A Herrero Ambrosio

Biosimilares: situación regulatoria para su autorización

Resumen Los medicamentos biotecnologicos representan el futuro en la medicina. Al expirar la patente de algunos de ellos, aparecen las primeras “copias” de los mismos, que son conocidos como biosimilares. Estos son producidos por otro fabricante, utilizando nuevas lineas celulares, nuevos procesos y diferentes metodos analiticos. Por ello, su regulacion queda a cargo de la Agencia Europea del Medicamento (EMEA) a traves del procedimiento centralizado, la cual ha desarrollado unas guias perfectamente establecidas que defi nen el proceso de autorizacion que deben seguir los mismos, donde son necesarios estudios preclinicos y clinicos destinados a establecer su perfi l de calidad, efi cacia clinica y seguridad. Respecto a su denominacion, la Organizacion Mundial de la Salud (OMS) ha determinado que los biosimilares tengan el mismo International Nonpropietary Name (INN) que su medicamento de referencia.

Estudio de utilización de analgésicos opiáceos en un hospital general universitario

Resumen Objetivo El objetivo de este trabajo ha sido realizar un estudio de utilizacion de analgesicos opiaceos en el Hospital Universitario La Paz (Madrid) en el ano 2008 para conocer como se esta utilizando este grupo de medicamentos y cual es la tendencia del consumo. Para ello, se presentan los datos de uso de opiaceos en pacientes ingresados de forma global, por hospitales y por servicios clinicos. Se exponen los datos de consumo de los 5 ultimos anos y se ha cuantificado el uso del resto de principios activos empleados como analgesicos en nuestro hospital. Material y metodos Haciendo uso de la metodologia recomendada por la Organizacion Mundial de la Salud para los estudios de utilizacion de medicamentos en hospitales, presentamos nuestros datos en dosis diarias definidas (DDD) por 100 estancias. Los datos de consumo se han obtenido del programa de gestion de medicamentos del Servicio de Farmacia Farma Tools (Dominion ® ) Resultados El valor global de utilizacion de opiaceos en 2008 ha sido de 8,1 DDD/100 estancias. Los principios activos mas consumidos han sido la morfina parenteral y el fentanilo transdermico, y entre los 2 representan el 83% del consumo total de opiaceos. En el analisis por hospitales apreciamos que el Hospital General y el de Traumatologia son los que presentan un mayor empleo de opiaceos y siguen el mismo patron de utilizacion que el global. Los servicios mas representativos del consumo de opiaceos han sido las reanimaciones del Hospital General y de Traumatologia, los Servicios de Oncologia, Cuidados paliativos y Hematologia. En estos ultimos 5 anos se ha producido un incremento global del consumo de aproximadamente el 20%, viendose implicados todos los principios activos. Con relacion al consumo total de analgesicos, los datos reflejan una amplia utilizacion en el hospital (104 DDD/100 estancias). Los opiaceos representan un 7,4% del consumo total de analgesicos, siendo el paracetamol y el metamizol los analgesicos mas ampliamente utilizados. Conclusiones Los datos de nuestro estudio reflejan una tendencia al incremento del consumo de opiaceos en el hospital, lo que consideramos una mejora en el tratamiento del dolor, tanto agudo como cronico, pues en este incremento se ven involucrados todos los principios activos opiaceos. En un hospital con elevada actividad y complejidad asistencial como el Hospital La Paz, este tipo de estudios constituyen una herramienta que nos permite conocer y comparar el uso de opiaceos en los distintos hospitales y servicios clinicos. Nos permiten conocer la evolucion del consumo asi como detectar posibles desviaciones e implementar acciones de mejora en los diferentes servicios clinicos implicados en el tratamiento del dolor.

CP-153 Effectiveness of new direct acting antivirals for chronic hepatitis C

Background Recently, new direct acting antivirals (DAAs) for chronic hepatitis C have been licensed. These drugs achieve a virologic sustained response (SVR) above 90% in clinical trials. SVR is defined as undetectable HCV RNA 12 weeks after treatment completion (SVR12). Purpose To evaluate the effectiveness of treatment with new DAAs for chronic hepatitis C in real medical practice. Material and methods Observational retrospective study that included patients with chronic hepatitis C treated with new DAAs, who had finished treatment and had results for HCV RNA levels 12 weeks post-treatment. We considered that the drug was effective if the patient achieved SVR12. Data collected were: age, gender, HIV coinfection, prior treatment experience, genotype, hepatic fibrosis stage, DAA regimen and HCV RNA level. Results We included 86 patients; 66% were males. Median age was 57 years (29–84). 31 (36%) patients were HIV coinfected. Regarding previous treatment, 38 (44%) patients were naïve, 26 (30%) non-responders, 13 (15%) relapsers, 7 (8%) partial responders and 2 (2.33%) patients had no data. The most frequent genotype was 1b (62%). The hepatic fibrosis stage was F4 in 55 (64%) patients, F3 in 19 (22%), F2 in 11 (13%) and 1 (1.16%) patient had no data. The treatment regimens were: dasabuvir+paritaprevir/ritonavir+ombitasvir+ribavirine 12 weeks: 22 (25.58%) patients. sofosbuvir+ledipasvir 8–12 weeks: 22 (25.58%) patients. simeprevir+PegIFN+ribavirine 24 weeks: 5 (5.81%) patients. sofosbuvir+daclatasvir 24 weeks: 7 (8.14%) patients. sofosbuvir+daclatasvir+ribavirine 12–24 weeks: 6 (6.98%) patients. sofosbuvir+simeprevir+ribavirine: 12 weeks: 13 (15.12%) patients and 24 weeks 4 (4.65%) patients. sofosbuvir+simeprevir: 24 weeks, 4 (4.65%) and 12 weeks, 1 (1.6%) patient. sofosbuvir+ribavirine 16 weeks: 1 (1.16%) patient. paritaprevir/ritonavir+ombitasvir+ribavirine 12 weeks: 1 (1.16%) patient. 81 (94%) patients achieved RVS12. Patients did not achieve RVS12 with: sofosbuvir+daclatasvir 24 weeks (2 patients), simeprevir+PegIFN+ribavirine 24 weeks (2 patients) and dasabuvir+paritaprevir/ritonavir+ombitasvir+ribavirine 12 weeks (1 patient). Conclusion The RVS12 rate achieved with the new DAAs in this study matches the results obtained in published clinical trials. These results are very good but now we have to face the challenge of how to treat patients who have not responded to these therapies and look for possible causes, such as low adherence and resistance. References and/or Acknowledgements European Association for Study of Liver. EASL Recommendations on Treatment of Hepatitis C 2015. J Hepatol 2015;63:199–236 No conflict of interest.

CP-062 Defibrotide for the treatment of severe hepatic veno-occlusive disease. A single centre experience

Background Hepatic veno-occlusive (VOD) disease is a potentially life threatening complication that mainly occurs after myeloablative conditioning therapy and haematopoietic stem cell transplantation (HSCT). The disease is characterised by increased serum bilirubin concentrations, tender hepatomegaly, fluid retention and weight gain. Severe VOD is one of the most frequent causes of early death in the HSCT setting, with a mortality rate of up to 98% by day +100 post-HSCT. There are few effective options that target the underlying cause. Defibrotide has recently been authorised via the centralised procedure of the EMA for the treatment of severe VOD in adults and children, as it has been associated with complete response (CR) rates of 36–76%, and by 100 days post-HSCT survival rates of 32–79% in clinical trials. Purpose To determine the CR rate in patients with severe VOD following HSCT treated with defibrotide, and survival rates by 100 days post-HSCT. Material and methods A retrospective observational study. Adults or children with VOD treated with defibrotide were included. CR was defined as normalisation of total serum bilirubin levels and resolution of multiple organ failure (renal, pulmonary and central nervous system). A secondary endpoint was survival by 100 days post- HSCT. Results 42 patients (30 adults and 12 children) with VOD received defibrotide. Mean age was 46 (range 19–70) years for adults and 7 (range 0.25–16) years for children. Patients received their first dose at a median of 18 (range 3–56) days after myeloablative conditioning therapy. The mean dose of defibrotide was 25 (range 10–45) mg/kg/day and the median duration of therapy was 11 (range 1–40) days. After treatment with defibrotide, CR was found in 13 patients (30.95%). By 100 days post-HSCT, CR in the evaluable population was achieved in 12 patients (28.57%) and the survival rate was 50%; 21 patients were still alive with resolution of VOD. Conclusion Defibrotide has demonstrated a limited effectiveness in our study and other published studies. We have to consider that VOD is a rare disorder, and as a result the first limitation of studies is the small number of patients that can be included. Consequently, more effectiveness studies with more patients are needed. References and/or Acknowledgements Hospital La Paz No conflict of interest.

CP-011 Pirfenidone in Idiopathic Pulmonary Fibrosis

Background The search for effective treatment in idiopathic pulmonary fibrosis (IPF) has involved numerous clinical trials without significant success. However, in 2011, pirfenidone was the first drug to be approved for the treatment of IPF in Europe. Purpose To evaluate the effectiveness and safety of pirfenidone. Materials and methods A retrospective, longitudinal, observational and descriptive study from January 2012 to April 2013. Clinical data were obtained by medical record review of 3 patients undergoing treatment with pirfenidone for twelve, thirteen and fifteen months. The main clinical variable studied was the variation of the forced vital capacity (FVC) from basal levels, considering it a positive response to the treatment if FVC didn’t decrease more than 10%. Other variables analysed were: FEV1/FVC (increased in IPF), forced expiratory volume in one second (FEV1) and diffusion capacity of the lung for carbon monoxide (DLCO) (both decreased in IPF). Results Two patients showed an FVC increase of 16.1% and 1.7%; in the third patient it decreased by 1.35%. FEV1 increased in all patients by 13.6%, 1.9% and 1.4%. FEV1/FVC increased in all patients by 2%, 0.26% and 2.31%. DLCO decreased in all cases at rates of: 8%, 6% and 2.4%. Adverse effects detected were: gastrointestinal disturbances and dyspepsia (3 patients), rash (2 patients), asthenia (2 patients), insomnia (1 patient), backache (1 patient), respiratory infection (1 patient), and diarrhoea (1 patient). Conclusions In patients with idiopathic pulmonary fibrosis, pirfenidone has proven to be effective on the main variable FCV and secondary variable FEV1, but not on FEV1/FVC and DLCO. Detected adverse reactions matched with those described in the literature. Despite some indications of efficacy, further studies are required to evaluate the potential benefit. No conflict of interest.Background The search for effective treatment in idiopathic pulmonary fibrosis (IPF) has involved numerous clinical trials without significant success. However, in 2011, pirfenidone was the first drug to be approved for the treatment of IPF in Europe. Purpose To evaluate the effectiveness and safety of pirfenidone. Materials and methods A retrospective, longitudinal, observational and descriptive study from January 2012 to April 2013. Clinical data were obtained by medical record review of 3 patients undergoing treatment with pirfenidone for twelve, thirteen and fifteen months. The main clinical variable studied was the variation of the forced vital capacity (FVC) from basal levels, considering it a positive response to the treatment if FVC didn’t decrease more than 10%. Other variables analysed were: FEV1/FVC (increased in IPF), forced expiratory volume in one second (FEV1) and diffusion capacity of the lung for carbon monoxide (DLCO) (both decreased in IPF). Results Two patients showed an FVC increase of 16.1% and 1.7%; in the third patient it decreased by 1.35%. FEV1 increased in all patients by 13.6%, 1.9% and 1.4%. FEV1/FVC increased in all patients by 2%, 0.26% and 2.31%. DLCO decreased in all cases at rates of: 8%, 6% and 2.4%. Adverse effects detected were: gastrointestinal disturbances and dyspepsia (3 patients), rash (2 patients), asthenia (2 patients), insomnia (1 patient), backache (1 patient), respiratory infection (1 patient), and diarrhoea (1 patient). Conclusions In patients with idiopathic pulmonary fibrosis, pirfenidone has proven to be effective on the main variable FCV and secondary variable FEV1, but not on FEV1/FVC and DLCO. Detected adverse reactions matched with those described in the literature. Despite some indications of efficacy, further studies are required to evaluate the potential benefit. No conflict of interest.

OHP-042 Impact of the Paediatric Regulation on the environment of paediatric medicines use: paediatric investigation versus off-label drug use

Background In 2006, the European Parliament approved paediatric standards (Paediatric Regulation 1901/2006) in order to stimulate the development of paediatric clinical trials (PCT) reducing off-label drug use (ODU). Purpose To evaluate the variation in PCT and ODU in children over the last 6 years since this paediatric regulation came into force. We also analysed the type of PCT and characteristics of drugs involved in PCTs or prescribed in conditions that they are not approved (off label). Materials and methods Observational retrospective study in a 252-bed children’s hospital which forms part of a tertiary hospital. The main outcome measured was the number of PCT carried out per year and ODU per year (from 2007 to 2012). Furthermore, PCT design, type of drugs used in both conditions (experimental and off-label), and reasons for off-label use according to the summary of product characteristics were assessed as well. Results We analysed 87 drugs involved in PCT and 449 non-investigational drugs, of which 117 (26%) were considered off-label prescriptions. We observed an increase in PCT carried out per year from 9 in 2007 to 23 in 2011, reaching 19.3% of total clinical trials performed in our centre. Off-label drug use remained stable over the study period. The most common type of PCT design was phase III non-randomised open-label (27.6%). Concerning the drugs involved, antibiotics and antineoplastic-immunosuppressant agents were the most common drugs investigated in PCT, while off-label prescriptions mainly involved hypnotics-sedatives and anticoagulants. Most cases of these off-label prescriptions were related to the lack of studies. Conclusions Since January 2007 when the paediatric regulations came into force in the European Union, an increase of PCT performed has been detected in our centre. However, this fact has not affected off-label drug use which has not changed mainly due to a lack of research into drugs in children. No conflict of interest.

GRP-035 Boceprevir and Telaprevir: Safety

Background Protease inhibitors boceprevir and telaprevir were approved by the European Medicines Agency in July and September 2011 respectively for the treatment of hepatitis C genotype-1 in combination with peginterferon and ribavirin (triple therapy). Purpose To describe the safety of boceprevir and telaprevir in clinical practise. Materials and Methods All patients who received triple therapy prior to commercialization (compassionate use) with boceprevir or telaprevir to September 2012 were included. Data collected were: drugs administered for triple therapy, analytical parameters (haemoglobin, neutrophils and platelets) and subjective adverse effects. Patients were educated by the pharmacist about the medicines at the start of triple therapy and interviewed about adverse effects monthly with each refill of triple therapy. Results Of the 36 patients with chronic hepatitis C included, 16 were treated with telaprevir and 20 with boceprevir. The most frequent adverse reactions were anaemia, neutropenia and thrombocytopenia. Anaemia was managed by reducing the dose of ribavirin (7 patients), erythropoiesis-stimulating agents (11 patients) and packed cells (7 patients). Neutropenia and thrombocytopenia were controlled with peginterferon dose reduction (2 patients) and granulocyte colony-stimulating factor (4 patients). Other adverse effects were fatigue or discomfort (16 patients), insomnia (5 patients), fever (5 patients), pruritus, dysgeusia, headache, nausea, diarrhoea and irritability. Eight patients had to discontinue treatment due to adverse reactions which were not controlled with dose adjustment or supportive drugs. Conclusions All adverse events observed were reported in the EMA studies. Protease inhibitors have shown improve sustained virological response in clinical trials but these drugs are associated with a lot of adverse reactions. It is very important to have close collaboration between the physician and the pharmacist for medicines management, so that adverse reactions not described in the drug information will be reported to health agencies. Abstract GRP-035 Table 1 Protease inhibitor No. of patients Anaemia Neutropenia Thrombocytopenia n (%) Boceprevir 20 17 (85) 14 (70) 15 (75) Telaprevir 16 11 (69) 6 (38) 13 (81) No conflict of interest.

GRP-143 Potassium Monitoring: Do We Give It the Attention It Deserves?

Background Potassium (K+) is the principal intracellular cation and is essential to maintain the function of multiple organs. It is a critical component of cardiac conduction and has a narrow therapeutic/toxic range. Purpose To investigate the effect of pharmaceutical intervention through computerised prescription order entry (CPOE) in hospitalised patients with K+ disorders. Materials and Methods Prospective study carried out over 7 weeks. Pharmacists first added information about drugs that affect the K+ level as a support in the prescription programme. We then identified patients with abnormal K+ levels using a link with laboratory data (<3.1 and >5.3 mmol/l). Pharmacists reviewed the pharmacotherapy daily in order to detect possible medication errors related to K+ disorders. Lastly we analysed the effect of pharmaceutical recommendations and physician acceptance rate. Results 183 patients were included (67 ± 17 years old on average), 128 patients (69.9%) with hypokalaemia and 55 (30.1%) with hyperkalaemia. A total of 3,380 electronic prescriptions were selected. Of them, 540 (16.0%) could affect K+ levels mainly through furosemide, piperacillin-tazobactam and meropenem; pharmacists checked 383 orders thoroughly to prevent possible medication errors. 232 (60.6%) required pharmaceutical recommendations, 130 of them (56.0%) were related to optimising K+ therapy in hypokalaemic patients and 35 (15.0%) were safety recommendations for closer monitoring. Clinicians accepted 72.4% of recommendations. Conclusions There is a high rate of prescription errors related to K+ disorders that could jeopardise patient safety. Pharmaceutical intervention through CPOE helps to minimise them and increases physician awareness of the necessity of closer K+ monitoring in these patients. No conflict of interest.

Clinical use of tigecycline in a university hospital

Background Tigecycline, a glycylcycline antibiotic, is indicated in adults for the treatment of complicated skin and soft tissue infections and complicated intra-abdominal infections. FDA and EMA have reviewed their indications. Purpose The aim of this study is to describe the use of tigecycline in our hospital. Materials and methods The patients clinical histories were reviewed to verify the correct use of tigecycline. A descriptive observational study was performed to evaluate the use of tigecycline over a 3 months period. Several variables were studied, including patient information, diagnosis, evaluation of empirical treatment, duration of treatment or change of antibiotic and clinical resolution. Results 39 patients, 22 men and 17 women, with mean age 61 years old (range 49-72) were investigated. 29 (74,4%) were sent to the Urgency Service. Co-morbilities were: diabetes mellitus (25,6%), renal failure (23,1%), cancer (18%), congestive cardiac failure (15,8%), chronic obstructive pulmonary disease (10%) and peripheral arteriopathy (10%). The majority of the treatments were prescribed in medical intensive care units. Of the 39 patients: 15 were assessed in Anaesthesia and Reanimation Unit and 13 in the Intensive Care. An internal medicine physician specialising in infectious diseases prescribed tigecycline to 5 patients (12,8%). And the rest were from surgical units. The most common infections were: intra-abdominal infection (35,8%), skin and soft tissue (17,9%), bacteraemia (15,4%), pneumonia (10,3%), fever syndrome (7,7%), central catheter infections (5,1%), central nervous system infection (2,6%), respiratory infections (2,6%), and not identified (12,8%). In 18 patients (46,2%) treatment was suspended due to clinical resolution, 2 of them were de-escalated. 15 patients (38%) died during the study period. In 6 patients were not collected. Conclusions Tigecycline was prescribed to many infections, most of them were not indicated. It was necessary to insist on dissemination of the protocols of empirical treatment to ensure the proper use of antibiotics.