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

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

PD-L1 testing

If specified in the indication, patient selection for treatment with KEYTRUDA based on the tumour expression of PD-L1 should be confirmed by a validated test (see sections 4.1, 4.4, 4.8 and 5.1).

MSI/MMR testing

If specified in the indication, patient selection for treatment with KEYTRUDA based on MSI-H/dMMR tumour status should be confirmed by a validated test (see sections 4.1 and 5.1).

Posology

The recommended dose of KEYTRUDA in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes.

The recommended dose of KEYTRUDA as monotherapy in paediatric patients aged 3 years and older with cHL or patients aged 12 years and older with melanoma is 2 mg/kg bodyweight (bw) (up to a maximum of 200 mg), every 3 weeks administered as an intravenous infusion over 30 minutes.

For use in combination, see the Summary of Product Characteristics (SmPC) for the concomitant therapies.

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

For the adjuvant treatment of melanoma, NSCLC, or RCC, KEYTRUDA should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year.

For the neoadjuvant and adjuvant treatment of resectable NSCLC, patients should be treated with neoadjuvant KEYTRUDA in combination with chemotherapy for 4 doses of 200 mg every 3 weeks or 2 doses of 400 mg every 6 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as monotherapy for 13 doses of 200 mg every 3 weeks or 7 doses of 400 mg every 6 weeks or until disease recurrence or unacceptable toxicity. Patients who experience disease progression that precludes definitive surgery or unacceptable toxicity related to KEYTRUDA as neoadjuvant treatment in combination with chemotherapy should not receive KEYTRUDA monotherapy as adjuvant treatment.

For the neoadjuvant and adjuvant treatment of TNBC, patients should be treated with neoadjuvant KEYTRUDA in combination with chemotherapy for 8 doses of 200 mg every 3 weeks or 4 doses of 400 mg every 6 weeks or until disease progress ion that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as monotherapy for 9 doses of 200 mg every 3 weeks or 5 doses of 400 mg every 6 weeks or until disease recurrence or unacceptable toxicity. Patients who experience disease progression that precludes definitive surgery or unacceptable toxicity related to KEYTRUDA as neoadjuvant treatment in combination with chemotherapy should not receive KEYTRUDA monotherapy as adjuvant treatment.

Dose delay or discontinuation (see also section 4.4)

No dose reductions of KEYTRUDA are recommended. KEYTRUDA should be withheld or discontinued to manage adverse reactions as described in Table 1.

Table 1. Recommended treatment modifications for KEYTRUDA:

Note: toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4).
^* If treatment- related toxicity does not resolve to Grades 0-1 within 12 weeks after last dose of KEYTRUDA, or if corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks, KEYTRUDA should be permanently discontinued.

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

KEYTRUDA, as monotherapy or as combination therapy, should be permanently discontinued for Grade 4 or recurrent Grade 3 immune-mediated adverse reactions, unless otherwise specified in Table 1.

For Grade 4 haematological toxicity, only in patients with cHL, KEYTRUDA should be withheld until adverse reactions recover to Grades 0-1.

KEYTRUDA in combination with axitinib in RCC

For RCC patients treated with KEYTRUDA in combination with axitinib, see the SmPC regarding dosing of axitinib. When used in combination with pembrolizumab, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer (see section 5.1).

For liver enzyme elevations, in patients with RCC being treated with KEYTRUDA in combination with axitinib:

• If ALT or AST ≥3 times ULN but <10 times ULN without concurrent total bilirubin ≥2 times ULN, both KEYTRUDA and axitinib should be withheld until these adverse reactions recover to Grades 0-1. Corticosteroid therapy may be considered. Rechallenge with a si ngle medicine or sequential rechallenge with both medicines after recovery may be considered. If rechallenging with axitinib, dose reduction as per the axitinib SmPC may be considered.
• If ALT or AST ≥10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN, both KEYTRUDA and axitinib should be permanently discontinued and corticosteroid therapy may be considered.

KEYTRUDA in combination with lenvatinib

When used in combination with lenvatinib, one or both medicines should be interrupted as appropriate. Lenvatinib should be withheld, dose reduced, or discontinued in accordance with the instructions in the lenvatinib SmPC for combination with pembrolizumab. No dose reductions are recommended for KEYTRUDA.

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

Special populations

Elderly

No dose adjustment is necessary in patients ≥65 years (see sections 4.4 and 5.1).

Renal impairment

No dose adjustment is needed for patients with mild or moderate renal impairment. KEYTRUDA has not been studied in patients with severe renal impairment (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment is needed for patients with mild or moderate hepatic impairment. KEYTRUDA has not been studied in patients with severe hepatic impairment (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of KEYTRUDA in children below 18 years of age have not been established except in paediatric patients with melanoma or cHL. Currently available data are described in sections 4.8, 5.1 and 5.2.

Method of administration

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

When administering KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be administered first.

When administering KEYTRUDA as part of a combination with enfortumab vedotin, KEYTRUDA should be administered after enfortumab vedo tin when given on the same day.

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

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.

Unopened vial:

2 years.

After preparation of infusion:

Chemical and physical in-use stability has been demonstrated for up to 42 days at 2°C to 8°C or at 23°C to 27°C. Protect from light. 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, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 7 days at 2°C to 8°C, or 12 hours at room temperature, unless dilution has taken place in controlled and validated aseptic conditions. If refrigerated, the vials and/or intravenous bags must be allowed to come to room temperature prior to use.

Store in a refrigerator (2°C–8°C).

Do not freeze.

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

For storage conditions after dilution of the medicinal product, see section 6.3.

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

Each carton contains one vial.

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.
• If refrigerated, the vials and/or intravenous bags must be allowed to come to room temperatu re prior to use. Translucent to white proteinaceous particles may be seen in diluted solution. 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.