Keytruda

Overdose

There is no information on overdose with pembrolizumab.

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.

Shelf life

Unopened vial

2 years.

After preparation of infusion

From a microbiological point of view, the product, once diluted, should be used immediately. The diluted solution must not be frozen. If not used immediately, chemical and physical in-use stability of KEYTRUDA has been demonstrated for 24 hours at 2°C to 8°C. This 24 hour hold may include up to 6 hours at room temperature (at or below 25°C). If refrigerated, the vials and/or intravenous bags must be allowed to come to room temperature prior to use.

List of excipients

L-histidine

L-histidine hydrochloride monohydrate

Sucrose

Polysorbate 80

Water for injections

Pharmaceutical form

Concentrate for solution for infusion.

Clear to slightly opalescent, colourless to slightly yellow solution, pH 5.2 - 5.8.

Undesirable effects

Summary of the safety profile

Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of pembrolizumab (see “Description of selected adverse reactions” below).

The safety of pembrolizumab has been evaluated in 3,830 patients with advanced melanoma, NSCLC, cHL or urothelial carcinoma across four doses (2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks) in clinical studies. In this patient population, the most common adverse reactions (> 10%) with pembrolizumab were fatigue (21%), pruritus (16%), rash (13%), diarrhoea (12%) and nausea (10%). The majority of adverse reactions reported were of Grade 1 or 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions.

Tabulated list of adverse reactions

Adverse reactions observed in clinical studies and 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), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 2: Adverse reactions in patients treated with pembrolizumab

The following terms represent a group of related events that describe a medical condition rather than a single event.

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

b. hypothyroidism (myxoedema)

c. hypophysitis (hypopituitarism)

d. type 1 diabetes mellitus (diabetic ketoacidosis)

e. uveitis (iritis and iridocyclitis)

f. pneumonitis (interstitial lung disease)

g. colitis (colitis microscopic and enterocolitis)

h. abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower)

i. pancreatitis (autoimmune pancreatitis and pancreatitis acute)

j. hepatitis (autoimmune hepatitis and drug induced liver injury)

k. rash (rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular and genital rash)

l. pruritus (urticaria, urticaria papular, pruritus generalized and pruritus genital)

m. severe skin reactions (dermatitis exfoliative, erythema multiforme, exfoliative rash, pemphigoid and Grade > 3 of the following: pruritus, rash, rash generalised and rash maculo-papular, dermatitis psoriasiform, pruritus generalised)

n. vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid)

o. lichenoid keratosis (lichen planus and lichen sclerosus)

p. myositis (myalgia, myopathy, polymyalgia rheumatica and rhabdomyolysis)

q. musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain and torticollis)

r. arthritis (joint swelling, polyarthritis and joint effusion)

s. tenosynovitis (tendonitis, synovitis and tendon pain)

t. nephritis (nephritis autoimmune, tubulointerstitial nephritis and renal failure or renal failure acute with evidence of nephritis, nephrotic syndrome)

u. oedema (oedema peripheral, generalised oedema, fluid overload, fluid retention, eyelid oedema and lip oedema, face oedema, localized oedema and periorbital oedema)

Description of selected adverse reactions

Data for the following immune-related adverse reactions are based on patients who received pembrolizumab across three doses (2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks) in clinical studies.

Immune-related adverse reactions

Immune-related pneumonitis

Pneumonitis occurred in 139 (3.6%) patients, including Grade 2, 3, 4 or 5 cases in 56 (1.5%), 38 (1.0%), 9 (0.2%) and 5 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of pneumonitis was 3.7 months (range 2 days to 21.3 months). The median duration was 2.1 months (range 1 day to 17.2+ months). Pneumonitis led to discontinuation of pembrolizumab in 60 (1.6%) patients. Pneumonitis resolved in 81 patients, 1 with sequelae.

Immune-related colitis

Colitis occurred in 71 (1.9%) patients, including Grade 2, 3 or 4 cases in 15 (0.4%), 44 (1.1%) and 3 (<0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of colitis was 3.6 months (range 7 days to 16.2 months). The median duration was 1.3 months (range 1 day to 8.7+ months). Colitis led to discontinuation of pembrolizumab in 18 (0.5%) patients. Colitis resolved in 61 patients.

Immune-related hepatitis

Hepatitis occurred in 23 (0.6%) patients, including Grade 2, 3 or 4 cases in 4 (0.1%), 16 (0.4%) and 2 (<0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hepatitis was 1.3 months (range 8 days to 21.4 months). The median duration was 1.5 months (range 8 days to 20.9+ months). Hepatitis led to discontinuation of pembrolizumab in 7 (0.2%) patients. Hepatitis resolved in 19 patients.

Immune-related nephritis

Nephritis occurred in 15 (0.4%) patients, including Grade 2, 3 or 4 cases in 3 (0.1%), 10 (0.3%) and 1 (<0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of nephritis was 4.9 months (range 12 days to 12.8 months). The median duration was 1.8 months (range 10 days to 10.5+ months). Nephritis led to discontinuation of pembrolizumab in 7 (0.2%) patients. Nephritis resolved in 9 patients.

Immune-related endocrinopathies

Hypophysitis occurred in 21 (0.5%) patients, including Grade 2, 3 or 4 cases in 6 (0.2%), 12 (0.3%) and 1 (<0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypophysitis was 3.7 months (range 1 day to 17.7 months). The median duration was 3.3 months (range 4 days to 12.7+ months). Hypophysitis led to discontinuation of pembrolizumab in 6 (0.2%) patients. Hypophysitis resolved in 10 patients, 2 with sequelae.

Hyperthyroidism occurred in 135 (3.5%) patients, including Grade 2 or 3 cases in 32 (0.8%) and 4 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hyperthyroidism was 1.4 months (range 1 day to 21.9 months). The median duration was 2.1 months (range 10 days to 15.5+ months). Hyperthyroidism led to discontinuation of pembrolizumab in 2 (0.1%) patients. Hyperthyroidism resolved in 104 (77%) patients, 1 with sequelae.

Hypothyroidism occurred in 345 (9.0%) patients, including Grade 2 or 3 cases in 251 (6.6%) and 4 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypothyroidism was 3.5 months (range 1 day to 18.9 months). The median duration was not reached (range 2 days to 29.9+ months). One patient (< 0.1%) discontinued pembrolizumab due to hypothyroidism. Hypothyroidism resolved in 81 (23%) patients, 6 with sequelae. In patients with cHL (n=241) the incidence of hypothyroidism was 14.1% (all Grades) with 0.4% Grade 3.

Immune-related skin adverse reactions

Immune-related severe skin reactions occurred in 63 (1.6%) patients, including Grade 2 or 3 cases in 4 (0.1%) and 52 (1.4%) patients, respectively, receiving pembrolizumab. The median time to onset of severe skin reactions was 2.5 months (range 4 days to 21.5 months). The median duration was 2.0 months (range 3 days to 17.8+ months). Severe skin reactions led to discontinuation of pembrolizumab in 6 (0.2%) patients. Severe skin reactions resolved in 41 patients.

Rare cases of SJS and TEN, some of them with fatal outcome, have been observed.

Complications of allogeneic HSCT in classical Hodgkin lymphoma

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

Immunogenicity

In clinical studies in patients treated with pembrolizumab 2 mg/kg every three weeks, 200 mg every three weeks, or 10 mg/kg every two or three weeks, 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.

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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Preclinical safety data

The safety of pembrolizumab was evaluated in a 1-month and a 6-month repeat-dose toxicity study in Cynomolgus monkeys administered intravenous doses of 6, 40 or 200 mg/kg once a week in the 1-month study and once every two weeks in the 6-month study, followed by a 4-month treatment-free period. No findings of toxicological significance were observed and the no observed adverse effect level (NOAEL) in both studies was > 200 mg/kg, which is 19 times the exposure in humans at the highest clinically tested dose (10 mg/kg).

Animal reproduction studies have not been conducted with pembrolizumab. The PD-1/PD-L1 pathway is thought to be involved in maintaining tolerance to the foetus throughout pregnancy. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to result in an increase in foetal loss.

Animal fertility studies have not been conducted with pembrolizumab. In 1 month and 6 month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, many animals in these studies were not sexually mature.

Therapeutic indications

KEYTRUDA as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults.

KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a >50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations.

KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic NSCLC 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.

KEYTRUDA as monotherapy is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) and brentuximab vedotin (BV), or who are transplant-ineligible and have failed BV.

KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy.

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.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies. ATC code: L01XC18

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.

Clinical efficacy and safety

Dosing for patients with melanoma and previously treated NSCLC

In clinical studies comparing pembrolizumab doses of 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, and 10 mg/kg every 2 weeks in patients with melanoma or previously treated patients with NSCLC, efficacy and safety were similar. The recommended dose is 2 mg/kg every 3 weeks.

Melanoma

KEYNOTE-006: Controlled trial in melanoma patients naïve to treatment with ipilimumab

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-006, a multicentre, 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 every 2 (n=279) or 3 weeks (n=277) or ipilimumab 3 mg/kg 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.

Of the 834 patients, 60% were male, 44% were > 65 years (median age was 62 years [range 18-89]) and 98% were white. Sixty-five percent of patients had M1c stage, 9% had a history of brain metastases, 66% had no and 34% had one prior therapy. Thirty-one percent had an ECOG Performance Status of 1, 69% had ECOG Performance Status of 0 and 32% had elevated LDH. BRAF mutations were reported in 302 (36%) patients. Among patients with BRAF mutant tumours, 139 (46%) were previously treated with a BRAF inhibitor.

The primary efficacy outcome measures were progression free survival (PFS; as assessed by Integrated Radiology and Oncology Assessment [IRO] review using Response Evaluation Criteria in Solid Tumours [RECIST], version 1.1) and overall survival (OS). Secondary efficacy outcome measures were overall response rate (ORR) and response duration. Table 3 summarises key efficacy measures in patients naïve to treatment with ipilimumab at the final analysis performed after a minimum of 21 months of follow-up. Kaplan-Meier curves for OS and PFS based on the final analysis are shown in Figures 1 and 2.

Table 3: Efficacy results in KEYNOTE-006

Figure 1: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-006 (intent to treat population)

Figure 2: Kaplan-Meier curve for progression-free survival by treatment arm in KEYNOTE-006 (intent to treat population)

KEYNOTE-002: Controlled trial in melanoma patients previously treated with ipilimumab

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-002, a multicentre, controlled study for the treatment of advanced melanoma in patients previously treated with ipilimumab and if BRAF V600 mutation-positive, with a BRAF or MEK inhibitor. Patients were randomised (1:1:1) to receive pembrolizumab at a dose of 2 (n=180) or 10 mg/kg (n=181) every 3 weeks or chemotherapy (n=179; including dacarbazine, temozolomide, carboplatin, paclitaxel, or carboplatin+paclitaxel). The study excluded patients with autoimmune disease or those receiving immunosuppression; further exclusion criteria were a history of severe or life-threatening immune-related adverse reactions from treatment with ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (> 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; ongoing adverse reactions > Grade 2 from previous treatment with ipilimumab; previous severe hypersensitivity to other monoclonal antibodies; a history of pneumonitis or interstitial lung disease; HIV, hepatitis B or hepatitis C infection and ECOG Performance Status > 2.

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. Patients on chemotherapy who experienced independently verified progression of disease after the first scheduled disease assessment were able to crossover and receive 2 mg/kg or 10 mg/kg of pembrolizumab every 3 weeks in a double blind fashion.

Of the 540 patients, 61% were male, 43% were > 65 years (median age was 62 years [range 15-89]) and 98% were white. Eighty-two percent had M1c stage, 73% had at least two and 32% of patients had three or more prior systemic therapies for advanced melanoma. Forty-five percent had an ECOG Performance Status of 1, 40% had elevated LDH and 23% had a BRAF mutated tumour.

The primary efficacy outcome measures were PFS as assessed by IRO using RECIST version 1.1 and OS. Secondary efficacy outcome measures were ORR and response duration. Table 4 summarises key efficacy measures at the final analysis in patients previously treated with ipilimumab, and the Kaplan-Meier curve for PFS is shown in Figure 3. Both pembrolizumab arms were superior to chemotherapy for PFS, and there was no difference between pembrolizumab doses. There was no statistically significant difference between pembrolizumab and chemotherapy in the final OS analysis that was not adjusted for the potentially confounding effects of crossover. Of the patients randomised to the chemotherapy arm, 55% crossed over and subsequently received treatment with pembrolizumab.

Table 4: Efficacy results in KEYNOTE-002

Figure 3: Kaplan-Meier curve for progression-free survival by treatment arm in KEYNOTE-002 (intent to treat population)

KEYNOTE-001: Open label study in melanoma patients naïve and previously treated with ipilimumab

The safety and efficacy of pembrolizumab for patients with advanced melanoma were investigated in an uncontrolled, open-label study, KEYNOTE-001. Efficacy was evaluated for 276 patients from two defined cohorts, one which included patients previously treated with ipilimumab (and if BRAF V600 mutation-positive, with a BRAF or MEK inhibitor) and the other which included patients naïve to treatment with ipilimumab. Patients were randomly assigned to receive pembrolizumab at a dose of 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks. 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. Exclusion criteria were similar to those of KEYNOTE-002.

Of the 89 patients receiving 2 mg/kg of pembrolizumab who were previously treated with ipilimumab, 53% were male, 33% were > 65 years of age and the median age was 59 years (range 18-88). All but two patients were white. Eighty-four percent had M1c stage and 8% of patients had a history of brain metastases. Seventy percent had at least two and 35% of patients had three or more prior systemic therapies for advanced melanoma. BRAF mutations were reported in 13% of the study population. All patients with BRAF mutant tumours were previously treated with a BRAF inhibitor.

Of the 51 patients receiving 2 mg/kg of pembrolizumab who were naïve to treatment with ipilimumab, 63% were male, 35% were > 65 years of age and the median age was 60 years (range 35-80). All but one patient was white. Sixty-three percent had M1c stage and 2% of patients had a history of brain metastases. Forty-five percent had no prior therapies for advanced melanoma. BRAF mutations were reported in 20 (39%) patients. Among patients with BRAF mutant tumours, 10 (50%) were previously treated with a BRAF inhibitor.

The primary efficacy outcome measure was ORR as assessed by independent review using RECIST 1.1. Secondary efficacy outcome measures were disease control rate (DCR; including complete response, partial response and stable disease), response duration, PFS and OS. Tumour response was assessed at 12-week intervals. Table 5 summarises key efficacy measures in patients previously treated or naïve to treatment with ipilimumab, receiving pembrolizumab at the recommended dose based on a minimum follow-up time of 30 months for all patients.

Table 5: Efficacy results in KEYNOTE-001

* Includes patients without measurable disease at baseline by independent radiology

† IRO = Integrated radiology and oncologist assessment using RECIST 1.1

‡ Based on best response of stable disease or better

§ Based on patients with a confirmed response by independent review, starting from the date the response was first recorded; n=23 for patients previously treated with ipilimumab; n=18 for patients naïve to treatment with ipilimumab

¶ Based on Kaplan-Meier estimation

Results for patients previously treated with ipilimumab (n=84) and naïve to treatment with ipilimumab (n=52) who received 10 mg/kg of pembrolizumab every 3 weeks were similar to those seen in patients who received 2 mg/kg of pembrolizumab every 3 weeks.

Sub-population analyses

BRAF mutation status in melanoma

A subgroup analysis was performed as part of the final analysis of KEYNOTE-002 in patients who were BRAF wild type (n=414; 77%) or BRAF mutant with prior BRAF treatment (n=126; 23%) as summarised in Table 6.

Table 6: Efficacy results by BRAF mutation status in KEYNOTE-002

A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients who were BRAF wild type (n=525; 63%), BRAF mutant without prior BRAF treatment (n=163; 20%) and BRAF mutant with prior BRAF treatment (n=139; 17%) as summarised in Table 7.

Table 7: Efficacy results by BRAF mutation status in KEYNOTE-006

PD-L1 status in melanoma

A subgroup analysis was performed as part of the final analysis of KEYNOTE-002 in patients who were PD-L1 positive (PD-L1 expression in > 1% of tumour and tumour-associated immune cells) vs. PD-L1 negative. PD-L1 expression was tested retrospectively by immunohistochemistry assay with the 22C3 anti-PD-L1 antibody. Among patients who were evaluable for PD-L1 expression (79%), 69% (n=294) were PD-L1 positive and 31% (n=134) were PD-L1 negative. Table 8 summarises efficacy results by PD-L1 expression.

Table 8: Efficacy results by PD-L1 expression in KEYNOTE-002

A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients who were PD-L1 positive (n=671; 80%) vs. PD-L1 negative (n=150; 18%). Among patients who were evaluable for PD-L1 expression (98%), 82% were PD-L1 positive and 18% were PD-L1 negative. Table 9 summarizes efficacy results by PD-L1 expression.

Table 9: Efficacy results by PD-L1 expression in KEYNOTE-006

Ocular melanoma

In 20 subjects with ocular melanoma included in KEYNOTE-001, no objective responses were reported; stable disease was reported in 6 patients.

NSCLC

KEYNOTE-024: Controlled trial of NSCLC patients naïve to treatment

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-024, a multicentre, controlled study for the treatment of pr

Pharmacokinetic properties

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 every 2 or 3 weeks.

Absorption

Pembrolizumab is dosed 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 (~7.5 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

The systemic clearance of pembrolizumab is ~0.2 L/day (CV: 37%) and the terminal half-life (t½) is ~25 days (CV: 38%).

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. Upon repeated dosing, the clearance of pembrolizumab was found to be independent of time, and systemic accumulation was approximately 2.1-fold when administered every 3 weeks. Near steady-state concentrations of pembrolizumab were achieved by 18 weeks; the median steady-state through concentrations (Cmin) at 18 weeks were approximately 21 mcg/mL at a dose of 2 mg/kg every 3 weeks and 28 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 658 mcg∙day/mL at a dose of 2 mg/kg every 3 weeks and 876 mcg∙day/mL at a dose of 200 mg every 3 weeks.

Following administration of pembrolizumab 200 mg every 3 weeks in patients with cHL, the observed median Cmin at steady-state was up to 40% higher than that in other tumour types treated with the same dosage; however, the range of trough concentrations is similar. There are no notable differences in median Cmax between cHL and other tumour types. Based on available safety data in cHL and other tumour types, these differences are not clinically meaningful.

Special populations

The effects of various covariates on the pharmacokinetics of pembrolizumab were assessed in population pharmacokinetic analyses. The following factors had no clinically important effect on the clearance of pembrolizumab: age (range 15-94 years), gender, race, mild or moderate renal impairment, mild hepatic impairment and tumour burden. The relationship between body weight and clearance supports the use of either fixed dose or body weight-based dosing to provide adequate and similar control of exposure.

Renal impairment

The effect of renal impairment on the clearance of pembrolizumab was evaluated by population pharmacokinetic analyses in patients with mild or moderate renal impairment compared to patients with normal renal function. No clinically important differences in the clearance of pembrolizumab were found between patients with mild or moderate renal impairment and patients with normal renal function. Pembrolizumab has not been studied in patients with severe renal impairment.

Hepatic impairment

The effect of hepatic impairment on the clearance of pembrolizumab was evaluated by population pharmacokinetic analyses in patients with mild hepatic impairment (as defined using the US National Cancer Institute criteria of hepatic dysfunction) compared to patients with normal hepatic function. No clinically important differences in the clearance of pembrolizumab were found between patients with mild hepatic impairment and normal hepatic function. Pembrolizumab has not been studied in patients with moderate or severe hepatic impairment.

Date of revision of the text

23 March 2018

Marketing authorisation holder

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

Special precautions for storage

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Store in the original carton in order to protect from light.

Nature and contents of container

4 mL of concentrate in a 10 mL Type I clear glass vial, with a coated grey chlorobutyl stopper and an aluminium seal with a dark blue coloured flip-off cap, containing 100 mg pembrolizumab.

Each carton contains one vial.

Marketing authorisation number(s)

EU/1/15/1024/002

Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

There are no data on the use of pembrolizumab in pregnant women. Animal reproduction studies have not been conducted with pembrolizumab; however, in murine models of pregnancy blockade of PD-L1 signaling has been shown to disrupt tolerance to the foetus and to result in an increased foetal loss. 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.

Qualitative and quantitative composition

One vial of 4 mL of concentrate contains 100 mg of pembrolizumab.

Each mL of concentrate contains 25 mg of pembrolizumab.

Pembrolizumab is a humanised monoclonal anti-programmed cell death-1 (PD-1) antibody (IgG4/kappa isotype with a stabilising sequence alteration in the Fc region) produced in Chinese hamster ovary cells by recombinant DNA technology.

Special warnings and precautions for use

Assessment of PD-L1 status

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

Immune-related adverse reactions

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

For suspected immune-related adverse reactions, adequate evaluation to confirm aetiology or exclude other causes should be ensured. Based on the severity of the adverse reaction, pembrolizumab should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroid taper should be initiated and continued over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered.

Pembrolizumab may be restarted within 12 weeks after last dose of KEYTRUDA if the adverse reaction remains at Grade ≤ 1 and corticosteroid dose has been reduced to ≤ 10 mg prednisone or equivalent per day.

Pembrolizumab must be permanently discontinued for any Grade 3 immune-related adverse reaction that recurs and for any Grade 4 immune-related adverse reaction toxicity, except for endocrinopathies that are controlled with replacement hormones.

Immune-related pneumonitis

Pneumonitis, including fatal cases, has been reported in patients receiving pembrolizumab . 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.

Immune-related colitis

Colitis has been reported in patients receiving pembrolizumab. Patients should be monitored for signs and symptoms of colitis, and other causes excluded. Corticosteroids should be administered for Grade > 2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper); pembrolizumab should be withheld for Grade 2 or Grade 3 colitis, and permanently discontinued for Grade 4 colitis. The potential risk of gastrointestinal perforation should be taken into consideration.

Immune-related hepatitis

Hepatitis has been reported in patients receiving pembrolizumab. 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.

Immune-related nephritis

Nephritis has been reported in patients receiving pembrolizumab. 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.

Immune-related endocrinopathies

Severe endocrinopathies, including hypophysitis, type 1 diabetes mellitus, diabetic ketoacidosis, hypothyroidism, and hyperthyroidism have been observed with pembrolizumab treatment.

Long-term hormone replacement therapy may be necessary in cases of immune-related endocrinopathies.

Hypophysitis has been reported in patients receiving pembrolizumab. Patients should be monitored for signs and symptoms of hypophysitis (including hypopituitarism and secondary adrenal insufficiency) and other causes excluded. Corticosteroids to treat secondary adrenal insufficiency and other hormone replacement should be administered as clinically indicated, and pembrolizumab should be withheld for symptomatic hypophysitis until the event is controlled with hormone replacement. Continuation of pembrolizumab may be considered, after corticosteroid taper, if needed. 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. Patients should be monitored for hyperglycaemia or other signs and symptoms of diabetes. Insulin should be administered for type 1 diabetes, and pembrolizumab should be withheld in cases of Grade 3 hyperglycaemia until metabolic control is achieved.

Thyroid disorders, including hypothyroidism, hyperthyroidism and thyroiditis, have been reported in patients receiving pembrolizumab and can occur at any time during treatment; therefore, patients should be monitored for changes in thyroid function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and clinical signs and symptoms of thyroid disorders. Hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids. Hyperthyroidism may be managed symptomatically. Pembrolizumab should be withheld for Grade > 3 until recovery to Grade ≤ 1 hyperthyroidism. For patients with Grade 3 or Grade 4 hyperthyroidism that improved to Grade 2 or lower, continuation of pembrolizumab may be considered, after corticosteroid taper, if needed. Thyroid function and hormone levels should be monitored to ensure appropriate hormone replacement.

Immune-related skin adverse reactions

Immune-related severe skin reactions have been reported in patients receiving pembrolizumab. Patients should be monitored for suspected severe skin reactions and other causes should be excluded. Based on the severity of the adverse reaction, pembrolizumab should be withheld or permanently discontinued, and corticosteroids should be administered.

Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with fatal outcome, have been reported in patients receiving pembrolizumab. For signs or symptoms of SJS or TEN, pembrolizumab should be withheld and the patient should be referred to a specialised unit for assessment and treatment. If SJS or TEN is confirmed, pembrolizumab should be permanently discontinued.

Caution should be used when considering the use of pembrolizumab in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune- stimulatory anticancer agents.

Other immune-related adverse reactions

The following additional clinically significant, immune-related adverse reactions, including severe and fatal cases, have been reported in clinical trials or in post-marketing experience: uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, haemolytic anaemia, sarcoidosis and encephalitis.

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

Pembrolizumab may be restarted within 12 weeks after last dose of KEYTRUDA if the adverse reaction remains at Grade ≤ 1 and corticosteroid dose has been reduced to ≤ 10 mg prednisone or equivalent per day.

Pembrolizumab must be permanently discontinued for any Grade 3 immune related adverse reaction that recurs and for any Grade 4 immune related adverse reaction.

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with pembrolizumab may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with pembrolizumab versus the risk of possible organ rejection should be considered in these patients.

Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT)

Allogeneic HSCT after treatment with pembrolizumab

Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been observed in patients with classical Hodgkin lymphoma undergoing allogeneic HSCT after previous exposure to pembrolizumab. Until further data become available, careful consideration to the potential benefits of HSCT and the possible increased risk of transplant-related complications should be made case by case.

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. For severe infusion reactions, infusion should be stopped and pembrolizumab permanently discontinued. Patients with mild or moderate infusion reaction may continue to receive pembrolizumab with close monitoring; premedication with antipyretic and antihistamine may be considered.

Disease-specific precautions

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

Physicians should consider the delayed onset of pembrolizumab effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In urothelial cancer, a higher number of deaths within 2 months was observed in pembrolizumab compared to chemotherapy. Factors associated with early deaths were fast progressive disease on prior platinum therapy and liver metastases.

Use of pembrolizumab in urothelial cancer for patients who are considered cisplatin ineligible

The baseline and prognostic disease characteristics of the study population of KEYNOTE-052 included a proportion of patients eligible for a carboplatin-based combination or mono-chemotherapy for whom the benefit has not yet been assessed in a comparative study. 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.

Patients excluded from clinical trials

Patients with the following conditions were excluded from clinical trials: active CNS metastases; ECOG PS > 2 (except for urothelial carcinoma); HIV, hepatitis B or hepatitis C infection; active systemic autoimmune disease; interstitial lung disease; prior pneumonitis requiring systemic corticosteroid therapy; a history of severe hypersensitivity to another monoclonal antibody; receiving immunosuppressive therapy and a history of severe immune-related adverse reactions from treatment with ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (> 10 mg/day prednisone or equivalent) for greater than 12 weeks. Patients with active infections were excluded from clinical trials and were required to have their infection treated prior to receiving pembrolizumab. Patients with active infections occurring during treatment with pembrolizumab were managed with appropriate medical therapy. Patients with clinically significant renal (creatinine > 1.5 x ULN) or hepatic (bilirubin > 1.5 x ULN, ALT, AST > 2.5 x ULN in the absence of liver metastases) abnormalities at baseline were excluded from clinical trials, therefore information is limited in patients with severe renal and moderate to severe hepatic impairment.

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

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

Patient Alert Card

All prescribers of KEYTRUDA must be familiar with the Physician Information and Management Guidelines. The prescriber must discuss the risks of KEYTRUDA therapy with the patient. The patient will be provided with the Patient Alert Card with each prescription.

Effects on ability to drive and use machines

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

Dosage (Posology) and method of administration

Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer.

PD-L1 testing for patients with NSCLC

Patients with NSCLC should be selected for treatment based on the tumour expression of PD-L1 confirmed by a validated test.

Posology

KEYTRUDA should be administered as an intravenous infusion over 30 minutes every 3 weeks.

The recommended dose of KEYTRUDA is:

- 200 mg for NSCLC that has not been previously treated with chemotherapy cHL or for urothelial carcinoma.

- 2 mg/kg for NSCLC that has been previously treated with chemotherapy or for melanoma.

Patients should be treated with KEYTRUDA until disease progression or unacceptable toxicity. Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.

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Table 1: Recommended treatment modifications for KEYTRUDA

The safety of re-initiating pembrolizumab therapy in patients previously experiencing immune-related myocarditis is not known.

KEYTRUDA should be permanently discontinued for Grade 4 or recurrent Grade 3 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 Grade 0-1.

Patients treated with KEYTRUDA must be given the Patient Alert Card and be informed about the risks of KEYTRUDA (see also package leaflet).

Special populations

Elderly

No overall differences in safety or efficacy were reported between elderly patients (> 65 years) and younger patients (< 65 years). No dose adjustment is necessary in this population.

Data from patients > 65 years are too limited to draw conclusions on cHL population.

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.

Hepatic impairment

No dose adjustment is needed for patients with mild hepatic impairment. KEYTRUDA has not been studied in patients with moderate or severe hepatic impairment.

Ocular melanoma

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

Eastern Cooperative Oncology Group (ECOG) performance status score > 2

Patients with ECOG performance status score > 2 were excluded from the clinical trials of melanoma, NSCLC and cHL.

Paediatric population

The safety and efficacy of KEYTRUDA in children below 18 years of age have not yet been established. No data are available.

Method of administration

KEYTRUDA must be administered by intravenous infusion over 30 minutes. KEYTRUDA must not be administered as an intravenous push or bolus injection.

Special precautions for disposal and other handling

Preparation and administration of the infusion

- Do not shake the vial.

- Equilibrate the vial to room temperature (at or below 25°C).

- Prior to dilution, the vial of liquid can be out of refrigeration (temperatures at or below 25°C) for up to 24 hours.

- Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration. The concentrate is a clear to slightly opalescent, colourless to slightly yellow solution. Discard the vial if visible particles are observed.

- Withdraw the required volume up to 4 mL (100 mg) of concentrate and transfer into an intravenous bag containing sodium chloride 9 mg/mL (0.9%) or glucose 50 mg/mL (5%) to prepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Each vial contains an excess fill of 0.25 ml (total content per vial 4.25 ml) to ensure the recovery of 4 ml of concentrate. Mix diluted solution by gentle inversion.

- From a microbiological point of view, the product, once diluted, should be used immediately. The diluted solution must not be frozen. If not used immediately, chemical and physical in-use stability of KEYTRUDA has been demonstrated for 24 hours at 2°C to 8°C. This 24 hour hold may include up to 6 hours at room temperature (at or below 25°C). If refrigerated, the vials and/or intravenous bags must be allowed to come to room temperature prior to use. Administer the infusion solution intravenously over 30 minutes using a sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line or add-on filter.

- Do not co-administer other medicinal products through the same infusion line.

- KEYTRUDA is for single use only. Discard any unused portion left in the vial.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Date of first authorisation/renewal of the authorisation

Date of first authorisation: 17 July 2015

Interaction with other medicinal products and other forms of interaction

No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. Since pembrolizumab is cleared from the circulation through catabolism, no metabolic drug-drug interactions are expected.

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