KEYTRUDA® 50 mg powder for concentrate for solution for infusion.

One vial of powder contains 50 mg of pembrolizumab.

After reconstitution, 1 mL of solution 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.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

White to off-white lyophilised powder.

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

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

Posology

The recommended dose of KEYTRUDA is 2 mg/kg administered intravenously over 30 minutes every 3 weeks. 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.

Dose delay or discontinuation (see also section 4.4)

Table 1: Guidelines for withholding or discontinuation of KEYTRUDA

Note: toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4).

* until adverse reactions recover to Grade 0-1.

KEYTRUDA should be permanently discontinued:

• For Grade 4 toxicity except for endocrinopathies that are controlled with replacement hormones

• If corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks

• If a treatment-related toxicity does not resolve to Grade 0-1 within 12 weeks after last dose of KEYTRUDA

• If any event occurs a second time at Grade ≥ 3 severity.

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.

Renal impairment

No dose adjustment is needed for patients with mild or moderate renal impairment. KEYTRUDA has not been studied in patients with severe renal impairment (see section 5.2).

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 (see section 5.2).

Ocular melanoma

There are limited data on the safety and efficacy of KEYTRUDA in patients with ocular melanoma (see section 5.1).

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 should be administered by intravenous infusion over 30 minutes.

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

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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.

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

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

Pembrolizumab must be permanently discontinued for any Grade 3 immune related adverse reaction that recurs and for any Grade 4 immune related adverse reaction toxicity, except for endocrinopathies that are controlled with replacement hormones (see sections 4.2 and 4.8).

Immune-related pneumonitis

Pneumonitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other causes excluded. Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper); pembrolizumab should be withheld for Grade 2 pneumonitis, and permanently discontinued for Grade 3, Grade 4 or recurrent Grade 2 pneumonitis (see section 4.2). In a study involving 550 patients with non-small cell lung carcinoma (NSCLC), a fatal case of pneumonitis has been reported.

Immune-related colitis

Colitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for signs and symptoms of colitis, and other causes excluded. Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper); pembrolizumab should be withheld for Grade 2 or Grade 3 colitis, and permanently discontinued for Grade 4 colitis (see section 4.2). The potential risk of gastrointestinal perforation should be taken into consideration.

Immune-related hepatitis

Hepatitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for changes in liver function (at the start of treatment, periodically during treatment and as indicated based on clinical eva luation) and symptoms of hepatitis, and other causes excluded. Corticosteroids should be administered (initial dose of 0.5-1 mg/kg/day [for Grade 2 events] and 1-2 mg/kg/day (for Grade ≥ 3 events) prednisone or equivalent followed by a taper) and, based on severity of liver enzyme elevations, pembrolizumab should be withheld or discontinued (see section 4.2).

Immune-related nephritis

Nephritis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for changes in renal function, and other causes of renal dysfunction excluded. Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper) and, based on severity of creatinine elevations, pembrolizumab should be withheld for Grade 2, and permanently discontinued for Grade 3 or Grade 4 nephritis (see section 4.2).

Immune-related endocrinopathies

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

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

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

Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for hyperglycaemia or other signs and symptoms of diabetes. Insulin should be administered for type 1 diabetes, and pembrolizumab should be withheld in cases of Grade 3 hyperglycaemia until metabolic control is achieved (see section 4.2).

Thyroid disorders, including hypothyroidism, hyperthyroidism and thyroiditis, have been reported in patients receiving pembrolizumab and can occur at any time during treatment; therefore, patients should be monitored for changes in thyroid function (at the start of treatment, periodically during treatment and as indicated based on clinical eva luation) and clinical signs and symptoms of thyroid disorders. Hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids. Hyperthyroidism may be managed symptomatically. Pembrolizumab should be withheld for Grade ≥ 3 until recovery to Grade ≤ 1 hyperthyroidism. For patients with Grade 3 or Grade 4 hyperthyroidism that improved to Grade 2 or lower, continuation of pembrolizumab may be considered, after corticosteroid taper, if needed (see sections 4.2 and 4.8). Thyroid function and hormone levels should be monitored to ensure appropriate hormone replacement.

Other immune-related adverse reactions

The following additional clinically significant, immune-related adverse reactions have been reported in patients receiving pembrolizumab: uveitis, arthritis, myositis, pancreatitis, severe skin reactions, myasthenic syndrome, optic neuritis, rhabdomyolysis, haemolytic anaemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma (see section 4.8).

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

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

Pembrolizumab must be permanently discontinued for any Grade 3 immune related adverse reaction that recurs and for any Grade 4 immune related adverse reaction toxicity (see sections 4.2 and 4.8).

Infusion-related reactions

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

Patients excluded from clinical trials

The following patients were excluded from clinical trials: patients with HIV, hepatitis B or hepatitis C infection; active systemic autoimmune disease; prior pneumonitis; 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 abnormalities (bilirubin > 1.5 x ULN, ALT, AST > 2.5 x ULN in the absence of liver metastases) at baseline were excluded from clinical trials, therefore information is limited in patients with severe renal and moderate to severe hepatic impairment.

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

Patient Alert Card

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

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

The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. However, systemic corticosteroids or other immunosuppressants can be used after starting pembrolizumab to treat immune-related adverse reactions (see section 4.4).