Opinion Article
The Use of Biosimilar Drugs in Psoriasis: A Position Paper
Fármacos biosimilares en psoriasis: informe de posicionamiento
Leído
5565
Vecesse ha leído el artículo
2811
Total PDF
2754
Total HTML
Compartir estadísticas
array:22 [ "pii" => "S1578219015000517" "issn" => "15782190" "doi" => "10.1016/j.adengl.2015.03.001" "estado" => "S300" "fechaPublicacion" => "2015-05-01" "aid" => "1120" "copyright" => "Elsevier España, S.L.U. and AEDV" "copyrightAnyo" => "2015" "documento" => "article" "subdocumento" => "sco" "cita" => "Actas Dermosifiliogr. 2015;106:249-51" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 1375 "formatos" => array:3 [ "EPUB" => 46 "HTML" => 516 "PDF" => 813 ] ] "Traduccion" => array:1 [ "es" => array:18 [ "pii" => "S0001731015000290" "issn" => "00017310" "doi" => "10.1016/j.ad.2015.01.001" "estado" => "S300" "fechaPublicacion" => "2015-05-01" "aid" => "1120" "copyright" => "Elsevier España, S.L.U. and AEDV" "documento" => "article" "subdocumento" => "sco" "cita" => "Actas Dermosifiliogr. 2015;106:249-51" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 1611 "formatos" => array:3 [ "EPUB" => 2 "HTML" => 637 "PDF" => 972 ] ] "es" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Artículo de opinión</span>" "titulo" => "Fármacos biosimilares en psoriasis: informe de posicionamiento" "tienePdf" => "es" "tieneTextoCompleto" => "es" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "249" "paginaFinal" => "251" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "The Use of Biosimilar Drugs in Psoriasis: A Position Paper" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "G. Carretero Hernández, L. Puig" "autores" => array:3 [ 0 => array:2 [ "nombre" => "G." "apellidos" => "Carretero Hernández" ] 1 => array:2 [ "nombre" => "L." "apellidos" => "Puig" ] 2 => array:1 [ "colaborador" => "en representación del Grupo de Psoriasis de la AEDV" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S1578219015000517" "doi" => "10.1016/j.adengl.2015.03.001" "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/S1578219015000517?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731015000290?idApp=UINPBA000044" "url" => "/00017310/0000010600000004/v2_201505051016/S0001731015000290/v2_201505051016/es/main.assets" ] ] "itemSiguiente" => array:18 [ "pii" => "S1578219015000372" "issn" => "15782190" "doi" => "10.1016/j.adengl.2014.09.019" "estado" => "S300" "fechaPublicacion" => "2015-05-01" "aid" => "1061" "copyright" => "Elsevier España, S.L.U. and AEDV" "documento" => "article" "subdocumento" => "ssu" "cita" => "Actas Dermosifiliogr. 2015;106:252-9" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 1151 "formatos" => array:3 [ "EPUB" => 48 "HTML" => 624 "PDF" => 479 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Etanercept in the Treatment of Psoriatic Arthritis" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "252" "paginaFinal" => "259" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Etanercept en el tratamiento de la artritis psoriásica" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "L. Puig, A. López-Ferrer, A. Laiz" "autores" => array:3 [ 0 => array:2 [ "nombre" => "L." "apellidos" => "Puig" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "López-Ferrer" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Laiz" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0001731014004207" "doi" => "10.1016/j.ad.2014.09.004" "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/S0001731014004207?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219015000372?idApp=UINPBA000044" "url" => "/15782190/0000010600000004/v2_201505051007/S1578219015000372/v2_201505051007/en/main.assets" ] "en" => array:14 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Opinion Article</span>" "titulo" => "The Use of Biosimilar Drugs in Psoriasis: A Position Paper" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "249" "paginaFinal" => "251" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "G. Carretero Hernández, L. Puig" "autores" => array:3 [ 0 => array:4 [ "nombre" => "G." "apellidos" => "Carretero Hernández" "email" => array:1 [ 0 => "gcarreteroh58@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "L." "apellidos" => "Puig" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:1 [ "colaborador" => "en representación del Grupo de Psoriasis de la AEDV" ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Coordinador del Grupo de Trabajo de Psoriasis de la AEDV" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Ex-coordinador del Grupo de Trabajo de Psoriasis de la AEDV" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Fármacos biosimilares en psoriasis: informe de posicionamiento" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">–</span><p id="par0145" class="elsevierStylePara elsevierViewall">The development of biologic therapy has substantially improved the treatment of psoriasis and psoriatic arthritis. At the same time, the elevated cost of biologics has prompted debate on the economic sustainability of the public health system.</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">–</span><p id="par0150" class="elsevierStylePara elsevierViewall">As patents expire for biologics, business interests and the high capacity of today's biotechnology industry have encouraged laboratories to develop new drugs—called biosimilars—that have effects that resemble those of their reference biologics. In principle, these biosimilars are equal to their reference biologics in efficacy and safety, but they cost less.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">–</span><p id="par0020" class="elsevierStylePara elsevierViewall">This attractive theoretical situation, in combination with the influence of parties interested in the business of biologic therapy and the need to curtail public health system spending on this type of drug, has logically fueled a certain amount of debate about biosimilars. Physicians, patients, and the pharmaceutical industry have all taken part. A similar debate took place years ago when generic drugs were introduced.</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">–</span><p id="par0155" class="elsevierStylePara elsevierViewall">With 2 biosimilars for treating psoriasis and psoriatic arthritis already approved by the European Medicines Agency (EMA) and about to enter the market, this seemed to us to be a good time for dermatologists to state our position on several aspects related to these new drugs.</p></li></ul></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Considerations</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Definition</span><p id="par0030" class="elsevierStylePara elsevierViewall">A biosimilar is a biotechnological medicinal product that contains the same active substance as a reference biologic and is prescribed for treating the same disease at the same dose and route of administration. As their name indicates, biosimilars are highly similar to reference biologics, but because of differences in manufacturing processes they are not identical.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Approval</span><p id="par0160" class="elsevierStylePara elsevierViewall">The European Union (EU) approves biosimilars and authorizes their sale following a centralized procedure that upholds the same quality standards that apply to reference biologics and meets the specific requirements and regulations imposed by the EMA regarding manufacturing quality controls.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Biosimilarity</span><p id="par0040" class="elsevierStylePara elsevierViewall">Biosimilarity can be demonstrated by 2 basic conditions: 1) that the biosimilar drug's structure is highly analogous to that of the reference biologic, a condition that requires the new drug to be characterized through exhaustive analyses; and 2) that the biosimilar's quality, safety, efficacy and immunogenicity profile is similar to the reference biologic's, a condition that requires the completion of properly designed clinical trials. Changes in the reference biologic's manufacturing process can also cause small variations from the original drug and may also make it necessary to run trials to demonstrate comparability in the context of a particular use, followed by extrapolation to other uses.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Indications</span><p id="par0045" class="elsevierStylePara elsevierViewall">A biosimilar has the same indication as its reference biologic. The use we are concerned with in this paper is the treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to, are intolerant to, or have a contraindication for other systemic therapies, including cyclosporine, methotrexate, or psoralen plus UV-A therapy. The clinical use of a biosimilar is guided by the same criteria that apply to its reference biologic.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Efficacy</span><p id="par0050" class="elsevierStylePara elsevierViewall">EMA directives state that a biosimilar's clinical efficacy must be established by a randomized double-blind clinical trial in a population representative of patients with the condition the reference biologic is approved for. The trial must have sufficient power to detect differences between the biosimilar and the biologic. For the 2 infliximab biosimilars recently approved by the EMA (corresponding to CT-P13, developed by Celltrion), approval was supported by data from clinical trials in patients with rheumatoid arthritis and ankylosing spondylitis, but not specifically in patients with psoriasis.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Extrapolation</span><p id="par0055" class="elsevierStylePara elsevierViewall">Biosimilars can be approved for all or some of the indications the reference biologic is approved for, but not for more indications. Even though the EMA's recent approval of the 2 infliximab biosimilars is based on efficacy and safety results in patients with rheumatoid arthritis and ankylosing spondylitis, the agency's European Public Assessment Report lists the same indications approved for infliximab. South Korea, Colombia, Turkey, and Japan have done likewise, whereas the health authorities in Canada have chosen not to include Crohn disease or ulcerative colitis among the extrapolated indications. A trial (NCT02096861) is under way to demonstrate the noninferiority of CT-P13 and evaluate its efficacy in 214 patients with active Crohn disease.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Safety</span><p id="par0060" class="elsevierStylePara elsevierViewall">The dossier a manufacturer presents to the EMA when applying for approval of a biosimilar must contain data that show that there are no substantial differences between the biosimilar and its reference biologic. Once an approved biosimilar is on the market, it must submit to a pharmacovigilance program that matches in rigor the program set up for the reference biologic. To that end, each drug must be traceable and identifiable at all times so that the possible adverse effects that might be attributed to it can be registered. Therefore, so that a biosimilar given to a patient can be clearly identified, the label should include the common name (international nonproprietary name), commercial name, and/or the manufacturer's name.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Interchangeability and Switchability</span><p id="par0065" class="elsevierStylePara elsevierViewall">The EU does not address the issues of interchangeability or switchability between a reference biologic and a biosimilar. This aspect is left to the judgment of each member state. Regulations in Spain leave the decision to the physician: whereas a pharmacist may switch one manufacturer's generic drug for another's, a biosimilar may not be automatically substituted for its reference biologic. The prescribing physician is responsible for the decision.</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusions</span><p id="par0070" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">1.</span><p id="par0075" class="elsevierStylePara elsevierViewall">The Spanish Academy of Dermatology and Venereology (AEDV) celebrates the incorporation of biosimilars into the treatment regimens for psoriasis and psoriatic arthritis. Thanks to these new drugs, the high cost of biologic therapy is likely to decrease, reinforcing the sustainability of the public health system, a goal the AEDV supports. However, the use of biosimilars should not imply a reduction in therapeutic efficacy, patient safety, or the prescriber's freedom of choice.</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">2.</span><p id="par0080" class="elsevierStylePara elsevierViewall">Regarding innovation, biosimilars do not seem to offer advantages over reference biologics, but they do represent savings. Nevertheless, decisions about which drug to prescribe should not be based on economic considerations alone, but rather on scientific evidence. We therefore recommend that dermatologists, pharmacists, managers, and other stakeholders be involved in decisions about how biosimilars are introduced into our health care system.</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">3.</span><p id="par0085" class="elsevierStylePara elsevierViewall">The AEDV calls for psoriasis and psoriatic arthritis patients to be included in clinical trials of these new drugs to the degree possible. The purpose of such inclusion would be to obtain direct information about efficacy and safety, so that we do not have to extrapolate from findings for other disease contexts. Extrapolations are made to other diseases related to the ones reflected in trials, but these contexts are not necessarily identical with respect to how the biosimilar drug behaves (mechanism of action, dosage, or in possible combinations with other treatments). If possible, we need clinical trials for indications in which the difference in efficacy between the drug and placebo is greatest: such is the case in psoriasis in comparison to rheumatoid arthritis.</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">4.</span><p id="par0090" class="elsevierStylePara elsevierViewall">Once the biosimilar is on the market, both the new drug and its reference biologic should become available to prescribing dermatologists in hospitals. The physician will take responsibility for choosing to prescribe a biosimilar, and the choice must be guided by the same criteria applied to the clinical use of the biologic.</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">5.</span><p id="par0165" class="elsevierStylePara elsevierViewall">We believe that the decision to prescribe a biosimilar should be assessed on a case-by-case basis and that the patient must agree with the choice. Switching from a biologic to a biosimilar should also be decided by the physician with the patient's consent.</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">6.</span><p id="par0100" class="elsevierStylePara elsevierViewall">Given that it is impossible to absolutely establish that a biosimilar and a reference biologic are identical, even slight differences between them might have clinical consequences. Therefore, information about the true efficacy and safety of biosimilars in the treatment of psoriasis and psoriatic arthritis must be confirmed afterwards, once biosimilars are on the market and in use and once the relevant pharmacovigilance data are being registered.</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">7.</span><p id="par0105" class="elsevierStylePara elsevierViewall">Biosimilars on the market should come with patient and prescriber information that is clear and precise, so that prescriber and patient can make proper decisions about the acceptability of these drugs. Given the doubts that this new concept of biosimilarity may arouse among both dermatologists and users, we must take steps to inform and teach those concerned. Ideally information should reflect consensus formed before these new drugs are used routinely. The AEDV is willing to collaborate with other parties to achieve that goal.</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">8.</span><p id="par0170" class="elsevierStylePara elsevierViewall">The opinions we hold about biosimilars today may change in the light of the experience that will come after commercialization and/or the publication of new trails.</p></li></ul></p><p id="par0115" class="elsevierStylePara elsevierViewall">Date of final review: November 2014</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflicts of Interest</span><p id="par0120" class="elsevierStylePara elsevierViewall">Dr G. Carretero Hernández has participated in clinical trials and postapproval studies sponsored or funded by Abbvie, Celgene, Janssen, Lilly, MSD, Novartis, and Pfizer. He has received consultancy or speaker's fees from Abbvie, Celgene, Janssen, MSD, Novartis, Pfizer, and Leo.</p><p id="par0125" class="elsevierStylePara elsevierViewall">Dr L. Puig Sanz has participated in clinical trials and postapproval studies sponsored or funded by Abbvie, Amgen, Janssen, Lilly, MSD, Novartis, and Pfizer. He has received consultancy or speaker's fees from Amgen, Abbvie, Janssen, Lilly, Merck Serono, MSD, Novartis, Pfizer, and Leo.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 1 => array:3 [ "identificador" => "sec0010" "titulo" => "Considerations" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Definition" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Approval" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Biosimilarity" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Indications" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Efficacy" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Extrapolation" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Safety" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Interchangeability and Switchability" ] ] ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusions" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflicts of Interest" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-01-14" "fechaAceptado" => "2015-01-18" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Carretero Hernández G, Puig L, en representación del Grupo de Psoriasis de la AEDV. Fármacos biosimilares en psoriasis: informe de posicionamiento. Actas Dermosifiliogr. 2015;106:249–251.</p>" ] ] ] "idiomaDefecto" => "en" "url" => "/15782190/0000010600000004/v2_201505051007/S1578219015000517/v2_201505051007/en/main.assets" "Apartado" => array:4 [ "identificador" => "6152" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Opinion Article" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/15782190/0000010600000004/v2_201505051007/S1578219015000517/v2_201505051007/en/main.pdf?idApp=UINPBA000044&text.app=https://actasdermo.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219015000517?idApp=UINPBA000044" ]
| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 3 | 9 | 12 |
| 2024 Octubre | 55 | 58 | 113 |
| 2024 Septiembre | 58 | 35 | 93 |
| 2024 Agosto | 82 | 65 | 147 |
| 2024 Julio | 76 | 49 | 125 |
| 2024 Junio | 68 | 47 | 115 |
| 2024 Mayo | 54 | 29 | 83 |
| 2024 Abril | 61 | 33 | 94 |
| 2024 Marzo | 55 | 33 | 88 |
| 2024 Febrero | 52 | 32 | 84 |
| 2024 Enero | 36 | 47 | 83 |
| 2023 Diciembre | 39 | 18 | 57 |
| 2023 Noviembre | 45 | 29 | 74 |
| 2023 Octubre | 33 | 22 | 55 |
| 2023 Septiembre | 47 | 34 | 81 |
| 2023 Agosto | 45 | 28 | 73 |
| 2023 Julio | 38 | 62 | 100 |
| 2023 Junio | 53 | 22 | 75 |
| 2023 Mayo | 55 | 31 | 86 |
| 2023 Abril | 33 | 26 | 59 |
| 2023 Marzo | 27 | 32 | 59 |
| 2023 Febrero | 53 | 29 | 82 |
| 2023 Enero | 29 | 19 | 48 |
| 2022 Diciembre | 35 | 47 | 82 |
| 2022 Noviembre | 22 | 33 | 55 |
| 2022 Octubre | 17 | 20 | 37 |
| 2022 Septiembre | 22 | 33 | 55 |
| 2022 Agosto | 26 | 32 | 58 |
| 2022 Julio | 19 | 33 | 52 |
| 2022 Junio | 21 | 35 | 56 |
| 2022 Mayo | 46 | 56 | 102 |
| 2022 Abril | 41 | 37 | 78 |
| 2022 Marzo | 54 | 42 | 96 |
| 2022 Febrero | 38 | 26 | 64 |
| 2022 Enero | 38 | 43 | 81 |
| 2021 Diciembre | 20 | 57 | 77 |
| 2021 Noviembre | 41 | 60 | 101 |
| 2021 Octubre | 31 | 63 | 94 |
| 2021 Septiembre | 38 | 32 | 70 |
| 2021 Agosto | 51 | 40 | 91 |
| 2021 Julio | 26 | 26 | 52 |
| 2021 Junio | 56 | 59 | 115 |
| 2021 Mayo | 34 | 20 | 54 |
| 2021 Abril | 34 | 68 | 102 |
| 2021 Marzo | 76 | 25 | 101 |
| 2021 Febrero | 51 | 46 | 97 |
| 2021 Enero | 36 | 29 | 65 |
| 2020 Diciembre | 37 | 22 | 59 |
| 2020 Noviembre | 28 | 33 | 61 |
| 2020 Octubre | 20 | 15 | 35 |
| 2020 Septiembre | 37 | 15 | 52 |
| 2020 Agosto | 23 | 21 | 44 |
| 2020 Julio | 17 | 21 | 38 |
| 2020 Junio | 39 | 38 | 77 |
| 2020 Mayo | 18 | 33 | 51 |
| 2020 Abril | 24 | 26 | 50 |
| 2020 Marzo | 22 | 22 | 44 |
| 2020 Febrero | 3 | 4 | 7 |
| 2020 Enero | 0 | 5 | 5 |
| 2019 Diciembre | 4 | 6 | 10 |
| 2019 Noviembre | 0 | 2 | 2 |
| 2019 Octubre | 0 | 2 | 2 |
| 2019 Septiembre | 6 | 3 | 9 |
| 2019 Agosto | 0 | 1 | 1 |
| 2019 Julio | 0 | 13 | 13 |
| 2019 Junio | 0 | 8 | 8 |
| 2019 Mayo | 2 | 72 | 74 |
| 2019 Abril | 0 | 39 | 39 |
| 2019 Marzo | 0 | 11 | 11 |
| 2019 Febrero | 2 | 7 | 9 |
| 2019 Enero | 0 | 4 | 4 |
| 2018 Diciembre | 4 | 5 | 9 |
| 2018 Noviembre | 2 | 3 | 5 |
| 2018 Octubre | 1 | 0 | 1 |
| 2018 Septiembre | 6 | 2 | 8 |
| 2018 Agosto | 0 | 15 | 15 |
| 2018 Julio | 0 | 7 | 7 |
| 2018 Junio | 0 | 5 | 5 |
| 2018 Mayo | 0 | 12 | 12 |
| 2018 Abril | 0 | 8 | 8 |
| 2018 Marzo | 1 | 11 | 12 |
| 2018 Febrero | 23 | 9 | 32 |
| 2018 Enero | 38 | 14 | 52 |
| 2017 Diciembre | 29 | 15 | 44 |
| 2017 Noviembre | 24 | 18 | 42 |
| 2017 Octubre | 23 | 23 | 46 |
| 2017 Septiembre | 12 | 20 | 32 |
| 2017 Agosto | 25 | 16 | 41 |
| 2017 Julio | 19 | 22 | 41 |
| 2017 Junio | 26 | 43 | 69 |
| 2017 Mayo | 19 | 23 | 42 |
| 2017 Abril | 16 | 21 | 37 |
| 2017 Marzo | 12 | 56 | 68 |
| 2017 Febrero | 13 | 55 | 68 |
| 2017 Enero | 17 | 28 | 45 |
| 2016 Diciembre | 29 | 25 | 54 |
| 2016 Noviembre | 31 | 35 | 66 |
| 2016 Octubre | 23 | 30 | 53 |
| 2016 Septiembre | 0 | 15 | 15 |
| 2016 Agosto | 0 | 16 | 16 |
| 2016 Julio | 11 | 12 | 23 |
| 2016 Junio | 16 | 2 | 18 |
| 2016 Mayo | 11 | 24 | 35 |
| 2016 Abril | 6 | 2 | 8 |
| 2016 Marzo | 4 | 2 | 6 |
| 2016 Febrero | 10 | 1 | 11 |
| 2016 Enero | 7 | 1 | 8 |
| 2015 Diciembre | 12 | 4 | 16 |
| 2015 Noviembre | 8 | 3 | 11 |
| 2015 Octubre | 0 | 6 | 6 |
| 2015 Septiembre | 0 | 2 | 2 |
| 2015 Agosto | 0 | 4 | 4 |
| 2015 Julio | 8 | 1 | 9 |
| 2015 Junio | 4 | 11 | 15 |
| 2015 Mayo | 12 | 10 | 22 |
Mostrar todo
