Last Updated on eMC 12-07-2018 View medicine  | Merck Sharp & Dohme Limited Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties

Date of revision of text on the SPC:06-07-2018

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



4.1       Therapeutic indications

 

The indication for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy has been restricted to those patients whose tumours express PD‑L1 with a combined positive score (CPS) ≥ 10.

 

4.2          Posology and method of administration

 

The section on PD-L1 testing has been revised to also include patients with previously untreated urothelial carcinoma.

 

4.4       Special warnings and precautions for use

 

The subsection on Disease-specific precautions has been updated to reflect the restriction to the indication

 

5.1       Pharmacodynamic properties

 

The information on KEYNOTE-052: Open label trial in urothelial carcinoma patients ineligible for cisplatin-containing chemotherapy has been updated.

 

Information on KEYNOTE‑361: Ongoing Phase III, randomized, controlled, open-label clinical trial of pembrolizumab with or without platinum-based combination chemotherapy versus chemotherapy as first-line treatment in subjects with advanced or metastatic urothelial carcinoma, has been added.

 

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects
  • Change to section 7 - Marketing authorisation holder

Date of revision of text on the SPC:21-06-2018

Legal Category:POM

Black Triangle (CHM): YES

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Update to section 4.8    Undesirable effects

Pericarditis and pericardial effusion have been added as uncommon A/E’s under the sub heading of cardiac disorders.

A footnote has been added to the existing A/E ‘myasthenic syndrome’ to indicate that the event ‘myasthenia gravis’ is included.

 

 Update to section 7.       MARKETING AUTHORISATION HOLDER

The MAH has been transferred from Merck Sharp & Dohme in the UK to:

 

Merck Sharp & Dohme B.V.

Waarderweg 39

2031 BN Haarlem

The Netherlands

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

Date of revision of text on the SPC:23-03-2018

Legal Category:POM

Black Triangle (CHM): YES

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Updates to section 4.2

Table 1 has been updated to state that treatment should be permanently discontinued for Grade 3 or 4 encephalitis or Guillan- Barré Syndrome.

 

Updates to section 4.4

Sarcoidosis and encephalitis have been added under ‘Other immune-related adverse reactions’.

The information on Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT) has been updated and now reads as follows:

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 (see section 4.8).

 

Allogeneic HSCT prior to treatment with pembrolizumab

In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with pembrolizumab. Patients who experienced GVHD after their transplant procedure may be at an increased risk for GVHD after treatment with pembrolizumab. Consider the benefit of treatment with pembrolizumab versus the risk of possible GVHD in patients with a history of allogeneic HSCT.

 

Update to section 4.8

Encephalitis has been added as a rare adverse reaction under nervous system disorders.

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:08-12-2017

Legal Category:POM

Black Triangle (CHM): YES

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Section 4.8

Pneumonia has been added as an uncommon side effect under the sub heading of ‘Infections and Infestations’.

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Date of revision of text on the SPC:24-08-2017

Legal Category:POM

Black Triangle (CHM): YES

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Updates to section 4.1

The following new indications have been added;

·         Monotherapy for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy

·         Monotherapy for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy

 

Updates to section 4.2

The dose recommendation for urothelial carcinoma has been added as 200mg.

 

Additional information has been added to Table 1 on recommended treatment modifications for pembrolizumab.

Added that Keytruda should be permanently discontinued for Grade 4 or recurrent Grade 3 adverse reactions, unless otherwise specified in Table 1.

 

New information on myocarditis is added under ‘Other immune-related adverse reactions’.

 

Updates to section 4.4

Myocarditis has been added under “other immune-related adverse reactions”

It has been stated under infusion-related reactions that severe infusion related reactions can include hypersensitivity and anaphylaxis.

 

Under 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.

Update to section 4.8

Revisions to the adverse event profile in line with new data.

 

The additional uncommon side effect of myocarditis has been added.

Eczema and dry eye have changed in frequency from common to uncommon.

 

Update to section 5.1

A summary of the KEYNOTE-045 and -052 studies in urothelial carcinoma has been added.

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Date of revision of text on the SPC:23-06-2017

Legal Category:POM

Black Triangle (CHM): YES

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The SPC has been updated as follows:

 

4.2          Posology and method of administration

Information on patients with skin reactions has been added to the table on recommended treatment modifications for Keytruda.

 

4.4          Special warnings and precautions for use:

The following new information has been added:

Immune-related skin adverse reactions:

Immune-related severe skin reactions have been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for suspected severe skin reactions and other causes should be excluded. Based on the severity of the adverse reaction, pembrolizumab should be withheld or permanently discontinued, and corticosteroids should be administered (see section 4.2).

 

Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with fatal outcome, have been reported in patients receiving pembrolizumab (see section 4.8). 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 (see section 4.2).

 

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

 

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.

 

4.8          Undesirable effects

Solid organ transplant rejection has been added as an A/E with an unknown frequency, toxic epidermal necrolysis, Stevens-Johnson syndrome, have been added as rare A/E’s.

The following new section has been added:

Immune-related skin adverse reactions:

Immune-related severe skin reactions occurred in 53 (1.7%) patients, including Grade 2 or 3 cases in 3 (0.1%) and 45 (1.4%) patients, respectively, receiving pembrolizumab. The median time to onset of severe skin reactions was 2.4 months (range 4 days to 21.5 months). The median duration was 1.2 months (range 3 days to 17.8+ months). Severe skin reactions led to discontinuation of pembrolizumab in 5 (0.2%) patients. Severe skin reactions resolved in 36 patients.

 

Rare cases of SJS and TEN, some of them with fatal outcome, have been observed (see sections 4.2 and 4.4).

 

The A/E reporting statement has been updated in line with the latest guidance ( Annex V July 2017).

 

5.1          Pharmacodynamic properties

Updated to reflect the data from the post-authorisation efficacy studies (PAES) in melanoma; studies P001, P002 and P006.  

 

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.3 - Shelf life

Date of revision of text on the SPC:02-05-2017

Legal Category:POM

Black Triangle (CHM): YES

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4.1 -Therapeutic indications.

The new indication has been added  as follows:

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.

4.2         Posology and method of administration

The recommended dose of KEYTRUDA for cHL has been included  as 200mg.

It is noted that although pembrolizumab should be discontinued for Grade 4 toxicity,  there is an exception for haematological toxicity in patients with cHL in which treatment should be withheld until adverse reactions recover to Grade 0-1.

It has been added that data from patients ≥ 65 years are too limited to draw conclusions in the cHL population (see section 5.1).

4.4         Special warnings and precautions for use

The following information has been added:

Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT) in classical Hodgkin lymphoma

Cases of GVHD and hepatic veno-occlusive disease (VOD) have been observed in patients undergoing allogeneic HSCT after previous exposure to pembrolizumab. Until further data become available, careful consideration to the potential benefits of HSCT and the possible increased risk of transplant-related complications should be made case by case (see section 4.8).

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 (see section 5.1).

4.8         Undesirable effects

Update to section 4.8 with revisions to the adverse event profile and patient numbers in line with new data. Of particular note is the following new information:

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 graft-versus-host-disease (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).

5.1         Pharmacodynamic properties

Update to section 5.1 to include a summary of the Keynote 087 and 013 studies in cHL patients.

5.2         Pharmacokinetic properties

New information has been added under Linearity/non-linearity:

The median steady-state through concentrations (Cmin) at 18 weeks was 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.

6.3         Shelf life

The shelf life of the unopened vial of the 50 mg powder has been extended from 2 years to 3 years.

 

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 6.3 - Shelf life
  • Change to section 6.6 - Special precautions for disposal and other handling

Date of revision of text on the SPC:02-02-2017

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



4.4 Special warnings and precautions for use:

The following text has been added to the sub section headed Immune-related adverse reactions
 ‘Immune-related adverse reactions affecting more than one body system can occur simultaneously.’
In addition’ Immune-related adverse reactions, including severe and fatal cases, have been reported in clinical trials or in post-marketing experience’ has been added under the sub-heading "Other immune-related adverse reactions."

6.3 Shelf life:  minor changes to information on reconstitution

6.6 Special precautions for disposal and other handling:  minor changes to the information on preparation and administration

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties

Date of revision of text on the SPC:27-01-2017

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



4.1- Therapeutic indications:

The following new indication has been added : 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.

Minor changes have been made to the existing second line NSCLC indication- changes are in bold:

“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.”

4. 2 Posology and method of administration:

The dose for the new indication has been added: 200 mg for NSCLC that has not been previously treated with chemotherapy.

4.4 Special Warnings and precautions for use: minor changes

4.8 Undesirable effects:

The patient numbers and frequencies of A/E’s have been updated.

Dermatitis acneiform is now classified as uncommon instead of common.

Erythema nodosum has now been classified as rare rather than uncommon.

5.1 Pharmacodynamic properties – A summary of the results from KEYNOTE -024 – Controlled trial of NSCLC patients naive to treatment has been added.

5.2 Pharmacokinetic properties- Minor changes.

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Improved presentation of SPC

Date of revision of text on the SPC:18-08-2016

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



Minor editoral changes have been made throughout.

In section 4.2 the following additional advice is added:

        Method of administration

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

 


In 6.6    Special precautions for disposal and other handling the following clarifications are added.

 

Preparation and administration

·             Prior to reconstitution, the vial of lyophilised powder can be out of refrigeration (temperatures at or below 25°C) for up to 24 hours.

·             Aseptically add 2.3 mL of water for injections to yield a 25 mg/mL (pH 5.2‑5.8) solution of KEYTRUDA. Each vial contains an excess fill of 10 mg (0.4 mL) to ensure the recovery of 50 mg of KEYTRUDA per vial. After reconstitution, 1 mL of concentrate contains 25 mg of pembrolizumab.

·             To avoid foaming, deliver the water along the walls of the vial and not directly on the lyophilised powder.

·             Slowly swirl the vial to allow reconstitution of the lyophilised powder. Allow up to 5 minutes for the bubbles to clear. Do not shake the vial.

·             Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration. Reconstituted KEYTRUDA 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 2 mL (50 mg) of KEYTRUDA and transfer into an intravenous bag containing 0.9% sodium chloride 9 mg/mL (0.9%) or 5% glucose 50 mg/mL (5%) to prepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Mix diluted solution by gentle inversion.

·             Chemical and physical in‑use stability of the reconstituted and diluted solution has been demonstrated for 24 hours at room temperatures (at or below 25°C). From a microbiological point of view, the product must be used immediately. TDo not freeze the reconstituted or 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 must not be longer than a total of 24 hours. This 24 hour hold may include up to 6 hours at room temperatures (at or below 25°C); any additional hold time must be at 2°C 8°C. If refrigerated, allow 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.

 

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:29-07-2016

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

Section 4.1 has been updated to include the following new indication:

For the treatment of locally advanced or metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received approved therapy for these mutations prior to receiving KEYTRUDA.

Other sections of the SmPC have been updated in line with this and to reflect the data from  Keynote 010, a controlled trial in NSCLC patients previously treated with chemotherapy.

Reasons for adding or updating:

  • Change to section 10 - Date of revision of the text
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.4 - Special warnings and precautions for use

Date of revision of text on the SPC:01-04-2016

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



Under section 2. Qualitative and Quantitative Composition: Change to description of reconstituted product ie “After reconstitution, 1 mL of solution concentrate contains 25 mg of pembrolizumab.”

 

Update of sections 4.8, 5.1 and 5.2 of the SmPC with safety and PK data based on the CSR of Study P006v01. This includes the addition of new side effect Guillain-Barré Syndrome to sections 4.4 and 4.8 of the SmPC, changes to the frequencies and description of some AEs and changes to patients numbers.

 

In addition, section 4.4, the text referring to fatal cases of pneumonitis  was revised and minor editorial changes made throughout.

Reasons for adding or updating:

  • Change to section 6.3 - Shelf life

Date of revision of text on the SPC:03-02-2016

Legal Category:POM

Black Triangle (CHM): YES

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SmPC section 6.3:  Shelf life of unopened vial increased from 18 months to 2 years.

Reasons for adding or updating:

  • New SPC for new product

Date of revision of text on the SPC:01-01-0001

Legal Category:POM

Black Triangle (CHM): YES