Keytruda^® (Concentrate) Instructions for Use

Marketing Authorization Holder

MSD Pharmaceuticals, LLC (Russia)

Manufactured By

MSD International GmbH T/A MSD Ireland (Carlow) (Ireland)

Packaging and Quality Control Release

SCHERING-PLOUGH LABO, N.V. (Belgium)

Or

ORTAT, JSC (Russia)

Contact Information

MSD Pharmaceuticals LLC (Russia)

ATC Code

L01FF02 (Pembrolizumab)

Active Substance

Pembrolizumab (Rec.INN registered by WHO)

Dosage Form

Keytruda®

Concentrate for solution for infusion 100 mg/4 ml: vial 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion as a clear or opalescent solution from colorless to light yellow.

Excipients: L-histidine – 1.2 mg, L-histidine hydrochloride monohydrate – 6.8 mg, polysorbate-80 – 0.8 mg, sucrose – 280 mg, water for injections – up to 4 ml.

4 ml – type I colorless glass vials (1) – cardboard packs with first opening control (self-adhesive stickers).
4 ml – type I colorless glass vials (1) – cardboard trays (1) – cardboard packs with first opening control (self-adhesive stickers).

Clinical-Pharmacological Group

Antitumor drug. Monoclonal antibodies

Pharmacotherapeutic Group

Antineoplastic agent – monoclonal antibodies

Pharmacological Action

Pembrolizumab is a humanized monoclonal antibody that selectively blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2. Pembrolizumab is an immunoglobulin of the IgG4 kappa isotype with a molecular weight of approximately 149 kDa.

Mechanism of action

PD-1 is an immune checkpoint receptor that limits T-lymphocyte activity in peripheral tissues. Tumor cells can use the PD-1 signaling pathway to inhibit active T-cell immune surveillance.

Pembrolizumab is a high-affinity antibody to the PD-1 receptor; its inhibition results in dual blockade of the PD-1 signaling pathway involving PD-L1 and PD-L2 ligands on tumor or antigen-presenting cells. As a result of inhibiting the binding of the PD-1 receptor to its ligands, Pembrolizumab reactivates tumor-specific cytotoxic T-lymphocytes in the tumor microenvironment and thus reactivates anti-tumor immunity.

The antiangiogenic effect of lenvatinib (a multikinase inhibitor) in combination with the reactivation of the anti-tumor effect of pembrolizumab (anti-PD-1) leads to greater T-cell activation in the tumor microenvironment, which helps overcome primary and acquired resistance to immunotherapy and may improve tumor response compared to therapy with either active substance alone.

In preclinical mouse models, PD-1 inhibitors in combination with multikinase inhibitors demonstrated increased anti-tumor activity compared to therapy with either active substance alone.

Pharmacodynamics

Based on dose/exposure-response modeling conducted to evaluate the efficacy and safety of pembrolizumab, there are no clinically significant differences in efficacy and safety between the 200 mg or 2 mg/kg every 3 weeks or 400 mg every 6 weeks dosing regimens.

In the peripheral blood of patients who received Pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks, regardless of the dosing regimen used, an increase in the percentage of activated (i.e., HLA-DR+) CD4+ and CD8+ T-cells was observed without an increase in the total number of circulating T-lymphocytes.

Pharmacokinetics

The pharmacokinetics of pembrolizumab were studied in trials involving 2993 patients with various malignancies who received the drug at doses from 1 to 10 mg/kg every 2 weeks, from 2 to 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. No clinically significant differences in the pharmacokinetics of pembrolizumab were found across the studied indications.

Absorption

Keytruda^® is administered intravenously, therefore Pembrolizumab is immediately and completely bioavailable.

Distribution

Consistent with limited extravascular distribution, the steady-state V_d of pembrolizumab is low (approximately 6.0 L; coefficient of variation (CV): 20%). Like other antibodies, Pembrolizumab does not bind specifically to plasma proteins.

Metabolism

Pembrolizumab undergoes catabolism by non-specific pathways; metabolism does not affect its clearance.

Elimination

The clearance of pembrolizumab (CV%) is approximately 23% lower (geometric mean 195 ml/day (40%)) after reaching the maximum change at steady state compared to the first dose (252 ml/day (37%)); this decrease in clearance over time is not considered clinically significant. The geometric mean (CV%) for the terminal T_1/2 is 22 days (32%).

With repeated administration every 3 weeks, steady-state concentrations of pembrolizumab were reached by week 16, with systemic accumulation being 2.1-fold higher. The maximum concentration (C_max), the minimum concentration before the next dose (C_min), and the steady-state area under the concentration-time curve (AUC_ss) of pembrolizumab increased proportionally to the dose when administered from 2 to 10 mg/kg every 3 weeks.

Pharmacokinetics in special patient groups

The influence of various covariates on the pharmacokinetics of pembrolizumab was assessed in a population pharmacokinetic analysis. The following factors did not have a clinically significant effect on the clearance of pembrolizumab: age (from 15 to 94 years), sex, race, mild or moderate renal impairment, mild hepatic impairment, tumor mass. The relationship between body weight and clearance supports the use of a fixed dosing regimen or a body weight-based dosing regimen to ensure adequate and similar exposure control. Pembrolizumab concentrations with the body weight-based dosing regimen of 2 mg/kg every 3 weeks in pediatric patients (from 2 to 17 years) are comparable to those in adults with the same dosing regimen.

Renal impairment. The effect of renal impairment on the clearance of pembrolizumab was assessed in a population pharmacokinetic analysis in patients with mild (60≤GFR<90 ml/min/1.73 m²) or moderate (30≤GFR<60 ml/min/1.73 m²) renal impairment compared to patients with normal renal function (GFR≥90 ml/min/1.73 m²). No clinically significant differences in the clearance of pembrolizumab were identified between patients with mild or moderate renal impairment and those with normal renal function. Studies on the use of pembrolizumab have not been conducted in patients with severe renal impairment (15≤GFR<30 ml/min/1.73 m²) (see “Dosage Regimen”).

Hepatic impairment. The effect of hepatic impairment on the clearance of pembrolizumab was assessed in a population pharmacokinetic analysis in patients with mild hepatic impairment (total bilirubin concentration (TB) from 1 to 1.5 times the upper limit of normal (ULN) or aspartate aminotransferase (AST) activity above ULN) compared to patients with normal hepatic function (TB concentration and AST activity ≤ ULN). No clinically significant differences in the clearance of pembrolizumab were found between patients with mild hepatic impairment and those with normal hepatic function. Studies on the use of pembrolizumab have not been conducted in patients with moderate (TB concentration from 1.5 to 3 times ULN and any AST activity) or severe (TB concentration >3 times ULN and any AST activity) hepatic impairment (see “Dosage Regimen”).

Indications

Melanoma

• As monotherapy for the treatment of adult patients with unresectable or metastatic melanoma;
• As monotherapy as adjuvant therapy after surgical treatment in adult patients with stage III melanoma with lymph node involvement.

Non-small cell lung cancer

• In combination with chemotherapy, including a platinum drug and pemetrexed, as 1st-line therapy in adult patients with metastatic non-squamous non-small cell lung cancer (NSCLC) in the absence of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene mutations;
• In combination with carboplatin and paclitaxel or albumin-stabilized nanodispersed paclitaxel as 1st-line therapy in adult patients with metastatic squamous non-small cell lung cancer;
• As monotherapy as 1st-line treatment in adult patients with locally advanced or metastatic NSCLC with PD-L1 expression TPS ≥1% on tumor cells, determined by a validated test, in the absence of EGFR or ALK gene mutations;
• As monotherapy for the treatment of adult patients with advanced non-small cell lung cancer with PD-L1 expression TPS ≥1% on tumor cells, determined by a validated test, who have previously received therapy including platinum drugs. Patients with EGFR or ALK gene mutations should have received appropriate specific therapy before being prescribed Keytruda^® treatment.

Head and neck cancer

• As monotherapy as 1st-line treatment in adult patients with metastatic or unresectable recurrent squamous cell carcinoma of the head and neck (SCCHN) with PD-L1 expression (combined positive score, CPS) CPS ≥1;
• In combination with chemotherapy, including a platinum drug and 5-fluorouracil (5-FU), as 1st-line therapy in adult patients with metastatic or unresectable recurrent squamous cell carcinoma of the head and neck (SCCHN) with PD-L1 expression CPS ≥1;
• As monotherapy for the treatment of adult patients with metastatic or unresectable recurrent SCCHN with PD-L1 expression TPS ≥50% and disease progression during or after chemotherapy including platinum drugs.

Classical Hodgkin lymphoma (cHL)

• As monotherapy for the treatment of adults and children aged 3 years and older with relapsed or refractory classical Hodgkin lymphoma (cHL) after autologous hematopoietic stem cell transplantation (auto-HSCT) or after one or more prior lines of therapy if there are contraindications to auto-HSCT.

Urothelial carcinoma

• For the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy, with PD-L1 expression (combined positive score, CPS≥10) according to a validated test, as well as patients who are ineligible for chemotherapy with any platinum drugs, regardless of PD-L1 expression;
• As monotherapy for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who have previously received platinum-containing chemotherapy;
• For the treatment of adult patients with high-risk non-muscle invasive bladder cancer (NMIBC) unresponsive to BCG therapy, with carcinoma in situ (CIS) with or without papillary tumor, who are not candidates for cystectomy or have refused it.

Esophageal cancer

• In combination with chemotherapy based on platinum drugs and fluoropyrimidine as 1st-line therapy in adult patients with locally advanced unresectable or metastatic esophageal cancer, or HER-2 negative adenocarcinoma of the esophagogastric junction (tumors with the center from 1 to 5 cm above the esophagogastric junction) with PD-L1 expression CPS≥10.

Malignant neoplasms with high microsatellite instability

• As monotherapy for the treatment of adult patients with unresectable or metastatic malignant neoplasms with high microsatellite instability (MSI-H), including DNA mismatch repair deficiencies (dMMR), with disease progression after prior therapy in the absence of satisfactory alternative treatment options.

Colorectal cancer

• As monotherapy as 1st-line treatment in adult patients with unresectable or metastatic colorectal cancer (CRC) with high microsatellite instability (MSI-H) or DNA mismatch repair deficiencies (dMMR).

Cervical cancer

• In combination with chemotherapy with or without bevacizumab for the treatment of adult patients with persistent, recurrent, or metastatic cervical cancer with PD-L1 expression (CPS≥1) according to a validated test;
• As monotherapy for the treatment of adult patients with recurrent or metastatic cervical cancer with PD-L1 expression (CPS≥1) according to a validated test with disease progression during or after chemotherapy.

Renal cell carcinoma

• In combination with axitinib as 1st-line therapy in adult patients with advanced renal cell carcinoma (RCC);
• In combination with lenvatinib as 1st-line therapy in adult patients with advanced RCC;
• As monotherapy for adjuvant therapy in adult patients with RCC at intermediate-high or high risk of recurrence (see “Dosage Regimen”, section “Patient Selection”) after nephrectomy or after nephrectomy and resection of metastatic lesions.

Endometrial cancer

• In combination with lenvatinib for the treatment of adult patients with advanced endometrial cancer in the absence of high microsatellite instability (MSI-H) or DNA mismatch repair deficiencies (dMMR)) with disease progression after prior systemic therapy in any regimen, who are not candidates for surgical treatment or radiation therapy.

Cutaneous squamous cell carcinoma

• For the treatment of adult patients with recurrent or metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC that cannot be cured by surgical method or radiation therapy.

Triple-negative breast cancer

• In combination with chemotherapy for the treatment of adult patients with unresectable locally recurrent or metastatic triple-negative breast cancer (TNBC) with PD-L1 expression (CPS ≥10) according to a validated test.

ICD codes

Dosage Regimen

Treatment should be initiated and conducted under the supervision of qualified and experienced physicians.

Patient Selection

As indicated in the indication for use, patients for treatment with Keytruda^® should be selected based on positive PD-L1 expression, MSI-H or dMMR tumor status (see “Indications”).

PD-L1 expression should be determined using the “PD-L1 IHC 22C3 pharmDX” reagent kit or a similar kit.

Tumor MSI-H or dMMR status should be determined using a validated test. Since the effect of prior chemotherapy on MSI-H or dMMR status test results is undefined in patients with high-grade gliomas, testing for these indicators in such patients is recommended on primary tumor material obtained before initiation of temozolomide chemotherapy.

When using pembrolizumab as adjuvant therapy in patients with RCC, tumors of stage pT2 with grade 4 differentiation or the presence of a sarcomatoid component, as well as tumors of stage pT3 with any grade of differentiation, without lymph node involvement (N0) and without distant metastases (M0) were classified as intermediate-high risk. Tumors of stage pT4 with any grade of differentiation, N0 and M0, as well as tumors of any pT stage with any grade of differentiation, with lymph node involvement and M0 were classified as high risk. The M1 NED (no evidence of disease) category included patients with metastatic cancer who had undergone complete resection of the primary tumor and metastatic lesions.

Dosage

The recommended dose of Keytruda^® in adult patients is 200 mg every 3 weeks or 400 mg every 6 weeks, administered intravenously as a 30-minute infusion.

For combination therapy, refer to the prescribing information for the co-administered medicinal products. When Keytruda^® is administered as part of combination intravenous chemotherapy, Keytruda^® should be administered first.

For patients with RCC receiving treatment with Keytruda^® in combination with axitinib, refer to the axitinib dosing regimen in the axitinib prescribing information. When axitinib is co-administered with Keytruda^®, axitinib dose increases above the starting dose of 5 mg may be considered at intervals of 6 or more weeks.

For patients with endometrial carcinoma and RCC receiving treatment with Keytruda^® in combination with lenvatinib, the recommended starting dose of lenvatinib is 20 mg orally once daily until disease progression or unacceptable toxicity.

Treatment with Keytruda^® is continued until disease progression or unacceptable toxicity. Atypical responses (i.e., an initial, short-term increase in tumor size or small new lesions within the first few months followed by tumor shrinkage) have been observed. It is recommended to continue treatment in clinically stable patients with initial signs of disease progression until disease progression is confirmed.

Adjuvant therapy in patients with melanoma or RCC with Keytruda^® is continued for up to one year, or until disease recurrence, or until unacceptable toxicity.

Temporary or Permanent Treatment Discontinuation

Dose reduction of Keytruda^® is not recommended. Keytruda^® treatment is temporarily interrupted or permanently discontinued to manage adverse reactions according to Table 1.

Table 1. Recommended Dose Modifications (see “Special Instructions”)

Note: Toxicity grades are provided according to the US National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4).

* If corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks, or if treatment-related toxicity does not decrease to Grade 0-1 within 12 weeks after the last dose of Keytruda^®, then Keytruda^® treatment must be discontinued.

In patients with cHL with Grade 4 hematologic toxicity, Keytruda^® treatment should be temporarily withheld until adverse reactions decrease to Grade 0-1.

In patients with RCC receiving treatment with Keytruda^® in combination with axitinib

• If ALT or AST is > ULN ≥3 times but < ULN <10 times without total bilirubin > ULN ≥2 times, temporarily withhold both Keytruda^® and axitinib until adverse reactions decrease to Grade 0-1. Consider corticosteroid therapy. Consider re-initiating one drug or sequentially re-initiating both drugs after resolution of these adverse reactions. If re-initiating axitinib, consider dose reduction according to the axitinib prescribing information.

• If ALT or AST is > ULN ≥10 times or > ULN >3 times with total bilirubin > ULN ≥2 times, discontinue both Keytruda^® and axitinib and consider corticosteroid therapy.

For managing adverse reactions with Keytruda^® in combination with lenvatinib, it is recommended to interrupt one or both drugs as needed, or reduce the dose or discontinue lenvatinib. Refer to the recommendations for managing lenvatinib adverse reactions in the lenvatinib prescribing information. Dose reduction of Keytruda^® is not recommended.

Special Patient Populations

Elderly patients (≥65 years)

No differences in safety or efficacy were reported between elderly patients (≥65 years) and younger patients (<65 years). Elderly patients do not require dose adjustment.

Patients with renal impairment

Patients with mild or moderate renal impairment do not require dose adjustment. Treatment with Keytruda^®has not been studied in patients with severe renal impairment.

Patients with hepatic impairment

Patients with mild hepatic impairment do not require dose adjustment. Treatment with Keytruda^®has not been studied in patients with moderate or severe hepatic impairment.

Ocular melanoma

There are limited data on the safety and efficacy of Keytruda^® in patients with ocular melanoma.

Children

The recommended dose of Keytruda^® for the treatment of children with cHL is 2 mg/kg (up to a maximum of 200 mg), administered intravenously as a 30-minute infusion every 3 weeks.

Method of Administration

Keytruda^® should be administered intravenously as an infusion over 30 minutes.

Instructions for Preparation and Administration of the Infusion Solution

Preparation and Administration

The drug vial must be stored protected from light. Do not freeze. Do not shake.

The Keytruda^® vial should be allowed to reach room temperature.

The drug vial can be kept outside the refrigerator (at temperatures up to 25°C (77°F)) for up to 24 hours prior to dilution.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Keytruda^® is a clear or opalescent solution from colorless to light yellow. Do not use the vial if particulate matter is present.

Withdraw the required volume (up to 4 ml, 100 mg) of Keytruda^® and transfer it into an infusion bag containing 0.9% sodium chloride solution or 5% glucose (dextrose) solution, to prepare a diluted solution with a final concentration of 1 to 10 mg/ml. Mix the diluted solution by gently inverting the infusion bag.

Do not freeze the prepared infusion solution.

The product does not contain preservatives. The diluted product should be used immediately. If the diluted solution is not used immediately after preparation, it may be stored at room temperature for up to 6 hours in total. The diluted solution may be stored refrigerated at 2 to 8°C (46.4°F), provided the total time from preparation of the diluted solution to completion of infusion does not exceed 96 hours in total. After removal from the refrigerator and before use, vials and/or infusion bags should be allowed to reach room temperature.

The diluted solution may contain translucent or white proteinaceous particles.

The infusion solution is administered intravenously over 30 minutes through an intravenous line using a sterile, pyrogen-free, low protein-binding in-line or add-on filter with a pore size of 0.2 to 5 µm.

Other drugs should not be administered through the same intravenous line used for Keytruda^® administration.

Any unused product remaining in the vial should be discarded.

Adverse Reactions

Summary of the safety profile

The use of Keytruda^® is most commonly associated with the development of immune-mediated adverse reactions. Most of these, including severe reactions, resolved after initiation of appropriate therapy or after discontinuation of Keytruda^® (see below “Description of selected adverse reactions”). Based on all reported adverse drug reactions, the frequencies below and in Table 2 are provided regardless of the investigator’s assessment of causality.

Pembrolizumab as monotherapy (see “Dosage and Administration” section)

The safety of pembrolizumab as monotherapy was studied in clinical trials in 6185 patients with advanced melanoma, Stage III melanoma after surgery (adjuvant therapy), NSCLC, cHL, urothelial carcinoma, or head and neck cancer or CRC in four dosing regimens (2 mg/kg body weight every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg body weight every 2 or 3 weeks). In this patient population, the median follow-up time was 7.6 months (range from 1 day to 47 months), and the most frequent adverse reactions with pembrolizumab were fatigue (32%), nausea (21%), and diarrhea (21%). Most reported adverse reactions as monotherapy were Grade 1 or 2. The most serious adverse reactions were immune-mediated adverse reactions and severe infusion reactions (see “Special Instructions”).

Pembrolizumab in combination with chemotherapy (see “Dosage and Administration” section)

When using pembrolizumab in combination, refer to the prescribing information for the respective components of the combination therapy before starting treatment.

The safety of pembrolizumab in combination with chemotherapy was studied in clinical trials in 2033 patients with NSCLC, HNSCC, esophageal cancer, or TNBC in dosing regimens of 200 mg, 2 mg/kg body weight, or 10 mg/kg body weight every 3 weeks. In this patient population, the most frequent adverse reactions were anemia (52%), nausea (52%), fatigue (37%), constipation (34%), neutropenia (33%), diarrhea (32%), decreased appetite (30%), and vomiting (28%). The incidence of Grade 3-5 adverse reactions in patients with NSCLC was 67% with pembrolizumab in combination with chemotherapy and 66% with chemotherapy alone, in patients with HNSCC was 85% with pembrolizumab in combination with chemotherapy and 84% with chemotherapy in combination with cetuximab, in patients with esophageal cancer was 86% with pembrolizumab in combination with chemotherapy and 83% with chemotherapy alone, in patients with TNBC was 78% with pembrolizumab in combination with chemotherapy and 74% with chemotherapy alone.

Pembrolizumab in combination with a tyrosine kinase inhibitor (TKI) (see “Dosage and Administration” section)

When using pembrolizumab in combination with axitinib or lenvatinib, refer to the prescribing information for axitinib or lenvatinib before starting treatment. For additional safety information on lenvatinib, refer to the lenvatinib prescribing information. For additional safety information on axitinib regarding increased liver enzymes, also see the “Special Instructions” section.

The safety of pembrolizumab in combination with axitinib or lenvatinib in advanced RCC and in combination with lenvatinib in advanced endometrial carcinoma was studied in clinical trials in 1456 patients with advanced RCC or advanced endometrial carcinoma in the dosing regimen of 200 mg pembrolizumab every 3 weeks and either 5 mg axitinib twice daily or 20 mg lenvatinib once daily, respectively. In this patient population, the most frequent adverse events were diarrhea (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 erythrodysesthesia syndrome (26%), rash (26%), stomatitis (25%), constipation (25%), musculoskeletal pain (23%), headache (23%), and cough (21%). The incidence of Grade 3-5 adverse reactions in patients with RCC was 80% with pembrolizumab in combination with axitinib or lenvatinib and 71% with sunitinib monotherapy. The incidence of Grade 3-5 adverse reactions in patients with endometrial carcinoma was 89% with pembrolizumab in combination with lenvatinib and 73% with chemotherapy alone.

Tabulated list of adverse reactions

Adverse reactions observed in clinical trials of pembrolizumab as monotherapy, or in combination with chemotherapy, or with other anticancer drugs, or reported during the post-marketing use of Keytruda^®, are listed in Table 2. These reactions are presented by system organ class and 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Adverse reactions that occur with pembrolizumab alone or with the components of combination therapy taken separately may occur during their combined use, even if not reported in clinical trials of the combination therapy. For additional safety information on pembrolizumab in combination therapy, refer to the prescribing information for the respective components of the combination therapy.

Table 2. Adverse reactions in patients treated with Keytruda^®*

* The frequency of adverse reactions listed in Table 2 may be associated not only with the use of pembrolizumab as monotherapy, but also with the underlying disease or with other drugs used in combination therapy.

⁺Based on standard queries to the adverse reaction database, including bradyarrhythmias and tachyarrhythmias.

The following terms represent a group of interrelated events that describe a medical condition, not a single event.

^a infusion-related reactions (drug hypersensitivity, anaphylactic reaction, anaphylactoid reaction, hypersensitivity, infusion reaction, and cytokine release syndrome);

^b hypothyroidism (myxedema);

^cthyroiditis (autoimmune thyroiditis, thyroid disease, and acute thyroiditis);

^d hyperthyroidism (Graves’ disease);

^eadrenal insufficiency (primary adrenal insufficiency, acute adrenal insufficiency, secondary adrenal insufficiency);

^f hypophysitis (hypopituitarism);

^g type 1 diabetes mellitus (diabetic ketoacidosis);

H encephalitis (autoimmune encephalitis, non-infectious encephalitis);

ⁱ Guillain-Barré syndrome (axonal neuropathy and demyelinating polyneuropathy);

^j myelitis (including transverse myelitis);

^kmyasthenic syndrome (myasthenia gravis, including exacerbation);

^l aseptic meningitis (meningitis, non-infectious meningitis);

^muveitis (iritis and iridocyclitis);

ⁿmyocarditis (autoimmune myocarditis);

^o vasculitis (CNS vasculitis, aortitis, giant cell arteritis);

^p pneumonitis (interstitial lung disease and organizing pneumonia, immune-mediated pneumonitis);

^q abdominal pain (abdominal discomfort, upper abdominal pain, lower abdominal pain);

^r colitis (microscopic colitis, enterocolitis, hemorrhagic enterocolitis, autoimmune colitis and immune-mediated colitis);

^s pancreatitis (autoimmune pancreatitis, acute pancreatitis and immune-mediated pancreatitis);

^tGI wall ulceration (gastric ulcer and duodenal ulcer);

^u hepatitis (autoimmune hepatitis, immune-mediated hepatitis, drug-induced liver injury and acute hepatitis);

^vrash (erythematous rash, follicular rash, generalized rash, maculopapular rash, papular rash, pruritic rash, vesicular rash and genital rash);

^w pruritus (urticaria, papular urticaria, generalized pruritus and genital pruritus);

^x severe skin reactions (bullous dermatitis, exfoliative dermatitis, generalized exfoliative dermatitis, erythema multiforme, exfoliative rash, pemphigus, skin necrosis, toxicoderma and any of the following events ≥ grade 3: acute febrile neutrophilic dermatosis, bruising, pressure ulcer, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, erythema multiforme, jaundice, lichen planus, oral lichen planus, pemphigoid, pruritus, genital pruritus, rash, erythematous rash, maculopapular rash, pruritic rash, pustular rash, skin lesion and toxic skin eruption);

^y vitiligo (skin depigmentation, skin hypopigmentation and eyelid hypopigmentation);

^z lichenoid keratosis (lichen planus and lichen sclerosus);

^aa musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain and torticollis);

^bb myositis (myalgia, myopathy, necrotizing myositis, polymyalgia rheumatica and rhabdomyolysis);

^cc arthritis (joint swelling, polyarthritis and joint effusion);

^dd tenosynovitis (tendinitis, synovitis and tendon pain);

^ee nephritis (autoimmune nephritis, tubulointerstitial nephritis and renal failure, acute renal failure or acute kidney injury with signs of nephritis, nephrotic syndrome, glomerulonephritis and membranous glomerulonephritis);

^ff edema (peripheral edema, generalized edema, hypervolemia, fluid retention, eyelid edema and lip edema, facial edema, localized edema and periorbital edema).

Description of selected adverse reactions

Data for the following immune-mediated adverse reactions are based on information from patients who received Pembrolizumab in clinical trials in four dosing regimens (2 mg/kg body weight every 3 weeks, 10 mg/kg body weight every 2 or 3 weeks, or 200 mg every 3 weeks). Recommendations for the management of patients with these adverse reactions are described in the “Special Instructions” section.

Immune-mediated adverse reactions

Immune-mediated pneumonitis

Pneumonitis occurred in 286 (4.6%) patients who received Pembrolizumab, including grade 2, 3, 4, or 5 in 128 (2.1%), 73 (1.2%), 17 (0.3%), and 9 (0.1%) patients, respectively. The median time to onset of pneumonitis was 3.5 months (range from 2 days to 26.7 months). The median duration was 2.0 months (range from 1 day to 33.0 months). Pneumonitis occurred more frequently in patients with a history of chest radiation therapy (8.2%) than in patients without prior chest radiation therapy (4.2%). Discontinuation of pembrolizumab therapy due to pneumonitis was required in 117 (1.9%) patients. Pneumonitis resolved in 166 patients, with sequelae in 4 cases.

In patients with NSCLC, pneumonitis occurred in 160 (5.7%) cases, including grade 2, 3, 4, or 5 in 62 (2.2%), 47 (1.7%), 14 (0.5%), and 10 (0.4%) patients, respectively. In NSCLC patients with a history of radiation therapy, pneumonitis occurred in 8.9% of cases. In patients with cHL, the incidence of pneumonitis (all grades) ranged from 5.2% to 10.8% in the KEYNOTE-087 (n=210) and KEYNOTE-204 (n=148) studies in cHL patients, respectively.

Immune-mediated colitis

Colitis occurred in 121 (2.0%) patients who received Pembrolizumab, including grade 2, 3, or 4 in 35 (0.6%), 67 (1.1%), and 5 (0.1%) patients, respectively. The median time to onset of colitis was 4.7 months (range from 7 days to 24.3 months). The median duration was 1.0 month (range from 1 day to 12.4 months). Discontinuation of pembrolizumab therapy due to colitis was required in 34 (0.5%) patients. Colitis resolved in 99 patients, with sequelae in 2 cases. In patients with CRC who received 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 61 (1.0%) patients who received Pembrolizumab, including grade 2, 3, or 4 in 8 (0.1%), 41 (0.7%), and 8 (0.1%) patients, respectively. The median time to onset of hepatitis was 3.8 months (range from 8 days to 26.3 months). The median duration was 1.1 months (range from 1 day to 20.9+ months). Discontinuation of pembrolizumab therapy due to hepatitis was required in 24 (0.4%) patients. Hepatitis resolved in 46 patients.

Immune-mediated nephritis

Nephritis occurred in 25 (0.4%) patients who received Pembrolizumab as monotherapy, including grade 2, 3, or 4 in 5 (0.1%), 15 (0.2%), and 2 (<0.1%) patients, respectively. The median time to onset of nephritis was 5.1 months (range from 12 days to 21.4 months). The median duration was 3.3 months (range from 6 days to 19.6 months). Discontinuation of pembrolizumab therapy due to nephritis was required in 10 (0.2%) patients. Nephritis resolved in 15 patients, with sequelae in 4 cases. In patients with non-squamous NSCLC who received pembrolizumab therapy in combination with chemotherapy including pemetrexed and a platinum drug (n=488), the incidence of nephritis was 1.4% (all grades) with an incidence of 0.8% for grade 3 and 0.4% for grade 4.

Immune-mediated endocrinopathies

Adrenal insufficiency occurred in 52 (0.8%) patients who received Pembrolizumab, including grade 2, 3, or 4 in 23 (0.4%), 21 (0.3%), and 4 (0.1%) patients, respectively. The median time to onset of adrenal insufficiency was 5.5 months (range from 1 day to 23.7 months). The median duration was not reached (range from 3 days to 32.4+ months). Discontinuation of pembrolizumab therapy due to adrenal insufficiency was required in 5 (0.1%) patients. Adrenal insufficiency resolved in 18 patients, with sequelae in 5 cases.

Hypophysitis occurred in 38 (0.6%) patients who received Pembrolizumab, including grade 2, 3, or 4 in 15 (0.2%), 19 (0.3%), and 1 (<0.1%) patients, respectively. The median time to onset of hypophysitis was 5.9 months (range from 1 day to 17.7 months). The median duration was 3.6 months (range from 3 days to 30.4+ months). Discontinuation of pembrolizumab therapy due to hypophysitis was required in 9 (0.1%) patients. Hypophysitis resolved in 17 patients, with sequelae in 8 cases.

Hyperthyroidism occurred in 261 (4.2%) patients who received Pembrolizumab, including grade 2 or 3 in 64 (1.0%) and 7 (0.1%) patients, respectively. The median time to onset of hyperthyroidism was 1.4 months (range from 1 day to 23.2 months). The median duration was 1.8 months (range from 4 days to 27.6+ months). Discontinuation of pembrolizumab therapy due to hyperthyroidism was required in 3 (<0.1%) patients. Hyperthyroidism resolved in 207 (79.3%) patients, with sequelae in 5 cases. In the adjuvant study of patients with resected RCC receiving Keytruda^® as monotherapy (n=488), the incidence of hyperthyroidism was 12% (all grades) with an incidence of 0.2% for grade 3.

Hypothyroidism occurred in 699 (11.3%) patients who received Pembrolizumab, including grade 2 or 3 in 510 (8.2%) and 7 (0.1%) patients, respectively. The median time to onset of hypothyroidism was 3.4 months (range from 1 day to 25.9 months). The median duration was not reached (range from 2 days to 53.9+ months). Discontinuation of pembrolizumab therapy due to hypothyroidism was required in 2 patients (<0.1%). Hypothyroidism resolved in 171 (24.5%) patients, with sequelae in 14 cases. In patients with cHL (n=389), the incidence of hypothyroidism was 17%, all cases were grade 1 or 2. In patients with HNSCC, (n=909), who received Pembrolizumab as monotherapy, the incidence of hypothyroidism was 16.1% (all grades) with an incidence of 0.3% for grade 3. In patients with HNSCC (n=276), who received Pembrolizumab in combination with chemotherapy including a platinum drug and 5-FU, the incidence of hypothyroidism was 15.2%, all cases were grade 1 or 2. In the adjuvant study of patients with resected RCC receiving Keytruda^® as monotherapy (n=488), the incidence of hypothyroidism was 21% (all grades) with an incidence of 0.2% for grade 3.

Immune-mediated skin adverse reactions

Immune-mediated severe skin reactions occurred in 102 (1.6%) patients who received Pembrolizumab, including grade 2, 3, or 5 in 11 (0.2%), 77 (1.2%), and 1 (<0.1%) patients, respectively. The median time to onset of severe skin reactions was 3.5 months (range from 3 days to 25.5 months). The median duration was 1.9 months (range from 1 day to 33.0+ months). Discontinuation of pembrolizumab therapy due to severe skin reactions was required in 13 (0.2%) patients. Severe skin reactions resolved in 71 patients, with sequelae in 1 case.

Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been observed, some with fatal outcome (see “Dosage Regimen” and “Special Instructions”).

Other malignancies

Monotherapy

Adverse events in patients with high microsatellite instability malignancies, CRC or cervical cancer, recurrent or metastatic HNSCC or locally advanced HNSCC, or adjuvant RCC therapy were generally similar to those in patients with melanoma or NSCLC.

Complications of allogeneic hematopoietic stem cell transplantation in cHL

Of 14 patients in KEYNOTE-013 who underwent allogeneic hematopoietic stem cell transplantation after treatment with Keytruda^®, acute graft-versus-host disease was reported in 6 patients and chronic graft-versus-host disease in 1 patient, none of which were fatal. Two patients developed hepatic veno-occlusive disease, one with a fatal outcome. One patient developed engraftment syndrome.

Of 32 patients in KEYNOTE-087 who underwent allogeneic hematopoietic stem cell transplantation after treatment with Keytruda^®, acute graft-versus-host disease was reported in 16 patients and chronic graft-versus-host disease in 7 patients, with two fatal outcomes. No patient experienced hepatic veno-occlusive disease. No patient experienced engraftment syndrome.

Of 14 patients in KEYNOTE-204 who underwent allogeneic hematopoietic stem cell transplantation after treatment with pembrolizumab, acute graft-versus-host disease was reported in 8 patients and chronic graft-versus-host disease in 3 patients, none of which were fatal. No patient experienced hepatic veno-occlusive disease. One patient developed engraftment syndrome.

Increased Liver Enzyme Activity During Pembrolizumab Therapy in Combination 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 Grade 3 and 4 increased ALT activity (20%) and increased AST activity (13%) was observed. The median time to onset of increased ALT activity was 2.3 months (range from 7 days to 19.8 months). In patients with ALT increased above ULN by ≥3 times (Grade 2-4, n=116), the adverse reaction decreased to Grade 0-1 in 94% of cases. Fifty-nine percent of patients with increased ALT received systemic corticosteroids. Upon resolution, 92 patients (84%) were re-administered monotherapy with pembrolizumab (3%) or axitinib (31%) or combination therapy (50%). Among these patients, 55% did not experience recurrent ALT increase above ULN >3 times, and all patients with recurrent ALT increase above ULN >3 times experienced resolution. No Grade 5 hepatic events were reported.

Laboratory Abnormalities

Among patients receiving Pembrolizumab as monotherapy, the percentage of patients who experienced a shift from baseline to Grade 3 or 4 laboratory abnormalities was: decreased lymphocyte count 10.8%, decreased sodium 8.3%, decreased hemoglobin 6.4%, decreased phosphate 5.4%, increased glucose 5.0%, increased AST 3.1%, increased ALT 3.0%, increased alkaline phosphatase (ALP) 2.7%, decreased potassium 2.4%, decreased neutrophil count 2.1%, decreased platelet count 1.7%, increased calcium 1.9%, increased potassium 1.9%, increased bilirubin 1.9%, decreased albumin 1.6%, decreased calcium 1.5%, increased creatinine 1.5%, decreased white blood cell count 0.9%, increased magnesium 0.7%, decreased glucose 0.6%, decreased magnesium 0.2%, increased sodium 0.2%.

Among patients receiving Pembrolizumab in combination with chemotherapy, the proportion of patients who experienced a shift from baseline to Grade 3 or 4 laboratory abnormalities was: decreased neutrophil count 37.7%, decreased lymphocyte count 25.8%, decreased white blood cell count 25.2%, decreased hemoglobin 20.3%, decreased platelet count 13.3%, decreased sodium 11.3%, decreased phosphate 8.9%, decreased potassium 7.2%, increased glucose 6.7%, increased ALT 5.8%, increased AST 5.4%, decreased calcium 3.6%, increased potassium 3.4%, decreased albumin 2.8%, increased creatinine 2.7%, increased ALP 2.3%, increased bilirubin 1.9%, increased calcium 1.7%, decreased glucose 1.0%, increased sodium 0.6% and increased hemoglobin 0.1%.

Among patients receiving Pembrolizumab in combination with axitinib or lenvatinib, the proportion of patients who experienced a shift from baseline to Grade 3 or 4 laboratory abnormalities was: increased lipase 23.0% (not measured in patients receiving Pembrolizumab and axitinib), decreased lymphocyte count 12.0%, decreased sodium 11.4%, increased amylase 11.2%, increased triglycerides 11.2%, increased ALT 10.4%, increased AST 8.9%, increased glucose 7.8%, decreased phosphorus 7.3%, decreased phosphate 6.8%, decreased potassium 6.1%, increased potassium 5.1%, increased cholesterol 4.5%, increased creatinine 4.4%, decreased hemoglobin 4.2%, decreased magnesium 4.0%, decreased neutrophil count 3.5%, increased ALP 3.1%, decreased platelet count 3.0%, increased bilirubin 2.8%, decreased calcium 2.2%, decreased white blood cell count 1.7%, increased magnesium 1.6%, increased INR 1.5%, decreased glucose 1.4%, decreased albumin 1.2%, increased calcium 1.2%, increased sodium 0.4%, increased hemoglobin 0.1%.

Immunogenicity

Of 2034 evaluable patients who received Keytruda^® in clinical trials at doses of 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks as monotherapy, 36 (1.8%) tested positive for anti-pembrolizumab antibodies, of which 9 (0.4%) patients had neutralizing antibodies against pembrolizumab. No evidence of altered pharmacokinetic profile or safety profile following the appearance of binding or neutralizing antibodies against pembrolizumab was observed.

Pediatric Population

The safety of pembrolizumab administered as monotherapy at a dosage of 2 mg/kg every 3 weeks was evaluated in the KEYNOTE-051 Phase I/II trial in 161 pediatric patients aged 9 months to 17 years with advanced melanoma, lymphoma, or advanced, recurrent, or refractory PD-L1-positive solid tumors. The cHL population (n=22) included patients aged 11 to 17 years. The safety profile in pediatric patients was similar to that in adult patients who received Pembrolizumab. The most frequent adverse reactions (reported in at least 20% of pediatric patients) were pyrexia (33%), vomiting (30%), headache (26%), abdominal pain (22%), anemia (21%), cough (21%), and constipation (20%). Most reported adverse reactions when used as monotherapy were Grade 1 or 2. Seventy-six (47.2%) patients had one or more Grade 3-5 adverse reactions, of which 5 (3.1%) patients had one or more adverse reactions that were fatal. Frequency is based on all reported adverse drug reactions regardless of the investigator’s assessment of causality.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorization 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.

Contraindications

• Severe hypersensitivity to pembrolizumab or to other components of the drug;
• Severe renal failure;
• Moderate and severe hepatic impairment;
• Age under 18 years (for the treatment of HL – less than 3 years);
• Pregnancy;
• Breastfeeding period.

With caution

Immune-mediated adverse reactions, including severe and fatal cases, have been reported in patients receiving Keytruda^® (see “Special Precautions”).

Use in Pregnancy and Lactation

Pregnancy

There are no data on the use of pembrolizumab in pregnant women. Special studies on the effect of pembrolizumab on reproductive function in animals have not been conducted, however, in mouse pregnancy models, it has been shown that blockade of the PD-L1 signaling pathway leads to a decrease in maternal tolerance to the fetus and an increased risk of fetal loss. These findings indicate a potential risk (based on the mechanism of action) of adverse effects on the fetus, including increased incidence of miscarriage or stillbirth, when pembrolizumab is used during pregnancy. Human immunoglobulin G4 (IgG4) crosses the placental barrier, and since Pembrolizumab is an IgG4, it may potentially be transferred across the placenta from the mother to the developing fetus. Women of childbearing potential should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last infusion of pembrolizumab.

Breastfeeding period

There are no data on the excretion of pembrolizumab in breast milk. Pembrolizumab is contraindicated during breastfeeding.

Fertility

There are no clinical data on the possible effect of pembrolizumab on fertility. Although specific studies of the toxic effects of pembrolizumab on reproduction and development have not been conducted, in repeat-dose toxicity studies in monkeys for 1 and 6 months, no notable effects on the reproductive organs of males and females were found.

Use in Hepatic Impairment

The use of the drug is contraindicated in moderate and severe hepatic impairment.

No dose adjustment is required for patients with mild hepatic impairment.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal impairment.

No dose adjustment is required for patients with mild or moderate renal impairment.

Pediatric Use

The use of the drug is contraindicated under the age of 18 years (for the treatment of HL – less than 3 years).

Geriatric Use

No dose adjustment is required for elderly patients.

Special Precautions

Immune-mediated adverse reactions

Immune-mediated adverse reactions, including severe and fatal cases, have been reported in patients receiving Keytruda^®. Immune-mediated adverse reactions can occur after discontinuation of Keytruda^® therapy. Most immune-mediated adverse reactions observed in clinical trials were reversible and managed by temporarily withholding Keytruda^® therapy, administering corticosteroids, and/or symptomatic therapy. Immune-mediated adverse reactions affecting more than one body system can develop simultaneously.

If an immune-mediated adverse reaction is suspected, a thorough evaluation is required to confirm the etiology or rule out other possible causes. Based on the severity of the adverse reaction, Keytruda^® therapy should be temporarily withheld and the administration of corticosteroids considered. Upon improvement to Grade 1 or less, begin gradual corticosteroid dose reduction and continue it for at least 1 month. Based on limited data from clinical trials, in patients whose immune-mediated adverse reactions were not controlled with corticosteroids, the use of other systemic immunosuppressants may be considered. Resumption of Keytruda^® therapy is possible if the severity of the adverse reaction remains at Grade 1 or less after gradual corticosteroid dose reduction. If another episode of a severe adverse reaction occurs, Keytruda^® should be permanently discontinued (see “Dosage and Administration” and “Adverse Reactions”).

Immune-mediated pneumonitis

Cases of pneumonitis (including fatal cases) have been reported in patients receiving Keytruda^®. Patients should be actively monitored for signs and symptoms of pneumonitis. If pneumonitis is suspected, radiological examination should be performed to exclude other causes. Corticosteroid therapy is administered for Grade 2 or higher pneumonitis (initial dose 1-2 mg/kg/day prednisone or equivalent followed by gradual dose reduction). Withhold Keytruda^® for Grade 2 (moderate) pneumonitis and permanently discontinue Keytruda^® for Grade 3 (severe) or 4 (life-threatening) pneumonitis or recurrence of Grade 2 (moderate) pneumonitis (see “Dosage and Administration”).

Immune-mediated colitis

Cases of colitis have been reported in patients receiving Keytruda^® (see “Adverse Reactions”). Patients should be actively monitored for signs and symptoms of colitis and other causes should be excluded. Corticosteroid therapy is administered for Grade 2 or higher (initial dose 1-2 mg/kg/day prednisone or equivalent followed by gradual dose reduction). Withhold Keytruda^® for Grade 2 (moderate) or 3 (severe) colitis and permanently discontinue for Grade 4 (life-threatening) colitis (see “Dosage and Administration”).

Immune-mediated hepatitis

Cases of hepatitis have been reported in patients receiving Keytruda^® (see “Adverse Reactions”). Patients should be monitored for changes in liver function tests (at the start of treatment, periodically during therapy, and based on clinical assessment) and symptoms of hepatitis, and other causes should be excluded. Corticosteroid therapy is administered for Grade 2 hepatitis (initial dose 0.5-1 mg/kg/day prednisone (or equivalent) followed by gradual dose reduction) and for Grade 3 hepatitis or higher (1-2 mg/kg/day prednisone (or equivalent) followed by gradual dose reduction). Withhold or permanently discontinue Keytruda^® based on the level of liver enzyme elevation (see “Dosage and Administration”).

Immune-mediated nephritis

Cases of nephritis have been reported in patients receiving Keytruda^® (see “Adverse Reactions”). Patients should be monitored for changes in renal function and other causes should be excluded. Corticosteroid therapy is administered for Grade 2 and higher adverse events (initial dose 1-2 mg/kg/day prednisone (or equivalent) followed by gradual dose reduction). Withhold Keytruda^® for Grade 2 (moderate) nephritis and permanently discontinue for Grade 3 (severe) or 4 (life-threatening) nephritis (see “Dosage and Administration”).

Immune-mediated endocrinopathies

Cases of adrenal insufficiency (primary and secondary) have been reported in patients receiving Keytruda^®. Cases of hypophysitis have also been reported in patients receiving Keytruda^® (see “Adverse Reactions”). Patients should be monitored for signs and symptoms of adrenal insufficiency and hypophysitis (including hypopituitarism) and other causes should be excluded. In case of secondary adrenal insufficiency, corticosteroid therapy or other hormonal replacement therapy should be administered based on clinical assessment. Withhold Keytruda^® therapy for Grade 2 (moderate) hypophysitis, permanently discontinue for Grade 3 (severe) or 4 (life-threatening) adrenal insufficiency or hypophysitis (see “Dosage and Administration”).

Cases of type 1 diabetes mellitus, including cases of diabetic ketoacidosis, have been reported in patients receiving Keytruda^®. Patients should be monitored for hyperglycemia or other signs and symptoms of diabetes mellitus. For type 1 diabetes mellitus, insulin should be administered, and in cases of severe hyperglycemia, Keytruda^® should be temporarily withheld until metabolic control is achieved.

Thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis, have been reported in patients receiving Keytruda^®; they can occur at any time during treatment. Therefore, patients should be monitored for changes in thyroid function (at the start of treatment, periodically during therapy, and based on clinical assessment) and clinical signs and symptoms of thyroid dysfunction. Treatment of hypothyroidism can be managed with replacement therapy without interruption of treatment and without corticosteroids. Symptomatic treatment may be used for hyperthyroidism. Withhold or permanently discontinue Keytruda^® for Grade 3 (severe) or 4 (life-threatening) hyperthyroidism (see “Dosage and Administration”).

In patients with Grade 3 (severe) or 4 (life-threatening) endocrinopathy that improves to Grade 2 or below and is controlled with hormone replacement therapy, continuation of Keytruda^® may be considered.

Severe skin reactions

Cases of severe immune-mediated skin reactions have been reported in patients receiving Keytruda^®. Patients should be monitored for suspected severe skin reactions and other causes should be excluded. Based on the severity of the adverse reaction, Keytruda^® therapy should be temporarily or permanently withheld and corticosteroid therapy administered (see “Dosage and Administration”).

Cases of SJS and TEN, including fatal cases, have been reported in patients receiving Keytruda^®. If signs or symptoms of SJS or TEN appear, Keytruda^® therapy should be temporarily withheld and the patient should be referred for specialized care for examination and treatment. If SJS or TEN is confirmed, Keytruda^® therapy should be permanently discontinued (see “Dosage and Administration”).

Other immune-mediated adverse reactions

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

Based on the severity and type of adverse reaction, Keytruda^® should be temporarily withheld for Grade 2 and Grade 3 adverse reactions and corticosteroids should be administered.

Keytruda^® can be resumed within 12 weeks after the last dose if the adverse reaction grade is ≤1 and the corticosteroid dose is reduced to ≤10 mg per day of prednisone or equivalent.

Keytruda^® should be permanently discontinued in case of any recurrent Grade 3 immune-mediated adverse reaction, as well as in case of any Grade 4 immune-mediated adverse reaction.

For Grade 3 or 4 myocarditis, encephalitis, or Guillain-Barré syndrome, Keytruda^® should be permanently discontinued.

Transplantation-related adverse reactions

Transplant rejection has been reported post-marketing in patients receiving Keytruda^® treatment. Keytruda^® treatment may increase the risk of transplant rejection in recipients. The benefits of Keytruda^® treatment should be weighed against the risk of possible organ rejection in these patients.

Cases of acute graft-versus-host disease (GVHD), including fatal GVHD, have been reported following treatment with Keytruda^® in patients with a history of allogeneic hematopoietic stem cell transplantation (HSCT). Patients who developed GVHD after the transplant procedure may be at increased risk of GVHD following treatment with Keytruda^®. The benefits of treatment with Keytruda^® versus the risk of potential GVHD should be considered in patients with a history of allogeneic HSCT.

Elevation of liver enzymes during therapy with Keytruda^® in combination with axitinib in RCC

A higher than expected incidence of Grade 3 and 4 ALT and AST elevation was observed in patients with advanced RCC treated with Keytruda^® in combination with axitinib (see “Adverse Reactions”). Liver enzyme levels should be monitored prior to initiation and periodically during treatment. More frequent monitoring of liver enzymes should be considered compared to when the drugs are used as monotherapy. The dosing recommendations for both drugs should be followed (see “Dosage and Administration” and the axitinib prescribing information).

Increased mortality in multiple myeloma when Keytruda^® is added to a thalidomide analogue and dexamethasone

In two randomized clinical trials in patients with multiple myeloma, the addition of Keytruda^® to a thalidomide analogue and dexamethasone resulted in increased mortality; this is not an indicated use for PD-1 or PD-L1 blocking antibodies. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue and dexamethasone is not recommended outside of controlled clinical trials.

Infusion reactions

Severe infusion reactions, including hypersensitivity and anaphylaxis, were reported in 6 (0.2%) of 2799 patients treated with Keytruda^® in clinical trials KEYNOTE-001, KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010. For severe infusion reactions, the infusion must be interrupted and Keytruda^® should be permanently discontinued (see “Dosage and Administration”). For patients with mild or moderate infusion reactions, the possibility of continuing Keytruda^® therapy under close medical supervision may be considered; premedication with antipyretics and antihistamines can be used.

Precautions for specific conditions

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

Prior to initiation of treatment, the physician should consider the delayed onset of action of pembrolizumab in patients with poor prognosis and/or aggressive disease. In urothelial carcinoma, a higher number of deaths within 2 months were observed with pembrolizumab compared to chemotherapy. Factors associated with early death were rapidly progressive disease following prior platinum-based therapy and the presence of liver metastases.

Use of pembrolizumab as first-line therapy in patients with NSCLC

Overall, a higher frequency of adverse reactions was observed with pembrolizumab combination therapy compared to pembrolizumab monotherapy or chemotherapy alone, reflecting the contribution of each of these components. There are no direct comparison data between pembrolizumab in combination with chemotherapy and pembrolizumab monotherapy.

The physician should consider the benefit/risk ratio of the available treatment options (pembrolizumab monotherapy or pembrolizumab in combination with chemotherapy) prior to initiating treatment in previously untreated patients with NSCLC with PD-L1 expression in tumor cells.

In the KEYNOTE-042 trial, a higher number of deaths within the first 4 months after initiation of treatment was observed, followed by a long-term survival benefit with pembrolizumab monotherapy compared to chemotherapy.

Efficacy and safety data in patients aged ≥75 years are limited. In patients aged ≥75 years, pembrolizumab combination therapy should be used with caution after a thorough individual assessment of potential benefit/risk.

Use of pembrolizumab as first-line therapy in patients with HNSCC

Overall, a higher frequency of adverse reactions was observed with pembrolizumab combination therapy compared to pembrolizumab monotherapy or chemotherapy alone, reflecting the contribution of each of these components.

The physician should consider the benefit/risk ratio of the available treatment options (pembrolizumab monotherapy or pembrolizumab in combination with chemotherapy) prior to initiating treatment in patients with HNSCC with PD-L1 expression in tumor cells.

Use of pembrolizumab as adjuvant therapy in patients with melanoma

A trend towards an increased frequency of severe and serious adverse reactions was observed in patients aged ≥75 years. Safety data on the use of pembrolizumab as adjuvant therapy in melanoma patients aged ≥75 years are limited.

Use of pembrolizumab in combination with axitinib as first-line therapy in patients with RCC

A higher than expected incidence of Grade 3 and 4 ALT and AST elevation was observed in patients with advanced RCC treated with pembrolizumab in combination with axitinib. Liver enzyme levels should be monitored prior to initiation and periodically during treatment. More frequent monitoring of liver enzymes should be considered compared to when the drugs are used as monotherapy. The prescribing information for both medicinal products should be followed.

Use of pembrolizumab as first-line therapy in patients with MSI-H/dMMR CRC

In the KEYNOTE-177 study, a higher hazard ratio for overall survival events was observed with pembrolizumab compared to chemotherapy during the first 4 months of treatment, followed by a long-term survival benefit with pembrolizumab.

Use in children (<18 years)

In the KEYNOTE-051 study, 161 pediatric patients (62 children aged 6 months to 12 years and 99 adolescents aged 12 to 17 years) with advanced melanoma, lymphoma, or advanced, recurrent, or refractory PD-L1 positive solid tumors received therapy with Keytruda^®. Patients received a median of 4 doses of Keytruda^® (range from 1 to 35 doses), and 138 patients (86%) received 2 or more doses of Keytruda^®.

Keytruda^® concentrations in pediatric patients were comparable to those in adult patients at the same dosing regimen (2 mg/kg every 3 weeks).

The safety profile in pediatric patients was similar to that in adult patients who received Keytruda^®. The most frequent adverse reactions (reported in at least 20% of pediatric patients) were pyrexia, vomiting, headache, abdominal pain, anemia, cough, and constipation. The conclusion on efficacy in pediatric patients with cHL is based on data from the corresponding adult population.

Effect on ability to drive and use machines

Keytruda^® may have a minor influence on the ability to drive and use machines. Fatigue has been reported following pembrolizumab administration (see “Adverse Reactions”).

Overdose

There is no information on overdose with Keytruda^®. The maximum tolerated dose for Keytruda^® has not been established. In clinical trials, patients receiving pembrolizumab at doses up to 10 mg/kg had a safety profile comparable to that of patients receiving pembrolizumab at a dose of 2 mg/kg.

In case of overdose, patients should be closely monitored for signs and symptoms of adverse reactions and appropriate symptomatic treatment should be initiated.

Drug Interactions

Specific pharmacokinetic interaction studies of Keytruda^® with other drugs have not been conducted. As pembrolizumab is cleared from the circulation via catabolism, metabolic drug interactions are not expected.

The use of systemic corticosteroids or immunosuppressants prior to initiation of Keytruda^® therapy should be avoided, considering their potential impact on the pharmacodynamic activity and efficacy of Keytruda^®. However, systemic corticosteroids or other immunosuppressants can be used after initiation of pembrolizumab treatment for the management of immune-mediated adverse reactions (see “Special Instructions”). When Keytruda^® is administered in combination with chemotherapy, corticosteroids can be used as premedication to prevent vomiting and/or alleviate chemotherapy-related adverse reactions.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature between 2°C (35.6°F) and 8°C (46.4°F). Do not freeze. Do not shake.

Shelf Life

The shelf life is 2 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.