medicinal product contains 0.2 mg of polysorbate 80 in each mL of concentrate. Polysorbates may cause allergic reactions.
Patient 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 card with each prescription.

Applies to: KEYTRUDA 395 mg solution for injection / KEYTRUDA 790 mg solution for injection

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-mediated 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 or recurrent Grade 3 colitis (see section 4.2). The potential risk of gastrointestinal perforation should be taken into consideration.
Immune-mediated 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-mediated 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-mediated endocrinopathies
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 insufficiency 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 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 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 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. 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 skin adverse reactions
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.
Other immune-mediated adverse reactions
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, hypoparathyroidism, pericarditis and myocarditis-myositis-myasthenia gravis overlap syndrome (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).
Transplant-related adverse reactions
Solid organ transplant rejection
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 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.
Infusion-related reactions
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, injection should be stopped and pembrolizumab permanently discontinued (see section 4.2). Patients with Grades 1 or 2 infusion reactions may continue to receive pembrolizumab with close monitoring;
premedication with antipyretic and antihistamine may be considered.
Use of pembrolizumab in combination with chemotherapy
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).
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 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.
Use of pembrolizumab in urothelial carcinoma for patients who are considered ineligible for cisplatin-containing chemotherapy and whose tumours express PD-L1 with CPS ≥ 10 The baseline and prognostic disease characteristics of the study population of KEYNOTE-052 included a proportion of patients eligible for a carboplatin-based combination, for whom the benefit has been assessed in a comparative study (KEYNOTE-361). In KEYNOTE-361, a higher number of deaths within 6 months of treatment initiation followed by a long-term survival benefit was observed with 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 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 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).
Use of pembrolizumab for first-line treatment of patients with HNSCC
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).
Use of pembrolizumab for treatment of patients with advanced or recurrent MSI-H or dMMR endometrial carcinoma 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.
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.
Use of pembrolizumab in combination with axitinib for first-line treatment of patients with RCC 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).
Use of pembrolizumab for first-line treatment of patients with MSI-H/dMMR CRC
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).
Use of pembrolizumab for first-line treatment of patients with BTC
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 excluded from clinical studies
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 active 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 limited in patients with severe renal and moderate to severe hepatic impairment.
There are limited data on the safety and efficacy of KEYTRUDA in patients with ocular melanoma (see section 5.1).
After careful consideration of the potential increased risk, pembrolizumab may be used with appropriate medical management in these patients.
Excipients with known effect
Polysorbate
This medicinal product contains 0.2 mg of polysorbate 80 in each mL of solution. Polysorbates may cause allergic reactions.
Sodium
KEYTRUDA solution for injection contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.
Patient 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 card with each prescription.

4.5 (1.2+, 38.7+)

Applies to: KEYTRUDA 25 mg/mL concentrate for solution for infusion

% with duration ≥ 6 months
81%
36%
*
Cetuximab, platinum, and 5-FU
†
Based on the stratified Cox proportional hazard model
‡
Based on stratified log-rank test
§
Response: Best objective response as confirmed complete response or partial response ¶ Based on Miettinen and Nurminen method stratified by ECOG (0 vs. 1), HPV status (positive

vs. negative) and PD-L1 status (strongly positive vs. not strongly positive)

Figure 32: Kaplan-Meier curve for overall survival for pembrolizumab as monotherapy in KEYNOTE-048 with PD-L1 expression (CPS ≥ 1) An analysis was performed in KEYNOTE-048 in patients whose tumours expressed PD-L1 CPS ≥ 20 [pembrolizumab plus chemotherapy: n=126 (49%) vs. standard treatment: n=110 (43%) and pembrolizumab monotherapy: n=133 (52%) vs. standard treatment: n=122 (48%)] (see Table 34).
Table 34: Efficacy results for pembrolizumab plus chemotherapy and pembrolizumab as monotherapy by PD-L1 expression in KEYNOTE-048 (CPS ≥ 20) Endpoint Pembrolizumab + Platinum Chemotherapy + 5-FU n=126 Standard Treatment* n=110 Pembrolizumab Monotherapy n=133 Standard Treatment* n=122 OS Number (%) of patients with event 84 (66.7%) 98 (89.1%) 94 (70.7%) 108 (88.5%) Median in months (95% CI)

Applies to: KEYTRUDA 395 mg solution for injection / KEYTRUDA 790 mg solution for injection

vs. negative) and PD-L1 status (strongly positive vs. not strongly positive)

Figure 32: Kaplan-Meier curve for overall survival for pembrolizumab as monotherapy in KEYNOTE-048 with PD-L1 expression (CPS ≥ 1) An analysis was performed in KEYNOTE-048 in patients whose tumours expressed PD-L1 CPS ≥ 20 [pembrolizumab plus chemotherapy: n=126 (49%) vs. standard treatment: n=110 (43%) and pembrolizumab monotherapy: n=133 (52%) vs. standard treatment: n=122 (48%)] (see Table 35).
Table 35: Efficacy results for pembrolizumab plus chemotherapy and pembrolizumab as monotherapy by PD-L1 expression in KEYNOTE-048 (CPS ≥ 20) Endpoint Pembrolizumab + Platinum Chemotherapy + 5-FU n=126 Standard Treatment* n=110 Pembrolizumab Monotherapy n=133 Standard Treatment* n=122 OS Number (%) of patients with event 84 (66.7%) 98 (89.1%) 94 (70.7%) 108 (88.5%) Median in months (95% CI)

4.6 Fertility, pregnancy and lactation

Applies to: KEYTRUDA 25 mg/mL concentrate for solution for infusion · KEYTRUDA 395 mg solution for injection / KEYTRUDA 790 mg solution for injection

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 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.
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).

4.7 Effects on ability to drive and use machines

Applies to: KEYTRUDA 25 mg/mL concentrate for solution for infusion · KEYTRUDA 395 mg solution for injection / KEYTRUDA 790 mg solution for injection

Pembrolizumab has a minor influence on the ability to drive and use machines. In some patients, dizziness and fatigue have been reported following administration of pembrolizumab (see section 4.8).

4.9 (1.3+, 28.3+)

Applies to: KEYTRUDA 25 mg/mL concentrate for solution for infusion

% with duration ≥ 12 months¶
38%
25%
*
A total of 138 patients (51%) who discontinued study treatment in the placebo plus chemotherapy arm crossed over to receive monotherapy pembrolizumab or received a checkpoint inhibitor as subsequent therapy † Based on the stratified Cox proportional hazard model ‡ Based on stratified log-rank test § Based on method by Miettinen and Nurminen ¶ Based on Kaplan-Meier estimation

Figure 16: Kaplan-Meier Curve for Overall Survival in KEYNOTE-407

Treatment arm OS rate at 12 months OS rate at 18 months HR (95% CI) p-value Pembrolizumab 65% 48% 0.71 (0.58, 0.88) 0.0006 Control 50% 37% Overall Survival (%) Number at Risk Pembrolizumab:
Control :
Time in Months

Figure 17: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-407
An analysis was performed in KEYNOTE-407 in patients who had PD-L1 TPS < 1% [pembrolizumab plus chemotherapy arm: n=95 (34%) vs. placebo plus chemotherapy arm: n=99 (35%)], TPS 1% to 49% [pembrolizumab plus chemotherapy arm: n=103 (37%) vs. placebo plus chemotherapy arm:
n=104 (37%)] or TPS ≥ 50% [pembrolizumab plus chemotherapy arm: n=73 (26%) vs. placebo plus chemotherapy arm: n=73 (26%)] (see Table 19).
Table 19: Efficacy results by PD-L1 expression in KEYNOTE-407*
Endpoint
Pembrolizumab combination therapy
Chemotherapy
Pembrolizumab combination therapy
Chemotherapy
Pembrolizumab combination therapy
Chemotherapy

TPS < 1%
TPS 1 to 49%
TPS ≥ 50%
OS Hazard ratio†
(95% CI)

Applies to: KEYTRUDA 395 mg solution for injection / KEYTRUDA 790 mg solution for injection

Figure 16: Kaplan-Meier Curve for Overall Survival in KEYNOTE-407

Figure 17: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-407
An analysis was performed in KEYNOTE-407 in patients who had PD-L1 TPS < 1% [pembrolizumab plus chemotherapy arm: n=95 (34%) vs. placebo plus chemotherapy arm: n=99 (35%)], TPS 1% to 49% [pembrolizumab plus chemotherapy arm: n=103 (37%) vs. placebo plus chemotherapy arm:
n=104 (37%)] or TPS ≥ 50% [pembrolizumab plus chemotherapy arm: n=73 (26%) vs. placebo plus chemotherapy arm: n=73 (26%)] (see Table 20).
Table 20: Efficacy results by PD-L1 expression in KEYNOTE-407*
Endpoint
Pembrolizumab combination therapy
Chemotherapy
Pembrolizumab combination therapy
Chemotherapy
Pembrolizumab combination therapy
Chemotherapy

TPS < 1%
TPS 1 to 49%
TPS ≥ 50%
OS Hazard ratio†
(95% CI)

5.1 Pharmacodynamic properties

Applies to: KEYTRUDA 25 mg/mL concentrate for solution for infusion

Pharmacotherapeutic group: Antineoplastic agents, PD-1/PDL-1 (Programmed cell death protein 1/death ligand 1) inhibitors. ATC code: L01FF02

Mechanism of action
KEYTRUDA is a humanised monoclonal antibody which binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been shown to be involved in the control of T-cell immune responses. KEYTRUDA potentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour microenvironment.
The anti-angiogenic effect of lenvatinib (multi-TKI) in combination with the immune-stimulatory effect of pembrolizumab (anti-PD-1) results in a tumour microenvironment with greater T-cell activation to help overcome primary and acquired resistance to immunotherapy and may improve tumour responses compared to either treatment alone. In preclinical murine models, PD-1 plus TKI inhibitors have demonstrated enhanced anti-tumour activity compared to either agent alone.
Clinical efficacy and safety
Pembrolizumab doses of 2 mg/kg bw every 3 weeks, 10 mg/kg bw every 3 weeks, and 10 mg/kg bw every 2 weeks were evaluated in melanoma or previously treated NSCLC clinical studies. Based on the modelling and simulation of dose/exposure relationships for efficacy and safety for pembrolizumab, there are no clinically significant differences in efficacy or safety among the doses of 200 mg every 3 weeks, 2 mg/kg bw every 3 weeks, and 400 mg every 6 weeks (see section 4.2).
Melanoma
KEYNOTE-006: Controlled study in melanoma patients naïve to treatment with ipilimumab The safety and efficacy of pembrolizumab were investigated in KEYNOTE-006, a multicentre, open-label, controlled, Phase III study for the treatment of advanced melanoma in patients who were naïve to ipilimumab. Patients were randomised (1:1:1) to receive pembrolizumab 10 mg/kg bw every 2 (n=279) or 3 weeks (n=277) or ipilimumab 3 mg/kg bw every 3 weeks (n=278). Patients with BRAF V600E mutant melanoma were not required to have received prior BRAF inhibitor therapy.
Patients were treated with pembrolizumab until disease progression or unacceptable toxicity.
Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Assessment of tumour status was performed at 12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter.

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: KEYTRUDA 395 mg solution for injection / KEYTRUDA 790 mg solution for injection

Pharmacotherapeutic group: Antineoplastic agents, PD-1/PDL-1 (Programmed cell death protein 1/death ligand 1) inhibitors. ATC code: L01FF02 KEYTRUDA solution for injection contains the active substance pembrolizumab which provides the therapeutic effect of this medicinal product and recombinant berahyaluronidase alfa (variant of human hyaluronidase PH20), an enzyme that temporarily and locally breaks down hyaluronan. Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. Recombinant berahyaluronidase alfa activity results in enhanced dispersion and permeation, which facilitates delivery of medicinal products that are co-administered subcutaneously.

Mechanism of action
KEYTRUDA is a humanised monoclonal antibody which binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been shown to be involved in the control of T-cell immune responses. KEYTRUDA potentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour microenvironment.
The anti-angiogenic effect of lenvatinib (multi-TKI) in combination with the immune-stimulatory effect of pembrolizumab (anti-PD-1) results in a tumour microenvironment with greater T-cell activation to help overcome primary and acquired resistance to immunotherapy and may improve tumour responses compared to either treatment alone. In preclinical murine models, PD-1 plus TKI inhibitors have demonstrated enhanced anti-tumour activity compared to either agent alone.
Clinical efficacy and safety
Intravenous pembrolizumab doses of 2 mg/kg bw every 3 weeks, 10 mg/kg bw every 3 weeks, and 10 mg/kg bw every 2 weeks were evaluated in melanoma or previously treated NSCLC clinical studies. Based on the modelling and simulation of dose/exposure relationships for efficacy and safety for pembrolizumab, there are no clinically significant differences in efficacy or safety among the doses of 200 mg every 3 weeks, 2 mg/kg bw every 3 weeks, and 400 mg every 6 weeks for intravenous pembrolizumab across the approved dosing regimens.
The exposures from subcutaneous pembrolizumab doses of 790 mg every 6 weeks or 395 mg every 3 weeks are within the range of exposures from intravenous pembrolizumab doses.
Subcutaneous formulation
Study MK-3475A-D77

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Applies to: KEYTRUDA 25 mg/mL concentrate for solution for infusion

The pharmacokinetics of pembrolizumab was studied in 2 993 patients with metastatic or unresectable melanoma, NSCLC, or carcinoma who received doses in the range: of 1 to 10 mg/kg bw every 2 weeks, 2 to 10 mg/kg bw every 3 weeks, or 200 mg every 3 weeks.
Absorption
Pembrolizumab is administered via the intravenous route and therefore is immediately and completely bioavailable.
Distribution
Consistent with a limited extravascular distribution, the volume of distribution of pembrolizumab at steady-state is small (~6.0 L; CV: 20%). As expected for an antibody, pembrolizumab does not bind to plasma proteins in a specific manner.
Biotransformation
Pembrolizumab is catabolised through non-specific pathways; metabolism does not contribute to its clearance.
Elimination
Pembrolizumab CL is approximately 23% lower (geometric mean, 195 mL/day [CV%: 40%]) after achieving maximal change at steady-state compared with the first dose (252 mL/day [CV%: 37%]);
this decrease in CL with time is not considered clinically meaningful. The geometric mean value (CV%) for the terminal half-life is 22 days (32%) at steady-state.
Linearity/non-linearity
Exposure to pembrolizumab as expressed by peak concentration (Cmax) or area under the plasma concentration time curve (AUC) increased dose proportionally within the dose range for efficacy.
Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an every 3 week regimen and the systemic accumulation was 2.1-fold. The median trough concentrations (Ctrough) at steady-state were approximately 22 mcg/mL at a dose of 2 mg/kg bw every 3 weeks and 29 mcg/mL at a dose of 200 mg every 3 weeks. The median area under the concentration time curve at steady-state over 3 weeks (AUC0-3weeks) was 794 mcg•day/mL at a dose of 2 mg/kg bw every 3 weeks and 1 053 mcg•day/mL at a dose of 200 mg every 3 weeks.

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: KEYTRUDA 395 mg solution for injection / KEYTRUDA 790 mg solution for injection

The pharmacokinetics of pembrolizumab was studied in patients with various tumour types who received subcutaneous pembrolizumab (395 mg every 3 weeks or 790 mg every 6 weeks) or intravenous pembrolizumab (400 mg every 6 weeks) as monotherapy or in combination therapy. There are no clinically meaningful differences in pharmacokinetics of pembrolizumab across indications and across route of administration.
Steady-state concentrations of pembrolizumab were reached by 16 weeks. The systemic accumulation ratio was 1.6-fold following administration of subcutaneous pembrolizumab 790 mg every 6 weeks and 2.5-fold following administration of subcutaneous pembrolizumab 395 mg every 3 weeks.
Pembrolizumab model-based exposure following subcutaneous administration every 6 weeks was non- inferior to intravenous administration every 6 weeks, with a geometric mean ratio (GMR) of 1.14 (96% CI: 1.06, 1.22) for Cycle 1 AUC0-6wks and 1.67 (94% CI: 1.52, 1.84) for Cycle 3 Ctrough (i.e., steady state).
At steady state following subcutaneous administration, the geometric mean pembrolizumab model- based AUC0-6wks was 2 798 mcg•day/mL for the every 6 week dosing and pembrolizumab model-based AUC0-3wks was 1 343 mcg•day/mL for the every 3 week dosing. Pembrolizumab Ctrough was 39.2 mcg/mL for the every 6 week dosing and 49.0 mcg/mL for the every 3 week dosing.
Absorption
Following subcutaneous administration of pembrolizumab, the mean bioavailability (CV %) of pembrolizumab is approximately 60% (14%). The median time to maximum serum concentration (Tmax) of pembrolizumab is approximately 4 days (range:1 to 35 days). At steady state, the mean Cmax of pembrolizumab is 99.0 mcg/mL for subcutaneous pembrolizumab 790 mg every 6 weeks and 76.5 mcg/mL for subcutaneous pembrolizumab 395 mg every 3 weeks.
Distribution

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu.

Source: European Medicines Agency (EMA), product information. Not advertising, not a treatment recommendation. For questions about your own treatment, ask your doctor or pharmacist.