Gently swirl the multidose vial before and in between each dose withdrawal. search for MHRA Yellow Card in the Google Play or Apple App Store. /Pages 3 0 R Nephritis has been reported in patients receiving pembrolizumab (see section 4.8). Uncommon but serious: (see MHRA alerts below for more information) DKA Fournier's Gangrene Lower limb amputation -encourage regular preventative footcare Please see individual drug monographs in BNF/SPC for a complete side-effect profile -see hyperlink in table overleaf. In an independent study (CoV-BOOST study, EudraCT 2021-002175-19) evaluating the use of a Nuvaxovid booster dose in individuals who had completed primary vaccination with an authorised mRNA COVID-19 vaccine or adenoviral vector COVID-19 vaccine, no new safety concerns were identified. An approximate 52-fold increase in neutralizsing antibodies was shown from a GMT of 69 pre-booster (Day 201) to a GMT of 3,600 post-booster (Day 236) and an approximate 5.2-fold increase from a peak GMT (14 days post-Dose 2) of 694. Grades 3-5 adverse reactions in patients with RCC were 80% for pembrolizumab in combination with either axitinib or lenvatinib and 71% for sunitinib alone. Immune-related adverse reactions affecting more than one body system can occur simultaneously. We use some essential cookies to make this website work. In some patients, dizziness and fatigue have been reported following administration of pembrolizumab (see section 4.8). Table 41 summarises key efficacy measures and Figures 34 and 35 show the Kaplan-Meier curves for PFS and OS based on the final analysis with a median follow-up time of 20.2 months (range: 0.3 to 53.1 months) for patients with tumour PD-L1 expression CPS 10. KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic head and neck squamous cell carcinoma in adults whose tumours express PD-L1 with a 50% TPS and progressing on or after platinum-containing chemotherapy (see section 5.1). nephritis (autoimmune nephritis, tubulointerstitial nephritis and renal failure, renal failure acute, or acute kidney injury with evidence of nephritis, nephrotic syndrome, glomerulonephritis and glomerulonephritis membranous), gg. Hypothyroidism is more frequently reported in patients with HNSCC with prior radiation therapy. All patients with BRAF mutant tumours were previously treated with a BRAF inhibitor. Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (8.1%) than in patients who did not receive prior thoracic radiation (3.9%). Patients underwent imaging every 12 weeks after the first dose of pembrolizumab for the first two years, then every 6 months from year 3 to 5, and then annually. Colitis resolved in 130 patients, 2 with sequelae. KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults and adolescents aged 12 years and older with Stage IIB, IIC or III melanoma and who have undergone complete resection (see section 5.1). Administration of Nuvaxovid in pregnancy should only be considered when the potential benefits outweigh any potential risks for the mother and fetus. Assessment of tumour status was performed at 9 weeks, then every 6 weeks through Week 52, followed by every 9 weeks through 24 months. COVID-19 cases were confirmed by polymerase chain reaction (PCR) through a central laboratory. Patients without disease progression could be treated for up to 24 months. Alternatively, adverse events of concern in association with Nuvaxovid can be reported to Novavax at www.NovavaxCovidVaccine.com or via +44 020 3514 1838. stream For RCC patients treated with KEYTRUDA in combination with axitinib, see the SmPC regarding dosing of axitinib. Table 11: Efficacy results in KEYNOTE-054, Figure 6: Kaplan-Meier curve for recurrence-free survival by treatment arm in KEYNOTE-054 (intent to treat population), Figure 7: Kaplan-Meier curve for distant metastasis-free survival by treatment arm in KEYNOTE-054 (intent to treat population). Placebo on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and 5-FU 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for 5-FU administration. It explains how this product was assessed and its authorisation recommended, as well as its conditions of use. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. 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 anti-cancer agents. Safety data of pembrolizumab in the adjuvant melanoma setting in patients 75 years are limited. Among the 5 adolescent participants with advanced melanoma treated on KEYNOTE-051, no patient had a complete or a partial response, and 1 patient had stable disease. Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using RECIST 1.1. Adrenal insufficiency (primary and secondary) has been reported in patients receiving pembrolizumab. The median time to onset of hypothyroidism was 3.4 months (range 1 day to 25.9 months). endobj 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. A direct comparison of pembrolizumab when used in combination with chemotherapy to pembrolizumab monotherapy is not available. Table 43: Efficacy results in KEYNOTE-826 for patients with PD-L1 expression (CPS 1), Pembrolizumab 200 mg every 3 weeks plus Chemotherapy* with or without bevacizumab, Placebo plus Chemotherapy* with or without bevacizumab, * Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin), % 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. The median duration was 1.9 months (range 1 day to 47.1+ months). The baseline characteristics of these 129 patients included: median age 62 years (40% age 65 or older); 81% male; 78% White, 11% Asian, and 2% Black; 23% and 77% with an ECOG performance status 0 or 1, respectively; and 19% with HPV positive tumours. Of the patients who recovered, 92 (84%) were rechallenged with either pembrolizumab (3%) or axitinib (31%) monotherapy or with both (50%). The study also demonstrated a statistically significant improvement in EFS at its pre-specified analysis. This vaccine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially sodium-free. The efficacy of pembrolizumab in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was investigated in KEYNOTE-826, a multicentre, randomised, double-blind, placebo-controlled study that enrolled 617 patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitising agent. Nephritis resolved in 20 patients, 5 with sequelae. endobj Reporting forms and information can be found at https://coronavirus-yellowcard.mhra.gov.uk or you can search for MHRA Yellow Card in the Google Play or Apple App Store. Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Expires . Table 25: Response to pembrolizumab 200 mg every 3 weeks or chemotherapy in patients with previously untreated urothelial carcinoma for whom carboplatin rather than cisplatin was selected by the investigator as the better choice of chemotherapy in KEYNOTE-361, The initial analysis resulted in a HR for OS of 0.82 (95% CI: 0.67, 1.01) with a one-sided p-Value of 0.0316. 0086 136 9073 4191. domogres@spcfloorings.net. There were 20 cases of PCR-confirmed symptomatic mild COVID-19 (Nuvaxovid, n=6 [0.5%]; placebo, n=14 [2.4%]) resulting in a point estimate of efficacy of 79.5% (95% CI: 46.8%, 92.1%). To confirm the patient has no contra-indications to treatment and consider the relevance of any cautions. Non-clinical data reveal no special hazard for humans based on conventional studies of repeat-dose toxicity, local tolerance, genotoxicity, and reproductive and developmental toxicity. KEYTRUDA, in combination with lenvatinib, is indicated for the first-line treatment of advanced renal cell carcinoma in adults (see section 5.1). The KEYNOTE-426 study was not powered to evaluate efficacy of individual subgroups. << When used in combination with lenvatinib, one or both medicines should be interrupted as appropriate. Do not mix the vaccine in the same syringe with any other vaccines or medicinal products. KEYNOTE-204: Controlled study in patients with relapsed or refractory classical Hodgkin lymphoma (cHL). The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1). 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. Pituitary function and hormone levels should be monitored to ensure appropriate hormone replacement. OS was not formally assessed at the time of these analyses. Patients who received prior therapy for melanoma other than surgery were ineligible. 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. Based on the stratified Cox proportional hazard model, Nominal p-Value based on log-rank test stratified by American Joint Committee on Cancer (AJCC) 8th edition T stage. /Parent 3 0 R The median duration was 1.6 months (range 4 days to 43.1+ months). You can use the A-Z list to find an active substance, or search for a medicine. Overall, 431 participants were co-vaccinated with inactivated seasonal influenza vaccines; 217 sub-study participants received Nuvaxovid and 214 received placebo. Do not pool excess vaccine from multiple vials. >> Mutation status: 25% BRAF V600E, 24% KRAS/NRAS. The efficacy of pembrolizumab in combination with chemotherapy as neoadjuvant treatment and then continued as monotherapy as adjuvant treatment after surgery was investigated in the randomised, double-blind, multicentre, placebo-controlled study KEYNOTE-522. Treatment could continue beyond progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients received pembrolizumab 200 mg every 3 weeks until unacceptable toxicity or disease progression. This vaccine contains potassium, less than 1 mmol (39 mg) per dose, that is to say, essentially potassium-free. The study demonstrated statistically significant improvements in OS and PFS for patients randomised to pembrolizumab in combination with chemotherapy with or without bevacizumab compared to placebo in combination with chemotherapy with or without bevacizumab at a pre-specified interim analysis in the overall population. 17 0 obj This file may not be suitable for users of assistive technology. Patients were randomised (2:1) to one of the following treatment arms via intravenous infusion: Pembrolizumab 200 mg on Day 1 every 3 weeks in combination with nab-paclitaxel 100 mg/m2 on Days 1, 8 and 15 every 28 days, or paclitaxel 90 mg/m2 on Days 1, 8, and 15 every 28 days, or gemcitabine 1,000 mg/m2 and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days. Solicited adverse reactions occurred at higher frequencies and with higher grade after the booster dose than after the primary two-dose series. 09/24. Response: Best objective response as confirmed complete response or partial response. Treatment continued until unacceptable toxicity or disease progression as determined by the investigator and confirmed by BICR using RECIST 1.1. 6 0 obj /Type /Pages /Parent 3 0 R 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. All rights reserved. The M1 NED category included patients with metastatic disease who had undergone complete resection of primary and metastatic lesions. This 96-hour hold may include up to 6 hours at room temperature (at or below 25C). The median time to onset of hepatitis was 3.5 months (range 8 days to 26.3 months). The efficacy of pembrolizumab in combination with lenvatinib was investigated in KEYNOTE-775, a randomised, multicentre, open-label, active-controlled study conducted in patients with advanced EC who had been previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. If not used immediately, chemical and physical in-use stability of KEYTRUDA has been demonstrated for 96 hours at 2C to 8C. Hypophysitis occurred in 52 (0.7%) patients, including Grade 2, 3 or 4 cases in 23 (0.3%), 24 (0.3%) and 1 (< 0.1%) patients, respectively, receiving pembrolizumab. KEYTRUDA in combination with axitinib in RCC. Physicians should consider the delayed onset of pembrolizumab effect before initiating treatment in patients with urothelial carcinoma who are considered eligible for carboplatin-based combination chemotherapy. endobj COVID-19 was defined as first episode of PCR-confirmed mild, moderate, or severe COVID-19 with at least one or more of the predefined symptoms within each severity category. Treatment could continue beyond progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Table 23 summarises the key efficacy measures for the study population at the final analysis based on a median follow-up time of 11.4 months (range: 0.1, 41.2 months) for all patients. Patients randomised to pembrolizumab were permitted to continue beyond the first RECIST v1.1-defined disease progression if clinically stable until the first radiographic evidence of disease progression was confirmed at least 4 weeks later with repeat imaging. >> The primary efficacy outcome measures were OS and PFS as assessed by the investigator according to RECIST 1.1 in squamous cell histology, CPS 10, and in all patients. Pneumonitis occurred in 324 (4.2%) patients, including Grade 2, 3, 4 or 5 cases in 143 (1.9%), 81 (1.1%), 19 (0.2%) and 9 (0.1%) patients, respectively, receiving pembrolizumab. Available data suggest that the course of myocarditis and pericarditis following vaccination is not different from myocarditis or pericarditis in general. Medical management guidelines for both medicines should be followed (see section 4.2 and refer to the SmPC for axitinib). The baseline characteristics of these 754 patients included: median age of 61 years (range: 20 to 94); 36% age 65 or older; 82% male; 74% White and 19% Asian; 61% ECOG performance status of 1; and 77% former/current smokers. 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. Please refer to the UK approved SPC and PIL supplied electronically with the German KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma in adults whose tumours express PD-L1 with a 50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. Exclusion criteria were similar to those of KEYNOTE-002. Currently available data are described in sections 4.8, 5.1 and 5.2. Patients without disease progression were treated for up to 24 months (up to 35 cycles). EIR SPC Flooring ZXE2002. 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). Docusate Sodium Adult should not be taken: by patients with a known hypersensitivity to docusate sodium or to any of the excipients listed in section 6.1. 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. Each 0.5 mL dose is withdrawn into a sterile needle and sterile syringe to be administered by intramuscular injection, preferably in the deltoid muscle of the upper arm. Approval date: September 2019, updated December 2019 Review date: December 2021 (or earlier if indicated) South East London Area Prescribing Committee. Enrolment was completed in November 2020. PD-L1 expression was tested retrospectively by immunohistochemistry (IHC) assay with the 22C3 anti-PD-L1 antibody. /Type /Page << Long-term hormone replacement therapy may be necessary in cases of immune-related endocrinopathies. Among the 124 patients enrolled in KEYNOTE-164, the baseline characteristics were: median age 56 years (35% age 65 or older); 56% male; 68% White, 27% Asian; 41% and 59% had an ECOG performance status of 0 and 1, respectively. Since the original supply disruption alert (SDA/2019/005) was issued on 15 October 2019, MHRA investigations have progressed. Paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 + bevacizumab 15 mg/kg, 3. One-sided p-Value based on stratified log-rank test, 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). The baseline characteristics of these 548 patients were: median age of 51 years (range: 22 to 82), 16% age 65 or older; 59% White, 18% Asian, and 1% Black; 37% Hispanic or Latino; 56% and 43% ECOG performance status of 0 or 1, respectively; 63% received bevacizumab as study treatment; 21% with adenocarcinoma and 5% with adenosquamous histology; for patients with persistent or recurrent disease with or without distant metastases, 39% had received prior chemoradiation only and 17% had received prior chemoradiation plus surgery. No dose adjustment is necessary in patients 65 years (see sections 4.4 and 5.1). /Type /Metadata /Rotate 0 Email Address: Registration No: Table 28: Efficacy results for pembrolizumab plus chemotherapy and pembrolizumab as monotherapy by PD-L1 expression in KEYNOTE-048 (CPS 20), Each mL of concentrate contains 25 mg of pembrolizumab. Physicians should consider the benefit/risk balance of the available treatment options (pembrolizumab monotherapy or pembrolizumab in combination with chemotherapy) before initiating treatment in patients with HNSCC whose tumours express PD-L1 (see section 5.1). Based on Miettinen and Nurminen method stratified by MMR Status, ECOG performance status, geographic region, and history of pelvic radiation, Figure 36: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-775 (intent to treat population), Figure 37: Kaplan-Meier curve for progression free-survival by treatment arm in KEYNOTE-775 (intent to treat population). Jevany, 28163 A 30% reduction in antibody responses to Nuvaxovid was noted as assessed by an anti-spike IgG assay with seroconversion rates similar to participants who did not receive concomitant influenza vaccine (see section 4.5 and section 4.8). The incidences of immune-related adverse reactions were 36.1% all Grades and 8.9% for Grades 3-5 for pembrolizumab monotherapy in the adjuvant setting (n=1,480) and 24.2% all Grades and 6.4% for Grades 3-5 in the metastatic setting (n=5,375). This page includes guidance for pharmaceutical companies and regulators on how to prepare and review summaries of product characteristics (SmPCs) for human medicines. Where we have identified any third party copyright information you will need to obtain permission from the copyright holders concerned. Name of the medicinal product 2. Poisoning is usually minimal below 6.5 mmol per litre but may be severe above 8 mmol per litre. There were no Grade 5 hepatic events. Disease characteristics were: 21% HPV positive and 95% had stage IV disease (stage IVa 21%, stage IVb 6%, and stage IVc 69%). 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