Should intravitreal dexamethasone implant in refractory diabetic macular edema be used as an adjuvant therapy or switch therapy?

PURPOSE: To compare the outcomes of intravitreal dexamethasone implant used as either an adjuvant or a switching therapy for diabetic macular edema in patients with poor anatomic response after three consecutive monthly injections of ranibizumab. METHODS: This retrospective study included patients with diabetic macular edema who received three consecutive doses of ranibizumab as initial therapy and demonstrated poor response. A single dose of intravitreal de xamethasone implant was administered to these patients. The patients were divided into two groups according to the treatment modalities: the adjuvant therapy group, consisting of patients who continued treatment with ranibizumab injection after receiving intravitreal dexamethasone implant, and the switch therapy group, consisting of patients who were switched from ranibizumab treatment to intravitreal dexamethasone implant as needed. The main outcome measurements were best corrected visual acuity and central retinal thickness at baseline and at 3, 6, 9, and 12 months of follow-up. RESULTS: In this study that included 64 eyes of 64 patients, the best corrected visual acuity and central retinal thickness values did not significantly differ between the groups at baseline and at 6 months of follow-up (p>0.05). However, at 12 months, the best corrected visual acuity values in the adjuvant and switch therapy groups were 0.46 and 0.35 LogMAR, respectively (p=0.012), and the central retinal thickness values were 344.8 and 270.9, respectively (p=0.007). CONCLUSIONS: In a real-world setting, it seems more reasonable to use intravitreal dexamethasone implant as a switch therapy rather than an adjuvant therapy for diabetic macula edema refractory to ranibizumab despite three consecutive monthly injections of ranibizumab. Patients switched to intravitreal dexamethasone implant were found to have better anatomic and visual outcomes at 12 months than those who continued ranibizumab therapy despite their less-than-optimal responses.

ARE WE READY FOR MULTIPLE SWITCHES BETWEEN REFERENCE PRODUCTS AND BIOSIMILARS?

Inflammatory bowel diseases (IBD) currently impose an immense social and economic burden on society in terms of both direct and indirect healthcare costs. Their incurable and progressive nature results in an unavoidable lifetime expense. The introduction of infliximab more than two decades ago had revolutionized IBD treatment. Nowadays, while biologic drugs comprise various vital therapeutic options for patients, they can be associated to significant costs to healthcare systems. The most crucial benefit of biosimilars is that they bring more significant cost reduction and increase access to advanced therapies. They also allow the treatment of newly diagnosed patients and dose optimization for those who need it. There is an inverse relationship between price and demand for treatment with biologics. For a more significant reduction in cost to be possible, greater use of biosimilars is necessary. For this to occur, it is imperative not only to use biosimilars in naïve patients but also to switch to biosimilars in those patients who have started therapy with reference biologics. At present, randomized and observational studies have demonstrated effectiveness and safety results in recommending a single switch between a reference product and a biosimilar, and vice versa. The purpose of this manuscript is to review the literature and discuss whether scientific evidence is enough to support multiple switches of biologics and biosimilars in IBD patients.

Reversibility of Neuropsychiatric Adverse Events after Switching to Darunavir/Cobicistat or Doravirine in Men on INSTI-Based Regimen.

Integrase strand transfer inhibitors (INSTI) are associated with neuropsychiatric adverse events (NPAEs). The aim of this study was to evaluate improvements in NPAEs after switching an INSTI-based regimen to darunavir/cobicistat (DRV/c) or doravirine (DOR). Methods: A prospective cohort study was conducted to evaluate the reversibility of NPAEs via the Patient Health Questionnaire (PHQ-9), the Insomnia Severity Index (ISI), and the Hospital Anxiety and Depression Scale (HADS-A and D) in patients who started antiretroviral therapy with dolutegravir (DTG) or bictegravir (BIC). These patients were switched to DRV/c or DOR. Scales were compared at the moment of the switch and 12 weeks later. Results: We included 1153 treatment-naïve men, 676 (58.7%) with BIC and 477 (41.3%) with DTG. A total of 32 (2.7%) experienced NPAEs that led to discontinuation. Insomnia was found in 20 patients; depression via PHQ-9 in 21 patients, via HADS-D in 5 patients, and anxiety via HADS-A in 12 patients. All of them were evaluated by a psychiatrist at the moment of the symptoms; 7 (21.8%) started psychotropic drugs. After 12 weeks of follow-up, PHQ-9, ISI, HADS-A, and HADS-D decreased, with a p-value ≤ 0.05. Conclusions: NPAEs seem to improve after switching to a DRV/c- or DOR-based regimen after the first 4 and 12 weeks.

Foeniculum vulgare (fennel) and Cymbopogon winterianus (citronella) essential oils to replace a growth promoter in the diet of European quails / Óleos essenciais de Foeniculum vulgare (erva doce) e Cymbopogon winterianus (citronela) em substituição a um promotor de crescimento na dieta de codornas europeias

The objective of this study was to evaluate the replacement of a growth-promoting antibiotic by fennel (Foeniculum vulgare) and citronella (Cymbopogon winterianus) essential oils in the quail diet on performance variables (weight gain, feed intake, feed conversion), as well as the carcass and cut yield. To do so, 240 one-day-old male and female European quails were distributed in a completely randomized design with four treatments, five replications and 12 animals per experimental unit. The treatments consisted of: PC ­ positive control diet without fennel or citronella essential oils and with the growth promoter (zinc bacitracin); NC ­ negative control diet without essential oils and without growth promoter; CEO - Diet with +0.078% citronella essential oil without the growth promoter; and FEO - Diet with +0.078% fennel essential oil without the growth promoter. The experiment lasted 42 days, in which the performance variables were analyzed in three periods (1-14 days; 14-21 days; and 22-42 days) and the carcass and cut yield in two periods (at 21 and 42 days). The observed data were submitted to analysis of variance and the comparison of means was performed using the Tukey's test at 5% significance. The presence of essential oils positively influenced (P<0.05) the performance variables and the carcass and cuts yield in all analyzed periods. The use of fennel and citronella essential oils to replace zinc bacitracin in the diet of European quails improves performance and the carcass and cut yield.(AU)

Objetivou-se avaliar a substituição de um antibiótico promotor de crescimento por óleos essenciais de erva-doce (Foeniculum vulgare) e citronela (Cymbopogon winterianus) na dieta de codornas sobre o desempenho, rendimento de carcaça e cortes. Para isso, foram utilizadas 240 codornas europeias machos e fêmeas de um dia de idade distribuídos em delineamento inteiramente ao acaso com quatro tratamentos, cinco repetições e 12 animais por unidade experimental. Os tratamentos consistiram em: CP- Dieta sem os óleos essenciais de erva-doce ou citronela e com o promotor de crescimento (bacitracina de zinco); CN- Dieta sem os óleos essenciais e sem o promotor de crescimento; OC- Dieta com + 0,078% de óleo essencial de citronela sem o promotor de crescimento; OED- Dieta com + 0,078% de óleo essencial de erva-doce sem o promotor de crescimento. O experimento teve duração de 42 dias, no qual as variáveis de desempenho foram analisadas em três períodos (1-14 dias; 14-21 dias e 22-42 dias) e o rendimento de carcaça e cortes em dois períodos (aos 21 e 42 dias). Os dados observados foram submetidos à análise de variância e a comparação das médias foi realizada pelo teste de Tukey a 5%. A presença dos óleos essenciais influenciou positivamente (P<0,05) as variáveis de desempenho e o rendimento de carcaça e cortes em todos os períodos analisados. A utilização de óleos essenciais de erva-doce e citronela em substituição a bacitracina de zinco na dieta de codornas europeias melhora o desempenho e o rendimento de carcaça e cortes.(AU)

Biosimilar-to-Biosimilar Switching: What is the Rationale and Current Experience?

Over time, clinicians have become increasingly comfortable embracing the prescription of biosimilars-highly similar versions of innovator or reference biological agents-for their patients with inflammatory diseases. Although a switch from a reference product to a licensed biosimilar version (or vice versa) is a medical decision robustly supported by the stepwise accumulation of clinical trial evidence concerning comparable safety, immunogenicity, and efficacy between these products, a switch from one biosimilar to another biosimilar of the same reference product, or a cross-switch, is not. Similarity among biosimilars of a reference product is not a regulatory agency concern and therefore is unlikely to be investigated in randomized controlled trials in the foreseeable future. Yet in clinical practice, across a diverse range of patients, the option to cross-switch from one biosimilar to another can and does arise for valid reasons such as convenience or tolerability issues, or driven by third parties (e.g., payers). In the absence of clinical trial data, clinicians must attempt to objectively evaluate the emerging real-world cross-switching evidence within the context of what is known about the science underpinning a designation of biosimilar. That knowledge then needs to be integrated with what clinicians know about their patients and their disease on a case-by-case basis. This review aims to consolidate relevant emerging real-world data and other key information about biosimilar-to-biosimilar cross-switching for prescribing clinicians. In the absence of clear clinical guidelines addressing this topic at present, this review may serve to facilitate discretionary and educated treatment decision making.

[Hypersensitivity reactions associated with the use of asparaginase in children with acute lymphoblastic leukemia]. / Reacciones de hipersensibilidad asociadas al uso de asparaginasa en niños con leucemia linfoblástica aguda.

INTRODUCTION: The treatment of acute lymphoblastic leukemia (ALL) includes the use of asparaginase (ASP), a drug associated with hypersensitivity reactions (HSR) that requires discontinuing its use. OBJECTIVE: To determine the incidence of HSR associated with ASP that require discontinuation of its use and des cribe them, and to verify if there is a relationship between HSR incidence and protocols or survival. PATIENTS AND METHOD: Retrospective study. Clinical records of all patients (1-15 years) diagnosed with ALL between January 2010 and December 2015 at the Hospital Luis Calvo Mackenna were reviewed. The incidence of HSR to ASP was determined and classified according to the CTCAE v5.0 severity score. We analyzed the relative risk of HSR using Fisher's test and the survival with the Kaplan-Meier estimator. RESULTS: 110 patients were collected. During the first treatment (ALL-IC- BFM), the incidence of HSR to L-ASP was 55%, therefore it was changed to PEG-ASP as second-line treatment, and 44% of them had HSR, and ASP should discontinued in 25% of patients. Of all the HSR to ASP, 77% were anaphylactic (CTCAE 3-5). Patients treated with augmented IB protocol were at higher risk of not completing ASP treatment due to HSR, RR 3.81 (95% CI, 1.98-7.31, p = 0.0001). Patients without HSR in ALL-IC-BFM were at lower risk of relapse, HR 0.29 (95% CI, 0.14-0.62, p = 0.0013). Considering all treatments (ALL-IC-BFM and relapse), patients who completed the ASP treatment had higher overall survival, HR 0.20 (95% CI, 0.07-0.57, p = 0.0026). CONCLUSIONS: HSR to ASP that require discontinuation of treatment are frequent in children with ALL, most of them were severe anaphylactic reactions. This study suggests a better prognosis in patients without HSR to ASP.

Cost and clinical impact of a nonmedical DPP-4 inhibitor switch in patients with diabetes.

BACKGROUND: Nonmedical formulary switches (NMFS) routinely occur in managed health care plans and involve changing preferred medications for reasons outside of clinical considerations. The cost implications of NMFS are infrequently published and the clinical outcomes rarely assessed. OBJECTIVE: To assess the real-world clinical and cost implications of an NMFS involving sitagliptin and linagliptin. METHODS: An NMFS was made to the Geisinger Health Plan (GHP) commercial, health care reform, and Medicaid formularies on February 1, 2018, involving a change in preferred medication from sitagliptin to linagliptin. Claims data from GHP and clinical information from electronic health records of the Geisinger Health System were used to evaluate the cost and clinical impact of this change. Patients aged 18 years or older who were continuously enrolled in a GHP commercial, health care reform, or Medicaid plan throughout the entire study period and had at least 1 fill for sitagliptin during the preswitch phase were included in the study. We investigated the differences in various clinical and economic outcomes from pre- to postswitch among those who switched and remained adherent to the new preferred therapy throughout the 12-month postperiod ("linagliptin switch" group) and patients who did not ("other switch" group). Clinical outcomes included all-cause hospitalization, diabetes-related hospitalization, and glycosylated hemoglobin (HbA1c), while economic measures included changes in per member per month (PMPM) spending. The negative binomial regression model was used to estimate utilization counts. A generalized linear model with a log link and gamma distribution was used to analyze cost data. RESULTS: 1,203 patients met the inclusion criteria. Of these, 501 (41.6%) individuals switched to and remained at least 80% adherent to linagliptin in the postperiod, while 702 (58.4%) did not. No difference between groups was found when comparing the pre- to postswitch change in all-cause hospitalization (incidence rate ratio (IRR) = 1.46, 95% CI = 0.66-3.23, P = 0.3436) or diabetes-related hospitalization (IRR = 1.39, 95% CI = 0.62-3.10, P = 0.4203). Additionally, no difference was found between groups regarding the change in HbA1c 12-month postswitch compared with baseline (difference between groups = -0.10%, 95% CI = -0.39%-0.19%, P = 0.4962). Total PMPM spending was 43% higher in the other switch group compared with the linagliptin switch group (IRR = 1.43, 95% CI = 1.25-1.63, P < 0.0001). This trend was driven by 92% higher medical PMPM spending in the other switch group compared with the linagliptin switch group (IRR = 1.92, 95% CI = 1.58-2.33, P < 0.0001) but was offset by 12% lower pharmacy PMPM spending in the other switch group (IRR = 0.88, 95% CI = 0.82-0.95, P = 0.0009). CONCLUSIONS: An NMFS from sitagliptin to linagliptin resulted in overall health plan savings with no significant changes in health outcomes. DISCLOSURES: Funding for this study was provided by Geisinger Health System, which had no role in the study outside of a final review of the submitted manuscript. Johns and Gionfriddo are Geisinger employees. The authors report no financial conflicts of interest.

Patient profiles as an aim to optimize selection in the second line setting: the role of aflibercept.

Colorectal cancer is the second leading cause of cancer-related death worldwide. For metastatic colorectal cancer (mCRC) patients, it is recommended, as first-line treatment, chemotherapy (CT) based on doublet cytotoxic combinations of fluorouracil, leucovorin, and irinotecan (FOLFIRI) and fluorouracil, leucovorin, and oxaliplatin (FOLFOX). In addition to CT, biological (targeted agents) are indicated in the first-line treatment, unless contraindicated. In this context, most of mCRC patients are likely to progress and to change from first line to second line treatment when they develop resistance to first-line treatment options. It is in this second line setting where Aflibercept offers an alternative and effective therapeutic option, thought its specific mechanism of action for different patient's profile: RAS mutant, RAS wild-type (wt), BRAF mutant, potentially resectable and elderly patients. In this paper, a panel of experienced oncologists specialized in the management of mCRC experts have reviewed and selected scientific evidence focused on Aflibercept as an alternative treatment.

Meloxicam and/or Etoricoxib Could Be Administered Safely in Two Equal Doses during an Open Oral Challenge in Patients with Nonsteroidal Anti-Inflammatory Drug Hypersensitivity.

BACKGROUND: Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are common. These patients require an effective and safe analgesic alternative. OBJECTIVE: The aim of the study was to demonstrate the safety of meloxicam and etoricoxib administered by open oral challenge in 2 equal steps in patients with NSAID hypersensitivity. METHODS: A cross-sectional, descriptive study of patients with a diagnosis of NSAID hypersensitivity who underwent an oral drug provocation test (DPT) with meloxicam or etoricoxib between January 2011 and August 2017 was conducted. The analysis was performed from a database in BD Clinic. RESULTS: Two hundred and twenty-eight oral provocations were performed with an alternative NSAID (203 with meloxicam and 25 with etoricoxib) in 217 patients with hypersensitivity to NSAIDs. The median age was 38 years. Ninety-eight percent of meloxicam and 100% of etoricoxib DPTs were performed in 2 steps (without previous placebo), and 52% and 64% of meloxicam and etoricoxib DPTs, respectively, were performed with 50% of the therapeutic dose in each step. Tolerance to meloxicam was demonstrated in 192 patients (94.5%) and in 100% of patients receiving etoricoxib. CONCLUSIONS: Open oral provocation with meloxicam and etoricoxib carried out in 2 steps without placebo seems to be safe and implies less costs and less time expenditure. Also, it could be performed with 2 equal doses.

Brand-to-Generic Substitution of Buprenorphine/Naloxone Sublingual Film in Puerto Rico: A Case Study.

A 56-year-old patient with a 1-year history of stable maintenance treatment with Suboxone for opioid use disorder (OUD) was switched to a generic formulation in May of 2019. The patient reported experiencing-over the course of the following 3 months-withdrawal symptoms when switched to the Alvogen-produced generic formulation in May of 2019 and then to the Sandoz-produced version in July of that same year, she also was positive for fentanyl during that time. As a result, the buprenorphine dose was increased, and the patient was stable at this new dose using the generic versions. Blood levels pre- and post-change (not reported in previous case reports) showed maximum buprenorphine concentration being reached more quickly when the brand-name drug was used. Additionally, the area under the curve (AUC) values indicate that the generic formulation had higher exposures than the brand-name drug. Based on the clinical impact of the brand-to generic switch in this patient, further research in this area is warranted. In the meantime, clinicians should carefully monitor their patients so that, if warranted, dose adjustments can be made quickly and safely to minimize negatively impacting the OUD therapy outcomes of patients.

Nivolumab treatment beyond progressive disease in advanced non-small cell lung cancer.

PURPOSE: This study evaluated the efficacy and safety of nivolumab treatment beyond progressive disease (PD) in non-small cell lung cancer (NSCLC). PATIENTS/METHODS: Medical records of consecutive patients with advanced NSCLC who received nivolumab between December 2015 and December 2018 were reviewed. Clinical outcomes of three groups of eligible patients who received nivolumab as a second-line treatment after PD were compared based on Response Evaluation Criteria in Solid Tumors v1.1. We conducted subgroup analyses in patients with and without new lesions at first PD. RESULTS: Twenty-eight patients continued nivolumab treatment beyond PD (TBP). Post PD, 46 patients switched to other anti-cancer treatment (OAT), and 21 received no further anti-cancer treatment (NAT). There were no significant differences in overall survival (OS) or survival post progression (SPP) between TBP and OAT groups (OS: 15.6 vs. 13.4 months, P = .40, SPP: 12.2 vs. 9.3 months, P = .42). Subgroup analyses indicated that among patients without new lesions at first PD, SPP was longer in the TBP than in the OAT groups (12.6 vs. 9.3 months, P = .22, HR: 0.64; 95% CI 0.31‒1.31). The frequency of immune-related adverse events leading to discontinuation during nivolumab beyond PD was equivalent to that for pre-PD (10.7 vs. 12.6%). CONCLUSIONS: No significant benefits were associated with continuation of nivolumab for advanced NSCLC patients. Continuation of nivolumab beyond PD could be a more useful option in patients without new lesions at first PD. Treatment-related toxicities require attention during nivolumab treatment not only before PD but also beyond PD.

COVID-19 et les soins palliatifs en contexte de pénuries pendant la pandémie / COVID-19 and palliative care in the context of shortages during the pandemic

CONTEXTE: Le présent document ainsi que les constats qu'il énonce ont été rédigés en réponse à une interpellation du ministère de la Santé et des Services sociaux dans le contexte de l'urgence sanitaire liée à la maladie à coronavirus (COVID-19) au Québec. L'objectif est de réaliser une recension sommaire des données publiées et de mobiliser les savoirs clés afin d'informer les décideurs publics et les professionnels de la santé et des services sociaux. Vu la nature rapide de cette réponse, les constats ou les positions qui en découlent ne reposent pas sur un repérage exhaustif des données publiées, une évaluation de la qualité méthodologique des études avec une méthode systématique ou sur un processus de consultation élaboré. Dans les circonstances d'une telle urgence de santé publique, l'INESSS reste à l'affût de toutes nouvelles données susceptibles de lui faire modifier cette réponse rapide. PRÉSENTATION DE LA DEMANDE: Le midazolam (VersedMC), lorazépam (AtivanMC) ainsi que le phénobarbital font partie des médicaments administrés en soins palliatifs. Le contexte actuel d'urgence sanitaire lié à la COVID-19 exerce une forte pression sur l'usage de ces médicaments. Afin d'être en mesure d'offrir des soins palliatifs de qualité aux personnes qui le nécessitent, et ce, même en cas de pénurie, le MSSS a demandé à l'INESSS de rechercher les médicaments pouvant constituer des alternatives au lorazépam, midazolam et au phénobarbital en soins palliatifs, tout en tenant compte des ruptures de stock actuelles et anticipées de ces médicaments. Une attention particulière a été portée aux moyens permettant de limiter les pertes de produits, ainsi que l'usage du matériel pouvant être appelé à manquer, tels les pompes volumétriques. MÉTHODOLOGIE: Revue de littérature Questions d'évaluation: 1. Quelles sont les alternatives au midazolam (VersedMC), au lorazépam (AtivanMC) et au phénobarbital en soins palliatifs? 2. Quels seraient les moyens permettant de limiter les pertes de ces médicaments? Repérage des publications : Date de la recherche: 9 avril. Une recherche rapide a été effectuée en utilisant les bases de données Pubmed, Medline, Embase, EBM Reviews et le moteur de recherche Google avec les mots-clés suivants: midazolam, lorazepam, phenobarbital, palliative care, palliative sedation, drug shortage. Une recherche manuelle de la littérature a également été effectuée en consultant les sites Web des agences règlementaires, d'agences d'évaluation des technologies de la santé ainsi que ceux d'organismes gouvernementaux, d'associations ou ordres professionnels en lien avec le thème des travaux. CONSTATS DE L'INESSS: Basé sur la documentation scientifique disponible au moment de sa rédaction, et sur les consultations menées, malgré l'incertitude existante dans cette documentation et dans la démarche utilisée, l'INESSS met en lumière que: La pénurie de médicaments, réelle ou potentielle, doit être communiquée localement dès maintenant aux différents intervenants et des actions mises en place immédiatement, si ce n'est pas déjà fait, dans tous les centres hospitaliers du Québec, qu'ils reçoivent ou non des patients atteints de la COVID-19. L'utilisation des options alternatives devrait donc être favorisée dès maintenant afin d'éviter une pression à la baisse sur les stocks des molécules déjà à risque de pénurie. Dans un contexte d'approvisionnement limité et incertain, il faut éviter le gaspillage et minimiser les pertes; de plus, l'usage de certains produits critiques devrait être priorisé et réservé aux situations pour lesquelles les options alternatives sont peu ou pas envisageables. Il est important de bien adapter le choix des médicaments en fonction des symptômes que l'on souhaite soulager, de l'état du patient et du degré de sédation désiré. Pour soutenir les plus petits centres hospitaliers dans l'usage des options alternatives en soins palliatifs, il serait important de faciliter le partage des connaissances développées dans les grands centres hospitaliers au moyen, par exemple, d'un programme de mentorat. Les patients atteints de COVID-19 chez qui l'approche préconisée est palliative devront faire l'objet d'une prise en charge adaptée qui tient compte de la mitigation des risques de transmission ou contamination. Considérant l'évolution de la pandémie et les milieux d'exercice des soins de fin de vie, les pratiques devront néanmoins s'adapter en tenant compte des éléments d'expertise locale et de capacité du milieu à offrir certains soins.

COVID-19 et impact de la substitution du CoumadinMD sur les tests de laboratoire / COVID-19 and the impact of Coumadin® substitution on laboratory tests

CONTEXTE: Le présent document ainsi que les constats qu'il énonce ont été rédigés en réponse à une interpellation du ministère de la Santé et des Services sociaux. L'annonce d'un arrêt de commercialisation de toutes les teneurs de ce produit utilisé par quelque 100000 patients au Québec en période de confinement a suscité des questions quant à la sécurité de la substitution pouvant être validée par des tests de laboratoire, notamment la nécessité de faire un suivi plus étroit du ratio normalisé international (RNI). L'objectif était de réaliser une recension sommaire des données publiées et de mobiliser les savoirs clés afin d'informer les décideurs publics et les professionnels de la santé et des services sociaux. Vu la nature rapide de cette réponse, les constats qui en découlent ne reposent pas sur un repérage exhaustif des données publiées, une évaluation de la qualité méthodologique des études avec une méthode systématique ou sur un processus de consultation élaboré. PRÉSENTATION DE LA DEMANDE: BRISTOL-MYERS SQUIBB CANADA cessera, dans les prochains mois, la vente de CoumadinMD au Canada en raison de problèmes de fabrication. Au Québec, une grande proportion des personnes qui utilisent de la warfarine reçoivent actuellement ce produit novateur. Ces personnes devront donc éventuellement recevoir une version générique de la warfarine pour la poursuite de leur traitement anticoagulant. Il a été demandé à l'INESSS, le 23 avril dernier, d'évaluer les enjeux associés à cette situation, notamment l'impact sur le suivi du RNI. MÉTHODOLOGIE: Revue de littérature Questions d'évaluation : Chez les personnes anticoagulées par la warfarine, est-ce que la substitution du CoumadinMD pour une version générique de la warfarine doit être accompagnée de précautions particulières? Critères de sélection : Aucune limite temporelle ni limitation sur le type de publication n'ont été imposées dans le cadre de cette recension sommaire. Méthodes de recension : La recherche documentaire a été effectuée dans Pubmed avec les mots-clés switch, warfarin et generic. Une recherche manuelle de la littérature a également été effectuée en consultant les sites Internet d'organismes gouvernementaux canadiens et le moteur de recherche Google. Les guides de pratique clinique (GPC) recensés par l'INESSS en 2019 pour l'élaboration d'un guide d'usage optimal (GUO) sur la fibrillation auriculaire chez l'adulte et d'un GUO sur la thrombose veineuse profonde et l'embolie pulmonaire chez l'adulte ont été consultés afin de savoir s'ils contenaient de l'information sur le passage du produit de marque à une version générique de la warfarine. Les monographies des versions génériques de la warfarine ont aussi été consultées, tout comme les différentes lois en vigueur. SOMMAIRE DES RÉSULTATS: État des connaissances scientifiques, expérience d'autres juridictions et contexte législatif: Les auteurs de deux revues systématiques, l'une publiée en 2011 et l'autre en 2008, ont conclu que les versions génériques de la warfarine sont aussi sécuritaires et efficaces que le produit de marque et que le passage du produit de marque à une version générique (jugée bioéquivalente par les autorités) est sécuritaire. Les auteurs précisent toutefois que le passage doit être accompagné d'un suivi étroit du ratio normalisé international (RNI), particulièrement chez les patients à risque [Dentali et al., 2011; Kesselheim et al., 2008]. Dans une étude québécoise publiée en 2019, les auteurs ont rapporté qu'entre le 2 janvier 1996 et le 2 janvier 2016, le taux moyen de visites à l'hôpital (consultation à l'urgence ou admission à l'hôpital, toutes causes confondues) était de 113 pour 100 utilisateurs de warfarine (produit de marque ou version générique) par période de 6 mois et que ce taux moyen était similaire avant et après l'arrivée des génériques de la warfarine sur le marché (le 2 janvier 2001) [Leclerc et al., 2019]. Les GPC recensés dans le cadre de l'élaboration des deux GUO de l'INESSS ne contenaient pas d'information sur le passage du produit de marque à une version générique de la warfarine. Dans les monographies des produits Apo-warfarinMC et Taro-warfarinMC, il est mentionné que pour garantir une maîtrise satisfaisante, il est recommandé d'effectuer des tests de mesure du temps de prothrombine lorsque la warfarine sodique en comprimé est remplacée par d'autres produits à base de warfarine et lorsqu'un traitement par un autre médicament est instauré, interrompu ou administré de façon irrégulière. Il est également mentionné que lorsqu'on passe d'un produit à base de warfarine à un autre, on doit mettre l'accent principalement sur la maîtrise du RNI. Du point de vue légal, au Québec, selon l'article 21 de la Loi sur la pharmacie (Loi sur la pharmacie, article 21. L.R.Q, Chapitre P-10), un pharmacien doit exécuter une ordonnance suivant sa teneur intégrale. Il peut toutefois, pourvu qu'il en avise le client et qu'il l'inscrive à son dossier, substituer au médicament prescrit un médicament dont la dénomination commune est la même, à moins d'indication contraire formulée par l'auteur de l'ordonnance lorsque la situation de la personne le requiert. L'expérience de l'Ontario et la Colombie-Britannique : Les autorités de l'Ontario et de la Colombie-Britannique n'ont pas identifié d'enjeu particulier lorsqu'une majeure partie des personnes traitées avec la warfarine dans leur province respective sont passées du produit de marque à une version générique de la warfarine il y a de cela plusieurs années. D'ailleurs, l'expérience ontarienne a fait l'objet d'une publication scientifique en 2006. Dans cette publication, il est mentionné que le régime provincial d'assurance-médicaments ontarien a instauré le 7 juin 2001 une politique demandant aux pharmaciens d'effectuer la substitution, chez les patients traités par la warfarine, du produit de marque par une version générique. Les médecins étaient informés de ce changement une semaine à l'avance. Les patients pouvaient continuer de recevoir le CoumadinMD en payant la différence de prix. Pour savoir si ce passage a eu des répercussions sur la santé ou les coûts, Paterson et ses collègues ont étudié toutes les prescriptions de warfarine au cours des 40 mois précédant l'adoption de la politique, au cours du mois pendant lequel la politique est entrée en vigueur et au cours des neuf mois suivants. Trois mois après l'entrée en vigueur de la politique, 87% des ordonnances de warfarine impliquaient une formulation générique. Entre les périodes précédant et suivant l'entrée en vigueur de la politique, il n'y a eu aucun changement dans les taux de mesures de RNI et d'hospitalisation pour hémorragie majeure ou thromboembolie cérébrale.

Antiphospholipid Syndrome Committee of the Brazilian Society of Rheumatology position statement on the use of direct oral anticoagulants (DOACs) in antiphospholipid syndrome (APS).

BACKGROUND: The term Direct Oral Anticoagulants (DOACs) refers to a group of drugs that inhibit factor Xa or thrombin. Even though their use for treating different thrombotic or prothrombotic conditions is increasing recently, there is no compelling evidence indicating that those medications are safe in all antiphospholipid syndrome (APS) patients. METHODOLOGY: To address this issue, specialists from the Antiphospholipid Syndrome Committee of the Brazilian Society of Rheumatology performed a comprehensive review of the literature regarding DOACs use in APS to answer the three following questions: (1) potential mechanisms of action of these drugs that could be relevant to APS pathogenesis, (2) DOACs interference on lupus anticoagulant testing, and (3) the efficacy of DOACs in APS. POSITION STATEMENT: After critically reviewing the relevant evidence, the authors formulated 8 Position Statements about DOACs use in APS. CONCLUSION: DOACs should not be routinely used in APS patients, especially in those with a high-risk profile (triple positivity to aPL, arterial thrombosis, and recurrent thrombotic events). In addition, DOACs interferes with LA testing, leading to false-positive results in patients investigating APS.

Satisfaction and knowledge among patients with HIV after switching from tenofovir to tenofovir alafenamide in regimens containing emtricitabine and rilpivirine / [Grado de satisfacción y conocimiento de pacientes positivos para HIV ante el cambio de tenofovir a tenofovir-alafenamida en tratamientos con emtricitabina y rilpivirina].

Introduction: Satisfaction and knowledge among patients with HIV after switching from tenofovir to tenofovir/alafenamide remain unexplored. Given that both parameters are associated with better health outcomes it is relevant to measure them in patients during routine clinical practice. Objective: To evaluate the degree of knowledge and satisfaction in patients who had their antiretroviral regimen switched from rilpivirine (RPV)/emtricitabine (FTC)/TDF to RPV/FTC/TAF. Materials and methods: We conducted a prospective study in a third-level hospital between September, 2018, and November, 2018. We included patients who had previously been treated with RPV/FTC/TDF and collected their RPV/FTC/TAF treatment in the second visit. A 5-point Likert-type agreement/disagreement scale was used to assess satisfaction and knowledge regarding the medication switch. Results: We included 116 patients in the study of whom 75% were satisfied and 64% had a high-level of knowledge. Young patients were less satisfied with the way in which the change was explained (p=0.0487). Concerning the new medication, the patients were better informed about its renal (85% of them) and bone benefits (82%) than about its adverse effects on the lipid profile (40%). Conclusions: The patients were generally satisfied with the change in medication and well nformed about the dosage and advantages of TAF over TDF, but less well informed about the possible adverse effects of TAF.

Introducción. La satisfacción y el conocimiento del cambio de tenofovir por tenofovir-alafenamida en pacientes con HIV no se han estudiado aún. Estos dos parámetros se relacionan con mejores resultados en salud y, por lo tanto, es importante medirlos durante la práctica clínica habitual. Objetivo. Evaluar el grado de conocimiento y satisfacción de los pacientes positivos para HIV ante el cambio de tratamiento antirretroviral con rilpivirina, emtricitabina y tenofovir (RPV-FTC-TDF) por rilpivirina, emtricitabina y tenofovir-alafenamida (RPV-FTC-TAF). Materiales y métodos. Se llevó a cabo un estudio prospectivo en un hospital de tercer nivel entre los meses de septiembre y noviembre de 2018. Se incluyeron pacientes previamente tratados con RPV-FTC-TDF que acudían por segunda vez a consulta para recibir el tratamiento con RPV-FTC-TAF. La satisfacción y el grado de conocimiento se analizaron mediante nueve preguntas, usando una escala de tipo Likert de 5 puntos para evaluar el grado de acuerdo. Resultados. Se incluyeron 116 pacientes en el estudio. El 75 % de ellos se mostró satisfecho con el cambio y se consideró que el 64 % conocía lo que implicaba. Los pacientes jóvenes se mostraron menos satisfechos con el modo en que se les explicó el cambio (p=0,0487). Los pacientes estaban mejor informados sobre las ventajas renales (85 % de conocimiento) y óseas (82 %) de la nueva medicación, que sobre sus inconvenientes para el perfil lipídico (40 %). Conclusiones. En general, los pacientes se mostraron satisfechos con el cambio de medicación y conocían la posología del medicamento y las ventajas de la tenofovir-alafenamida frente al tenofovir, pero no sus posibles efectos adversos.

Valuing the cost of improving Chilean primary vaccination: a cost minimization analysis of a hexavalent vaccine.

BACKGROUND: The phased withdrawal of oral polio vaccine (OPV) and the introduction of inactivated poliovirus vaccine (IPV) is central to the polio 'end-game' strategy. METHODS: We analyzed the cost implications in Chile of a switch from the vaccination scheme consisting of a pentavalent vaccine with whole-cell pertussis component (wP) plus IPV/OPV vaccines to a scheme with a hexavalent vaccine with acellular pertussis component (aP) and IPV (Hexaxim®) from a societal perspective. Cost data were collected from a variety of sources including national estimates and previous vaccine studies. All costs were expressed in 2017 prices (US$ 1.00 = $Ch 666.26). RESULTS: The overall costs associated with the vaccination scheme (4 doses of pentavalent vaccine plus 1 dose IPV and 3 doses OPV) from a societal perspective was estimated to be US$ 12.70 million, of which US$ 8.84 million were associated with the management of adverse events related to wP. In comparison, the cost associated with the 4-dose scheme with a hexavalent vaccine (based upon the PAHO reference price) was US$ 19.76 million. The cost of switching to the hexavalent vaccine would be an additional US$ 6.45 million. Overall, depending on the scenario, the costs of switching to the hexavalent scheme would range from an additional US$ 2.62 million to US$ 6.45 million compared with the current vaccination scheme. CONCLUSIONS: The switch to the hexavalent vaccine schedule in Chile would lead to additional acquisition costs, which would be partially offset by improved logistics, and a reduction in adverse events associated with the current vaccines.

Late Conversion to Sirolimus or Everolimus After Pancreas Transplant.

BACKGROUND: Pancreas transplant is an effective treatment for insulin-dependent diabetic individuals with end-stage renal disease, yet immunosuppression-associated adverse events may adversely affect patient and graft survival. The aim of the study was to document whether mammalian target of rapamycin inhibitors (mTORi) are safe and effective as a second-line drug after pancreas transplant. METHODOLOGY: An observational single-center study was performed in a cohort of 490 simultaneous pancreas-kidney transplant and 45 pancreas-after-kidney transplant individuals after conversion to mTORi (n = 13) owing to adverse events of either tacrolimus or mycophenolate. RESULTS: mTORi conversion was performed 11.5 ± 10.1 (range, 1-28) months after pancreas transplant, mainly owing to cytomegalovirus infection and gastrointestinal intolerance. We frequently observed clinical complications after mTORi conversion, yet creatinine, eGFR, proteinuria, fasting plasma glucose, HbA1c, and C-peptide remained stable throughout the study (mean follow-up 8.2 ± 5, range 1-17) years, as did the lipid profile (P > .05). However, graft loss occurred in almost 20% of patients owing to chronic alterations. LIMITATIONS: The small number of patients and a single-center cohort were limitations of the study. CONCLUSIONS: Late mTORi conversion is a safe and effective approach when tacrolimus or mycophenolate-mediated adverse events occur after pancreas transplant.

Clonidine as a strategy for discontinuing dexmedetomidine sedation in critically ill patients: A narrative review.

PURPOSE: To review the efficacy and safety of transitioning from dexmedetomidine to clonidine to facilitate weaning of patients from sedation with dexmedetomidine. There is a paucity of data describing dexmedetomidine withdrawal syndrome (DWS) as well as clonidine's place in therapy for DWS. This review will describe and analyze current literature to provide clinical recommendations. SUMMARY: A MEDLINE literature search was performed to identify original research articles describing DWS and/or transitioning from dexmedetomidine to clonidine for the purpose of weaning patients from sedation with dexmedetomidine. Four case reports describing DWS, 3 case reports describing the use of clonidine to treat DWS, and 3 observational studies describing the use of clonidine to facilitate dexmedetomidine weaning were identified. The incidence of and risk factors for DWS are unknown; factors including patient age and dexmedetomidine infusion rate, loading dose, and discontinuation strategy have inconsistent associations with DWS. All cases of DWS have been associated with infusion durations greater than 72 hours. While there are limited data describing clonidine use for the treatment of dexmedetomidine withdrawal, clonidine appears to be beneficial for dexmedetomidine weaning and its use for that purpose has been well described. Clonidine dosages that have been assessed for discontinuing dexmedetomidine vary from 0.1 to 0.3 mg orally or enterally every 6 to 8 hours; one study assessed use of transdermal clonidine (100 µg/24 h patch). Patients with extensive cardiac comorbidities may be more susceptible to adverse effects of clonidine, which may limit the drug's use for DWS intervention. CONCLUSION: Despite limited supportive data, clonidine provides a promising option for sedation management in adult ICU patients, with successful transitions from dexmedetomidine reported within 24 hours after clonidine initiation.