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"apellidos" => "Puig" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S1578219014001085" "doi" => "10.1016/j.adengl.2014.04.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219014001085?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731013002846?idApp=UINPBA000044" "url" => "/00017310/0000010500000005/v1_201405270041/S0001731013002846/v1_201405270041/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S1578219014001073" "issn" => "15782190" "doi" => "10.1016/j.adengl.2014.04.001" "estado" => "S300" "fechaPublicacion" => "2014-06-01" "aid" => "800" "copyright" => "Elsevier España, S.L. and AEDV" "documento" => "article" "crossmark" => 0 "subdocumento" => "ssu" "cita" => "Actas Dermosifiliogr. 2014;105:438-45" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 2568 "formatos" => array:3 [ "EPUB" => 35 "HTML" => 1954 "PDF" => 579 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Rituximab in the Treatment of Primary Cutaneous B-Cell Lymphoma: A Review" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "438" "paginaFinal" => "445" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Rituximab en el tratamiento de los linfomas cutáneos B primarios: revisión" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 601 "Ancho" => 801 "Tamanyo" => 99616 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Image of a patient with marginal zone lymphoma in the leg.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M. Fernández-Guarino, P.L. Ortiz-Romero, R. Fernández-Misa, C. Montalbán" "autores" => array:4 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Fernández-Guarino" ] 1 => array:2 [ "nombre" => "P.L." "apellidos" => "Ortiz-Romero" ] 2 => array:2 [ "nombre" => "R." "apellidos" => "Fernández-Misa" ] 3 => array:2 [ "nombre" => "C." "apellidos" => "Montalbán" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0001731013000355" "doi" => "10.1016/j.ad.2012.10.021" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731013000355?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219014001073?idApp=UINPBA000044" "url" => "/15782190/0000010500000005/v1_201405281018/S1578219014001073/v1_201405281018/en/main.assets" ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Opinion Article</span>" "titulo" => "Biosimilars and Reference Biologics: Decisions on Biosimilar Interchangeability Require the Involvement of Dermatologists" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "435" "paginaFinal" => "437" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "L. Puig" "autores" => array:1 [ 0 => array:3 [ "nombre" => "L." "apellidos" => "Puig" "email" => array:2 [ 0 => "lpuig@santpau.cat" 1 => "drlpuig@gmail.com" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Biosimilares y biológicos de referencia: la intercambiabilidad de los biosimilares requiere la participación del dermatólogo" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">On September 13, 2013, the European Medicines Agency (EMA) approved the first biosimilar<a class="elsevierStyleCrossRef" href="#fn0005"><span class="elsevierStyleSup">a</span></a> and treatment of moderate to severe psoriasis will be one of the indications. Undoubtedly this important news for dermatologists will have a major impact on prescribing patterns and management of patients with moderate to severe psoriasis.</p><p id="par0010" class="elsevierStylePara elsevierViewall">On June 27, 2013, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion and recommended that the EMA approve Inflectra (the applicant was Hospira UK) and Remsima (the applicant was Celltrion Healthcare Hungary Kft).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>These biosimilars (CT-P13, Remsima) have already been approved in South Korea.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The 2 manufacturers (Celltrion and Hospira) have reached an agreement to market 8 biosimilars in the United States, Europe, Canada, Australia, and New Zealand. The active substance in both cases is infliximab, and both are biological medicinal products, similar to the reference product Remicade (infliximab), approved in the European Union since August 13, 1999. Published studies suggest that both products have a quality, safety, and efficacy profile similar to Remicade (infliximab). Thus the clinical trials PLANETRA<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and PLANETAS<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> were able to show comparable efficacy to the innovator reference product infliximab in the treatment of active rheumatoid arthritis (in combination with methotrexate) and ankylopoietic spondylitis, respectively, as well as similar pharmacokinetic, pharmacodynamic, safety, and immunogenicity parameters to those of the original infliximab (innovator infliximab according to the terminology of the CHMP). Of note is that the marketing authorization application for biosimilars includes all the approved indications for Remicade, thereby setting a precedent in terms of extrapolating the results between indications which, according to guidance, should be examined in separate trials. Although the reduction in price proposed by the sponsor, Celltrion, could be as large as 30% compared to the original product, it is unlikely that the 2 biosimilars will be available in most European countries before February 2015, when the patent extension awarded to Johnson & Johnson expires. Johnson & Johnson and its partner, Merck & Co, could take legal action if these products are marketed before then.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">What are the implications for everyday clinical practice of the approval of the first monoclonal biosimilar, with full extrapolation to all indications, in the European Union?</p><p id="par0020" class="elsevierStylePara elsevierViewall">The introduction of biologic therapies for treating psoriasis has significantly improved the outcomes achievable with systemic treatments,<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and has in turn led to a change in therapeutic objectives.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> With some reference products approaching their patent expiry date, several manufacturers are developing follow-on versions or biosimilar products, which are expected to improve patient access to these drugs in health systems such as the Spanish one, reducing drug procurement costs and introducing competition to force down prices.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Biosimilars are biologic products very similar to the reference product in terms of quality, safety, and efficacy (EMA) or safety, purity, and potency (Food and Drug Administration [FDA]). Similarity is defined as no relevant difference in any of the parameters (quality/purity, safety, efficacy/potency). Demonstration of chemical similarity is not enough to demonstrate functional equivalence and comparative pharmacokinetic and pharmacodynamic trials should be conducted in healthy volunteers or patients, and there should be at least 1 clinical trial to demonstrate the equivalence of each formulation available.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The variability of biological products depends not only on their amino acid sequence and primary structure, but also on posttranscriptional modifications such as glycosylation, methylation, oxidation, and deamination that may have an impact on tertiary structure (subunit folding) and quaternary structure (spatial configuration of the entire molecule). This in turn may lead to differences in affinity, selectivity, and functional, biological, and immunogenic activity compared to the reference biologic agent. Given that the manufacturers of biosimilars do not have access to the information on the production process of the patented reference product, it is very difficult to exactly replicate these posttranscriptional modifications, in contrast to small molecules (which will have exactly the same molecular structure as the reference product). The biosimilar is compared with the reference product by using validated analytical methods that enable the physical and chemical properties, biological activity, and purity and possible impurities to be determined. The directives currently in force allow for possible changes in the manufacturing process compared to the original, but the impact of these changes must be systematically assessed. Although biosimilars and their reference products are not identical, the same can be said for different batches of a reference biologic, given that the manufacturing processes are updated with each lifecycle. Changes might include switching the supplier of culture media, new purification methods, and even changes in the manufacturing facilities.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Glycosylation patterns are extremely sensitive to minimal changes in the manufacturing process, and these probably lead to differences in the immunogenicity of the biological product. In the case of erythropoietins, the development of antibodies against the drug has given rise to cases of cross immunity with the physiological molecule, with potentially fatal outcomes.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Such a situation is unlikely in the case of anticytokine antibodies. However, the development of antibodies against any biologic product may lead to blockade of its effect (neutralizing antibodies) or an increased clearance, in both cases reducing the clinical efficacy.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The nature of the antibody also contributes to the development of antibodies (the risk decreases according to whether the antibody is chimeric, humanized, or human) and induction regimens have been designed in part to achieve high serum concentrations and in part to induce tolerance to the development of these antibodies (intravenous administration contributes to this aim). The development of antibodies against the biologic agent appears to be more frequent in patients with autoimmune diseases, when administration is intermittent, and when background immunosuppressive medication (such as methotrexate) is not used. A recent metaanalysis in rheumatoid patients found that the presence of antibodies against the biologic product increases the risk of abandoning treatment and presenting with hypersensitivity reactions, whereas concomitant treatment with antirheumatic disease-modifying drugs reduces the risk of such antibodies.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The clinical relevance of the loss of response, which determines adherence to a biologic and the need for switching to another agent, has contributed to the development of assays for detecting antidrug antibodies and for measuring serum concentrations of different biologics; these are currently available commercially and can be used in the clinical setting.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The importance of these analytical techniques will no doubt increase when biosimilars are introduced. The extent to which they will be able to differentiate between biosimilars and their reference products remains to be seen.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The requirements for demonstrating similar clinical efficacy between a biosimilar and the reference biologic differ between the European Union (EU) and the United States. However, in both cases, at least 1 equivalence trial must be conducted with sufficient statistical power to demonstrate comparability of the 2 products in terms of efficacy and safety, that is, these products should be both noninferior and nonsuperior to the reference product.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> According to the EMA, immunogenicity should be assessed during the safety trial, whereas the FDA in the United States requires a comparative trial prior to marketing and another postmarketing trial. In both cases, a pharmacovigilance plan is required (and so it is essential to be able to distinguish the biosimilar, even when the drugs are prescribed interchangeably).</p><p id="par0045" class="elsevierStylePara elsevierViewall">There has been plenty of discussion as to whether the findings of a clinical trial can be extrapolated to other indications, allowing the approval of a biosimilar for a therapeutic indication for which it has not been clinically assessed. Such an approach seems reasonable if the mechanisms of action are known and are common to both indications. When the mechanisms of action are different or not fully understood, or when the target organs or systems are different, separate clinical trials are probably required. In any case, any extrapolation should be made on a case-by-case basis and clearly highlighted as such in the Summary of Product Characteristics or Package Insert of the product.</p><p id="par0050" class="elsevierStylePara elsevierViewall">A completely different situation is the interchangeability of biosimilar products and their originals and, therefore, the possible clinical or therapeutic equivalence. This is discussed in another article in the same issue of this journal. Any generic drug is interchangeable with the original, and the pharmacist can make the change without the prior authorization of the prescribing physician. The guidelines of the EMA make no reference to interchangeability of biosimilars, and the leave the corresponding decisions in hands of the health authorities of each member state of the European Union. In contrast, the legislation in the United States allows the FDA to determine which biosimilars can be interchanged without consulting the physician. The definitive guidance, however, has yet to be published. The interchangeability of biosimilars would hinder the tasks of pharmacovigilance; hospital pharmacists would have to follow the regulations in each country and bear in mind that the same international nonproprietary name (INN) in the case of biologics does not imply they can be automatically be used interchangeably.</p><p id="par0055" class="elsevierStylePara elsevierViewall">The role of biosimilars in the treatment of psoriasis and other skin diseases would in part be determined by the assurances provided to the dermatologists by the regulatory requirements in the approval procedure, and to a large extent by the pressures of the national and regional health authorities and hospital management to save money. Although a saving of 15% to 30% seems small compared to generics, biologics account for a high proportion of hospital drug expenditure. The decreased procurement cost of biosimilars will likely bring down the price of the original biologic products, particularly in situations where bidding is required. In addition, the manufacturers of the reference biologics are enhancing their biosimilar portfolio in an effort to diversify their business, minimize the price decreases, and avoid the subsequent impact on their market value.</p><p id="par0060" class="elsevierStylePara elsevierViewall">In conclusion, the imminent arrival of biosimilars as therapeutic alternatives in dermatology should be welcomed if it allows savings to be made and more widespread access to treatment. The regulation introduced by the EMA in principle guarantees similarity between the approved biosimilars and the innovator product from the biochemical, pharmacokinetic, pharmacodynamic, immunogenic, and safety point of view for the indications in which trials have been performed. We should remember that the innovator biologics often end up becoming biosimilars of themselves (through changes in the manufacturing process) and in fact the regulatory framework for similarity is these cases is not so well defined as in the case of biosimilars. Although the good judgment of the experts at the EMA can be accepted a priori when they assess the extrapolation of indications, there are many gaps in our knowledge of the mechanism of action of different biologics, which can vary according to target organ. The clinician would feel much more assured with clinical trials that demonstrate the capacity to extrapolate the indication of the biosimilar to those of the original biologic when the target system/organ changes (musculoskeletal, digestive, or skin). Moreover, interchangeability brings with it issues with pharmacovigilance (if it is impossible to distinguish between biosimilars and originals) and ethics (can or should a treatment to which a patient is responding well be changed without the intervention of the prescribing physician and the consent of the patient?) In any case, it is imperative that the prescribing physician retains a say when making therapeutic decisions concerning biologics.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of Interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">Dr. Lluis Puig has received honoraria as a consultant and speaker for Abbvie, Boehringer, Janssen, Merck-Serono, MSD, Novartis, and Pfizer. He has participated in clinical trials sponsored by Abbvie, Amgen, Janssen, Lilly, MSD, Novartis, Pfizer, and VBL.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of Interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Remsima R, from Egis, will be marketed under this trade name in several central and eastern European countries, and under the trade name Flammegis R in several members of the Commonwealth of Independent States.</p>" ] 1 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Puig L. Biosimilares y biológicos de referencia: la intercambiabilidad de los biosimilares requiere la participación del dermatólogo. Actas Dermosifiliogr. 2014;105:435–437.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:13 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "European Medicines Agency recommends approval of first two monoclonal antibody biosimilars. Recommendation marks extension of biosimilar concept to new product-class [accessed July 12, 2013]. Available from: <a id="intr0005" class="elsevierStyleInterRef" href="http://www.ema.europa.eu/ema/index.jsp%3Fcurl=pages/news_and_events/news/2013/06/news_detail_001837.jsp%26mid=WC0b01ac058004d5c1">http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/06/news_detail_001837.jsp∣=WC0b01ac058004d5c1</a>" ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Biosimilars in dermatology: Starting with infliximab" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "L. 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año/Mes | Html | Total | |
---|---|---|---|
2024 Noviembre | 14 | 6 | 20 |
2024 Octubre | 90 | 53 | 143 |
2024 Septiembre | 122 | 37 | 159 |
2024 Agosto | 143 | 65 | 208 |
2024 Julio | 84 | 28 | 112 |
2024 Junio | 87 | 33 | 120 |
2024 Mayo | 92 | 38 | 130 |
2024 Abril | 90 | 29 | 119 |
2024 Marzo | 84 | 31 | 115 |
2024 Febrero | 78 | 21 | 99 |
2024 Enero | 66 | 33 | 99 |
2023 Diciembre | 56 | 16 | 72 |
2023 Noviembre | 71 | 31 | 102 |
2023 Octubre | 76 | 26 | 102 |
2023 Septiembre | 71 | 30 | 101 |
2023 Agosto | 49 | 17 | 66 |
2023 Julio | 50 | 33 | 83 |
2023 Junio | 54 | 23 | 77 |
2023 Mayo | 55 | 24 | 79 |
2023 Abril | 38 | 15 | 53 |
2023 Marzo | 52 | 23 | 75 |
2023 Febrero | 72 | 42 | 114 |
2023 Enero | 49 | 27 | 76 |
2022 Diciembre | 43 | 35 | 78 |
2022 Noviembre | 28 | 23 | 51 |
2022 Octubre | 27 | 16 | 43 |
2022 Septiembre | 23 | 38 | 61 |
2022 Agosto | 28 | 26 | 54 |
2022 Julio | 25 | 41 | 66 |
2022 Junio | 23 | 33 | 56 |
2022 Mayo | 35 | 37 | 72 |
2022 Abril | 39 | 30 | 69 |
2022 Marzo | 48 | 40 | 88 |
2022 Febrero | 24 | 25 | 49 |
2022 Enero | 33 | 43 | 76 |
2021 Diciembre | 16 | 38 | 54 |
2021 Noviembre | 34 | 54 | 88 |
2021 Octubre | 33 | 52 | 85 |
2021 Septiembre | 24 | 35 | 59 |
2021 Agosto | 24 | 25 | 49 |
2021 Julio | 14 | 25 | 39 |
2021 Junio | 22 | 30 | 52 |
2021 Mayo | 25 | 24 | 49 |
2021 Abril | 57 | 47 | 104 |
2021 Marzo | 49 | 31 | 80 |
2021 Febrero | 34 | 24 | 58 |
2021 Enero | 35 | 11 | 46 |
2020 Diciembre | 24 | 13 | 37 |
2020 Noviembre | 16 | 23 | 39 |
2020 Octubre | 21 | 7 | 28 |
2020 Septiembre | 40 | 7 | 47 |
2020 Agosto | 35 | 22 | 57 |
2020 Julio | 34 | 17 | 51 |
2020 Junio | 34 | 21 | 55 |
2020 Mayo | 22 | 18 | 40 |
2020 Abril | 30 | 10 | 40 |
2020 Marzo | 37 | 19 | 56 |
2020 Febrero | 1 | 0 | 1 |
2020 Enero | 3 | 2 | 5 |
2019 Diciembre | 8 | 6 | 14 |
2019 Noviembre | 4 | 6 | 10 |
2019 Octubre | 0 | 3 | 3 |
2019 Septiembre | 4 | 0 | 4 |
2019 Agosto | 4 | 1 | 5 |
2019 Julio | 4 | 4 | 8 |
2019 Junio | 4 | 3 | 7 |
2019 Mayo | 7 | 17 | 24 |
2019 Abril | 2 | 3 | 5 |
2019 Marzo | 2 | 8 | 10 |
2019 Febrero | 5 | 2 | 7 |
2019 Enero | 6 | 2 | 8 |
2018 Noviembre | 3 | 0 | 3 |
2018 Octubre | 4 | 0 | 4 |
2018 Septiembre | 4 | 0 | 4 |
2018 Junio | 0 | 6 | 6 |
2018 Mayo | 0 | 13 | 13 |
2018 Abril | 0 | 4 | 4 |
2018 Marzo | 1 | 2 | 3 |
2018 Febrero | 32 | 5 | 37 |
2018 Enero | 31 | 7 | 38 |
2017 Diciembre | 34 | 12 | 46 |
2017 Noviembre | 49 | 5 | 54 |
2017 Octubre | 27 | 7 | 34 |
2017 Septiembre | 21 | 28 | 49 |
2017 Agosto | 26 | 17 | 43 |
2017 Julio | 33 | 10 | 43 |
2017 Junio | 48 | 16 | 64 |
2017 Mayo | 38 | 15 | 53 |
2017 Abril | 35 | 13 | 48 |
2017 Marzo | 25 | 28 | 53 |
2017 Febrero | 26 | 12 | 38 |
2017 Enero | 30 | 7 | 37 |
2016 Diciembre | 40 | 16 | 56 |
2016 Noviembre | 34 | 17 | 51 |
2016 Octubre | 57 | 16 | 73 |
2016 Septiembre | 49 | 17 | 66 |
2016 Agosto | 59 | 12 | 71 |
2016 Julio | 48 | 9 | 57 |
2016 Junio | 10 | 11 | 21 |
2016 Mayo | 9 | 7 | 16 |
2016 Abril | 12 | 3 | 15 |
2016 Marzo | 17 | 3 | 20 |
2016 Febrero | 8 | 10 | 18 |
2016 Enero | 15 | 17 | 32 |
2015 Diciembre | 8 | 10 | 18 |
2015 Noviembre | 6 | 1 | 7 |
2015 Octubre | 8 | 3 | 11 |
2015 Septiembre | 4 | 4 | 8 |
2015 Agosto | 9 | 1 | 10 |
2015 Julio | 36 | 4 | 40 |
2015 Junio | 39 | 7 | 46 |
2015 Mayo | 56 | 7 | 63 |
2015 Abril | 27 | 7 | 34 |
2015 Marzo | 51 | 21 | 72 |
2015 Febrero | 43 | 15 | 58 |
2015 Enero | 39 | 9 | 48 |
2014 Diciembre | 44 | 16 | 60 |
2014 Noviembre | 30 | 10 | 40 |
2014 Octubre | 41 | 8 | 49 |
2014 Septiembre | 38 | 8 | 46 |
2014 Agosto | 28 | 8 | 36 |
2014 Julio | 16 | 7 | 23 |
2014 Junio | 18 | 9 | 27 |
2014 Mayo | 4 | 1 | 5 |