Supplemental material, sj-pdf-1-opp-10.1177_1078155220957079 for Real-world intensive safety moni... more Supplemental material, sj-pdf-1-opp-10.1177_1078155220957079 for Real-world intensive safety monitoring of biosimilars rituximab and trastuzumab in a Portuguese oncology hospital by Diogo Mendes, Joana Abrantes, Graça Rigueiro, Ana Filipa Pais, Ana Penedones, Carlos Alves and Francisco Batel-Marques in Journal of Oncology Pharmacy Practice
Background/Objective The Janus kinases (JAKs) are cytoplasmic tyrosine kinases associated with me... more Background/Objective The Janus kinases (JAKs) are cytoplasmic tyrosine kinases associated with membrane cytokine receptors that mediate signaling of multiple cytokines and growth factors, contributing to the pathogenesis of multiple autoimmune disorders. The JAK inhibitors are a new class of targeted therapies with proven efficacy in treating rheumatoid arthritis but are associated with an increased risk of infections. This study is aimed at comparing the relative safety of the different JAK inhibitors with regard to the risk of serious infections in patients with rheumatoid arthritis. Methods PubMed, EMBASE, Cochrane Library, and clinicaltrials.gov were searched to identify randomized controlled trials evaluating the efficacy and safety of JAK inhibitors in patients with rheumatoid arthritis. The outcomes assessed were the risk of total and serious infections, tuberculosis, and herpes zoster. Sensitivity analysis disaggregated the results according to background therapy and licensed doses of JAK inhibitors. Results Thirty-seven randomized controlled trials that were included met the inclusion criteria. Compared with filgotinib, adalimumab (4.81; 95% confidence interval [CI], 1.39–16.66), etanercept (6.04; 95% CI, 1.79–20.37), peficitinib (7.56; 95% CI, 1.63–35.12), tofacitinib (4.29; 95% CI, 1.43–12.88), and upadacitinib (4.35; 95% CI, 1.46–13.00) have an increased risk of herpes zoster infection. Risk differences between the drugs became statistically nonsignificant when the sensitivity analysis was conducted. Conclusions The risk of infections seems to be similar among the currently approved JAK inhibitor drugs. Although the initial results suggested that filgotinib could have a reduced risk of herpes zoster, the sensitivity analyses did not support those findings.
Purpose The aim of this study was to assess the safety profiles of two biosimilar medicines (ritu... more Purpose The aim of this study was to assess the safety profiles of two biosimilar medicines (rituximab and trastuzumab) in the treatment of cancer patients within a Portuguese oncology hospital. Methods This hospital-based prospective observational study followed a cohort event monitoring approach focused on signalling suspected adverse drug reactions (ADRs). Patients undergoing treatment with rituximab biosimilar CT-P10 (Truxima®) or trastuzumab biosimilar CT-P6 (Herzuma®) were recruited over an 11-month and a 6-month period, respectively. Clinicians identified eligible patients and used paper-based forms to report all ADRs associated with biosimilar medicines. ADR case reports were assessed for seriousness, expectedness and causality in the Pharmacovigilance Unit of Coimbra. Results Ninety-four patients received biosimilar medicines (rituximab, n = 35; trastuzumab, n = 59). Of those, 4 patients (11.4%) experienced 16 ADRs with rituximab and 1 patient (1.7%) experienced 5 ADRs with...
Purpose The aim of this study was to test the feasibility and the usefulness of an intensive safe... more Purpose The aim of this study was to test the feasibility and the usefulness of an intensive safety monitoring program to identify adverse drug reactions for medicines under additional monitoring that are used to treat cancer patients within a Portuguese oncology hospital. Methods This pilot intensive safety monitoring program was a three-month prospective, observational study. Patients undergoing treatment with one of the following medicines were included: nivolumab, olaparib, palbociclib, pembrolizumab, pertuzumab, ramucirumab, ribociclib, trastuzumab emtansine, or trifluridine/tipiracil. Potential eligible patients were identified by pharmacists based on prescription data. Clinicians used proper paper-based reporting forms to record adverse drug reactions. Clinical secretariats sent those reports through an electronic platform to the pharmacovigilance department for analysis. Results Seventy-five patients were on treatment with selected medicines. Of those, 33 (44%) experienced a...
The number needed to treat (NNT) is an absolute effect measure that has been used to assess benef... more The number needed to treat (NNT) is an absolute effect measure that has been used to assess beneficial and harmful effects of medical interventions. Several methods can be used to calculate NNTs, and they should be applied depending on the different study characteristics, such as the design and type of variable used to measure outcomes. Whether or not the most recommended methods have been applied to calculate NNTs in studies published in the medical literature is yet to be determined. The aim of this study is to assess whether the methods used to calculate NNTs in studies published in medical journals are in line with basic methodological recommendations. The top 25 high-impact factor journals in the "General and/or Internal Medicine" category were screened to identify studies assessing pharmacological interventions and reporting NNTs. Studies were categorized according to their design and the type of variables. NNTs were assessed for completeness (baseline risk, time hor...
Objectives The aim of this study was to analyze and characterize the outcomes of the Central Port... more Objectives The aim of this study was to analyze and characterize the outcomes of the Central Portugal Regional Pharmacovigilance Unit over a 6-year period. Methods Spontaneous reports received between January 2009 and December 2014 were considered. The annual reporting ratios were estimated. The cases were characterized according to their seriousness, previous description, causality assessment, reporting professional, pharmacotherapeutic groups of the suspected drugs, and type of adverse drug reactions most frequently reported. Results The Pharmacovigilance Unit received 1277 reports that contained 3222 adverse events. In 2014, the reporting rate was estimated at 124 reports per million inhabitants. Sixty-five percent of the reports were assessed as serious. Seventy-three percent of the cases were assessed as being at least possibly related with the suspected drug. Physicians reported 49% of the cases. The suspected drugs most frequently reported were “anti-infectives for systemic u...
To explore the usefulness of number needed to treat to be harmed (NNTH), in benefit-risk assessme... more To explore the usefulness of number needed to treat to be harmed (NNTH), in benefit-risk assessments, by studying the agreement between NNTH values and withdrawals of medicines from European market due to safety reasons. Medicines with data from longitudinal studies were included. Studies were identified from European Medicines Agency's Reports. Meta-analyses were performed to pool odds ratios (OR) with 95% confidence-intervals (CI). Published control event rates were applied to ORs to calculate NNTHs (95%CI) for selected adverse events. NNTH (95%CI) decreased from pre- to post-marketing for the eight medicines included: peripheral neuropathy (∞ vs. 12[non-significant; NS] with almitrine; heart valve disease with benfluorex (∞ vs. NNTH ranging from 7[4-13] to 7[5-9]); myopathy (-4096[NS] vs. 797[421-1690]), new-onset diabetes (113[NS] vs. 390[425-778]), bleeding (∞ vs. 517[317-1153]), and infection (∞ vs. 253[164-463]) with niacin-laropiprant; psychiatric disorders (12[7-34] vs....
This meta-analysis aims to evaluate the risk of ophthalmic adverse effects associated with MEK in... more This meta-analysis aims to evaluate the risk of ophthalmic adverse effects associated with MEK inhibitors. A literature search was conducted in PubMed and the Cochrane Library to identify randomized clinical trials (RCTs) which have been designed to evaluate the efficacy and safety of MEK inhibitors. Overall risk of ophthalmic adverse effects, chorioretinopathy, retinal detachment, blurred vision, uveitis, and eye haemorrhage were the assessed outcomes. Peto odds ratios (ORs) with their 95% confidence intervals (CIs) were pooled. Between-study heterogeneity was assessed using I2 statistics. Thirteen RCTs were included in this meta-analysis. Overall, MEK inhibitors were associated with an increased risk of ophthalmic adverse effects (OR 2.24; 95% CI 1.75-2.87; p < 0.0001; I2 = 86.5%). An increased risk was also estimated for chorioretinopathy (OR 5.44; 95% CI 2.89-10.23; p < 0.0001; I2 = 0%), retinal detachment (OR 6.54; 95% CI 3.28-13.03; p < 0.0001; I2 = 0%), and blurred v...
Introdução: Caracterizar as notificações espontâneas de eventos adversos a medicamentos recebidas... more Introdução: Caracterizar as notificações espontâneas de eventos adversos a medicamentos recebidas pela Unidade de Farmacovigilância do Centro.Material e Métodos: Consideraram-se todas as notificações reportadas entre 01/2001 e 12/2013. Estimaram-se taxas de notificação anuais. Os casos foram caracterizados quanto à gravidade, conhecimento prévio, causalidade imputada, origem e grupo profissional do notificador, tipo de evento adverso e grupos farmacoterapêuticos onde se incluem os medicamentos suspeitos com maior prevalência de notificação.Resultados: A Unidade recebeu 2408 notificações, que continham 5749 eventos adversos. No ano de 2013 foi registada uma taxa de notificação de 171 notificações/milhão de habitantes. Do total de notificações, 55% foram classificadas como graves. Das notificações com causalidade imputada, 90% tinham uma relação pelo menos possível com o medicamento suspeito. Os medicamentos que originaram maior número de notificações foram os anti-infeciosos para uso...
Pharmacoepidemiology and drug safety, Jan 16, 2015
Our aim is to investigate the usefulness of metric indices in post-marketing safety evaluations b... more Our aim is to investigate the usefulness of metric indices in post-marketing safety evaluations by estimating number needed to harm (NNH) values for cardiovascular (CV) adverse outcomes for rosiglitazone and pioglitazone. Reports from regulatory authorities (RAs) were consulted, and Medline searches were performed to identify studies assessing CV risks [all-cause death, CV death, myocardial infarction (MI), stroke, or congestive heart failure (CHF)] for thiazolidinediones. Meta-analyses were performed to pool evidence from randomized controlled trials (RCTs) and observational studies (OS). NNHs [with 95% confidence intervals (CI)] per year were estimated for CV adverse events. Reports from RAs included two meta-analyses of short-term RCTs, two long-term RCTs (RECORD and PROACTIVE), and a systematic review of OS (n = 29). The Medline search identified six additional OS. Statistically significant NNH values were obtained for the following: (i) rosiglitazone versus control on MI and CH...
ABSTRACT The aim of this work is to investigate the performance and energy efficiency achieved by... more ABSTRACT The aim of this work is to investigate the performance and energy efficiency achieved by an integrated system based on two different ethanol fuel processor configurations: a Conventional Reactor (CR) and a Membrane Reactor (MR). The CR-based configuration system consists of an ethanol reformer followed by two water-gas shift reactors operating at high and low temperatures. The final hydrogen purification is carried out by a preferential oxidizer in order to reduce the CO concentration before feeding the polymer electrolyte membrane fuel cell (PEMFC). A multi-tubular MR process using thin Pd–Ag tubes has also been considered, where the water-gas shift reaction and the hydrogen separation take place simultaneously.The analysis showed that the MR process configuration possesses a simpler system design with a minor advantage in terms of energy efficiency (30%) compared with the conventional system (27%). Moreover, a detailed parametric analysis concerning the effects of water-to-ethanol molar ratio, reaction pressure, reformer and MR temperature, sweep-gas molar ratio and MR configuration on the achieved performance (hydrogen yield) and energy efficiency of the system has also been done.The importance of optimizing integrated systems is shown since the optimal operating conditions from a global efficiency analysis point of view are in general distinct when compared with those obtained when focusing on the reformer reactor or individual process units alone.
Supplemental material, sj-pdf-1-opp-10.1177_1078155220957079 for Real-world intensive safety moni... more Supplemental material, sj-pdf-1-opp-10.1177_1078155220957079 for Real-world intensive safety monitoring of biosimilars rituximab and trastuzumab in a Portuguese oncology hospital by Diogo Mendes, Joana Abrantes, Graça Rigueiro, Ana Filipa Pais, Ana Penedones, Carlos Alves and Francisco Batel-Marques in Journal of Oncology Pharmacy Practice
Background/Objective The Janus kinases (JAKs) are cytoplasmic tyrosine kinases associated with me... more Background/Objective The Janus kinases (JAKs) are cytoplasmic tyrosine kinases associated with membrane cytokine receptors that mediate signaling of multiple cytokines and growth factors, contributing to the pathogenesis of multiple autoimmune disorders. The JAK inhibitors are a new class of targeted therapies with proven efficacy in treating rheumatoid arthritis but are associated with an increased risk of infections. This study is aimed at comparing the relative safety of the different JAK inhibitors with regard to the risk of serious infections in patients with rheumatoid arthritis. Methods PubMed, EMBASE, Cochrane Library, and clinicaltrials.gov were searched to identify randomized controlled trials evaluating the efficacy and safety of JAK inhibitors in patients with rheumatoid arthritis. The outcomes assessed were the risk of total and serious infections, tuberculosis, and herpes zoster. Sensitivity analysis disaggregated the results according to background therapy and licensed doses of JAK inhibitors. Results Thirty-seven randomized controlled trials that were included met the inclusion criteria. Compared with filgotinib, adalimumab (4.81; 95% confidence interval [CI], 1.39–16.66), etanercept (6.04; 95% CI, 1.79–20.37), peficitinib (7.56; 95% CI, 1.63–35.12), tofacitinib (4.29; 95% CI, 1.43–12.88), and upadacitinib (4.35; 95% CI, 1.46–13.00) have an increased risk of herpes zoster infection. Risk differences between the drugs became statistically nonsignificant when the sensitivity analysis was conducted. Conclusions The risk of infections seems to be similar among the currently approved JAK inhibitor drugs. Although the initial results suggested that filgotinib could have a reduced risk of herpes zoster, the sensitivity analyses did not support those findings.
Purpose The aim of this study was to assess the safety profiles of two biosimilar medicines (ritu... more Purpose The aim of this study was to assess the safety profiles of two biosimilar medicines (rituximab and trastuzumab) in the treatment of cancer patients within a Portuguese oncology hospital. Methods This hospital-based prospective observational study followed a cohort event monitoring approach focused on signalling suspected adverse drug reactions (ADRs). Patients undergoing treatment with rituximab biosimilar CT-P10 (Truxima®) or trastuzumab biosimilar CT-P6 (Herzuma®) were recruited over an 11-month and a 6-month period, respectively. Clinicians identified eligible patients and used paper-based forms to report all ADRs associated with biosimilar medicines. ADR case reports were assessed for seriousness, expectedness and causality in the Pharmacovigilance Unit of Coimbra. Results Ninety-four patients received biosimilar medicines (rituximab, n = 35; trastuzumab, n = 59). Of those, 4 patients (11.4%) experienced 16 ADRs with rituximab and 1 patient (1.7%) experienced 5 ADRs with...
Purpose The aim of this study was to test the feasibility and the usefulness of an intensive safe... more Purpose The aim of this study was to test the feasibility and the usefulness of an intensive safety monitoring program to identify adverse drug reactions for medicines under additional monitoring that are used to treat cancer patients within a Portuguese oncology hospital. Methods This pilot intensive safety monitoring program was a three-month prospective, observational study. Patients undergoing treatment with one of the following medicines were included: nivolumab, olaparib, palbociclib, pembrolizumab, pertuzumab, ramucirumab, ribociclib, trastuzumab emtansine, or trifluridine/tipiracil. Potential eligible patients were identified by pharmacists based on prescription data. Clinicians used proper paper-based reporting forms to record adverse drug reactions. Clinical secretariats sent those reports through an electronic platform to the pharmacovigilance department for analysis. Results Seventy-five patients were on treatment with selected medicines. Of those, 33 (44%) experienced a...
The number needed to treat (NNT) is an absolute effect measure that has been used to assess benef... more The number needed to treat (NNT) is an absolute effect measure that has been used to assess beneficial and harmful effects of medical interventions. Several methods can be used to calculate NNTs, and they should be applied depending on the different study characteristics, such as the design and type of variable used to measure outcomes. Whether or not the most recommended methods have been applied to calculate NNTs in studies published in the medical literature is yet to be determined. The aim of this study is to assess whether the methods used to calculate NNTs in studies published in medical journals are in line with basic methodological recommendations. The top 25 high-impact factor journals in the "General and/or Internal Medicine" category were screened to identify studies assessing pharmacological interventions and reporting NNTs. Studies were categorized according to their design and the type of variables. NNTs were assessed for completeness (baseline risk, time hor...
Objectives The aim of this study was to analyze and characterize the outcomes of the Central Port... more Objectives The aim of this study was to analyze and characterize the outcomes of the Central Portugal Regional Pharmacovigilance Unit over a 6-year period. Methods Spontaneous reports received between January 2009 and December 2014 were considered. The annual reporting ratios were estimated. The cases were characterized according to their seriousness, previous description, causality assessment, reporting professional, pharmacotherapeutic groups of the suspected drugs, and type of adverse drug reactions most frequently reported. Results The Pharmacovigilance Unit received 1277 reports that contained 3222 adverse events. In 2014, the reporting rate was estimated at 124 reports per million inhabitants. Sixty-five percent of the reports were assessed as serious. Seventy-three percent of the cases were assessed as being at least possibly related with the suspected drug. Physicians reported 49% of the cases. The suspected drugs most frequently reported were “anti-infectives for systemic u...
To explore the usefulness of number needed to treat to be harmed (NNTH), in benefit-risk assessme... more To explore the usefulness of number needed to treat to be harmed (NNTH), in benefit-risk assessments, by studying the agreement between NNTH values and withdrawals of medicines from European market due to safety reasons. Medicines with data from longitudinal studies were included. Studies were identified from European Medicines Agency's Reports. Meta-analyses were performed to pool odds ratios (OR) with 95% confidence-intervals (CI). Published control event rates were applied to ORs to calculate NNTHs (95%CI) for selected adverse events. NNTH (95%CI) decreased from pre- to post-marketing for the eight medicines included: peripheral neuropathy (∞ vs. 12[non-significant; NS] with almitrine; heart valve disease with benfluorex (∞ vs. NNTH ranging from 7[4-13] to 7[5-9]); myopathy (-4096[NS] vs. 797[421-1690]), new-onset diabetes (113[NS] vs. 390[425-778]), bleeding (∞ vs. 517[317-1153]), and infection (∞ vs. 253[164-463]) with niacin-laropiprant; psychiatric disorders (12[7-34] vs....
This meta-analysis aims to evaluate the risk of ophthalmic adverse effects associated with MEK in... more This meta-analysis aims to evaluate the risk of ophthalmic adverse effects associated with MEK inhibitors. A literature search was conducted in PubMed and the Cochrane Library to identify randomized clinical trials (RCTs) which have been designed to evaluate the efficacy and safety of MEK inhibitors. Overall risk of ophthalmic adverse effects, chorioretinopathy, retinal detachment, blurred vision, uveitis, and eye haemorrhage were the assessed outcomes. Peto odds ratios (ORs) with their 95% confidence intervals (CIs) were pooled. Between-study heterogeneity was assessed using I2 statistics. Thirteen RCTs were included in this meta-analysis. Overall, MEK inhibitors were associated with an increased risk of ophthalmic adverse effects (OR 2.24; 95% CI 1.75-2.87; p < 0.0001; I2 = 86.5%). An increased risk was also estimated for chorioretinopathy (OR 5.44; 95% CI 2.89-10.23; p < 0.0001; I2 = 0%), retinal detachment (OR 6.54; 95% CI 3.28-13.03; p < 0.0001; I2 = 0%), and blurred v...
Introdução: Caracterizar as notificações espontâneas de eventos adversos a medicamentos recebidas... more Introdução: Caracterizar as notificações espontâneas de eventos adversos a medicamentos recebidas pela Unidade de Farmacovigilância do Centro.Material e Métodos: Consideraram-se todas as notificações reportadas entre 01/2001 e 12/2013. Estimaram-se taxas de notificação anuais. Os casos foram caracterizados quanto à gravidade, conhecimento prévio, causalidade imputada, origem e grupo profissional do notificador, tipo de evento adverso e grupos farmacoterapêuticos onde se incluem os medicamentos suspeitos com maior prevalência de notificação.Resultados: A Unidade recebeu 2408 notificações, que continham 5749 eventos adversos. No ano de 2013 foi registada uma taxa de notificação de 171 notificações/milhão de habitantes. Do total de notificações, 55% foram classificadas como graves. Das notificações com causalidade imputada, 90% tinham uma relação pelo menos possível com o medicamento suspeito. Os medicamentos que originaram maior número de notificações foram os anti-infeciosos para uso...
Pharmacoepidemiology and drug safety, Jan 16, 2015
Our aim is to investigate the usefulness of metric indices in post-marketing safety evaluations b... more Our aim is to investigate the usefulness of metric indices in post-marketing safety evaluations by estimating number needed to harm (NNH) values for cardiovascular (CV) adverse outcomes for rosiglitazone and pioglitazone. Reports from regulatory authorities (RAs) were consulted, and Medline searches were performed to identify studies assessing CV risks [all-cause death, CV death, myocardial infarction (MI), stroke, or congestive heart failure (CHF)] for thiazolidinediones. Meta-analyses were performed to pool evidence from randomized controlled trials (RCTs) and observational studies (OS). NNHs [with 95% confidence intervals (CI)] per year were estimated for CV adverse events. Reports from RAs included two meta-analyses of short-term RCTs, two long-term RCTs (RECORD and PROACTIVE), and a systematic review of OS (n = 29). The Medline search identified six additional OS. Statistically significant NNH values were obtained for the following: (i) rosiglitazone versus control on MI and CH...
ABSTRACT The aim of this work is to investigate the performance and energy efficiency achieved by... more ABSTRACT The aim of this work is to investigate the performance and energy efficiency achieved by an integrated system based on two different ethanol fuel processor configurations: a Conventional Reactor (CR) and a Membrane Reactor (MR). The CR-based configuration system consists of an ethanol reformer followed by two water-gas shift reactors operating at high and low temperatures. The final hydrogen purification is carried out by a preferential oxidizer in order to reduce the CO concentration before feeding the polymer electrolyte membrane fuel cell (PEMFC). A multi-tubular MR process using thin Pd–Ag tubes has also been considered, where the water-gas shift reaction and the hydrogen separation take place simultaneously.The analysis showed that the MR process configuration possesses a simpler system design with a minor advantage in terms of energy efficiency (30%) compared with the conventional system (27%). Moreover, a detailed parametric analysis concerning the effects of water-to-ethanol molar ratio, reaction pressure, reformer and MR temperature, sweep-gas molar ratio and MR configuration on the achieved performance (hydrogen yield) and energy efficiency of the system has also been done.The importance of optimizing integrated systems is shown since the optimal operating conditions from a global efficiency analysis point of view are in general distinct when compared with those obtained when focusing on the reformer reactor or individual process units alone.
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