Exploratory analysis for the implementation of antineoplastic logarithmic dose banding.

Background Dose banding (DB) is a strategy to rationalise antineoplastic production at Hospital Pharmacy Aseptic Compounding Units (ACUs) and to reduce patient's waiting time. DB allows for optimizing workflows and workloads, facilitating adoption of new technologies, and increasing safety, quality and efficiency of the compounding process. Objective To evaluate the potential impact of implementation of Logarithmic DB and to identify antineoplastic agents and preparations that fulfil criteria published and establish the number and standard doses that could be compounded in advance at the ACU. Setting University and Polytechnic third level general hospital. Method Retrospective observational study (December 2015-May 2016). Antineoplastic dose production was analysed. Investigational drugs were excluded. Three criteria were applied following bibliography reviewed to select candidates to be compounded at our ACU as standardised using logarithmic DB: (a) Antineoplastic preparations > 250 per year; (b) psychochemical stability in optimal storage conditions at least 14 days; (c) maximum five logarithmic standardised doses that include at least 60% of all individualised doses compounded for a given drug. Main outcome measure Number of antineoplastic agents, preparations and logarithmic standard doses candidates to DB. Results 15,436 antineoplastic individualised doses corresponding to 69 antineoplastic agents were analysed. At our institution applying selection criteria, 19 (27%) antineoplastic drugs (3 monoclonal antibodies, 16 cytotoxic) were potential candidates to DB. 6285 (40%) of compounded individualised dose preparations could be prepared in 84 logarithmic standard doses in advance. Conclusion Dose banding implementations could contribute to rationalise antineoplastic production and increase the ACUs compounding capacity.

[Measurement of continuous improvement in the safety of oncologic patients]. / Medida de la mejora continua en la seguridad del paciente oncológico.

OBJECTIVE: To analyze continuous improvement in the safety of oncologic patients through the change of quality indicators established with the implementation of a quality management system (QMS) according to the ISO 9001-2008 regulation at a oncologic pharmacy unit (OPU). METHOD: Prospective and observational study carried out between January of 2008 and December of 2011. The ISO 9001-2008 certification of the OPU included the proceedings of electronic prescription,validation, preparation, delivery, and administration of the antineoplastic therapy. The following quality indicators were established: medication errors (ME), preparation and delivery errors not reaching the patient, and ME reaching the patient. The indicators were calculated quarterly through the Farmis-Oncofarm® software; the adherence standard was defined at ≤ 1 ME per one thousand and the follow-up was done through control graphs. One « post-implementation ¼ period (2008-2011) and one « pre-implementation ¼ period (2007) were established and the U Mann Whitney test was used to compare the median of the indicator for both periods.The differences between the two periods were considered to be statistically significant when the p value was p ≤ 0.05. RESULTS: 140,440 preparations were made at the OPU, for 4,770 patients, corresponding to 52,906 patients-day. The adherence to the standard during the first one-year period allowed reducing the three indicators to ≤ 0,5 ME per one thousand. For preparation ME an abnormal value was identified; the causes were analyzed and improvement measures were proposed. In the post-implementation period, ME were reduced during the post-implementation period as compared to the pre-implementation period (p<0.05). CONCLUSIONS: The follow-up of the quality indicators allows measuring and assessing the pharmaco-therapy safety in the oncologic patient. After the implementation of the QMS at the OPU, the number of ME has been reduced.

Medida de la mejora continua en la seguridad del paciente oncológico / Measurement of continuous improvement in the safety of oncologic patients

Objetivo: Analizar la mejora continua en la seguridad del paciente oncológico, a través de la evolución de los indicadores de calidad establecidos tras la implantación de un sistema de gestión de la calidad (SGC) según norma ISO 9001:2008, en una unidad de oncología farmacéutica (UOF). Método: Estudio observacional prospectivo realizado entre Enero 2008 y Diciembre de 2011. La certificación ISO 90012008 de la UOF incluyó los procesos de prescripción electrónica, validación, preparación, dispensación y administración del tratamiento antineoplásico. Se establecieron los indicadores de calidad: errores de medicación (EM) de preparación y dispensación que no alcanzan al paciente, y EM que alcanzan al paciente. Los indicadores se calcularon con una periodicidad trimestral a partir del aplicativo informático Farmis-Oncofarm®, se definió el estándar de cumplimiento en <1 EM por mil y el seguimiento se realizó mediante gráficos de control. Se definieron dos periodos "postimplantación" (2008-2011) y "preimplantación" (2007) y se aplicó la prueba estadística U de Mann Whitney para comparar la mediana del indicador en ambos periodos. Se consideraron diferencias estadísticamente significativas entre los periodos cuando p < 0,05. Resultados: Se realizaron 140.440 preparaciones en la UOF, para 4.770 pacientes, correspondientes a 52.906 pacientes-día. El cumplimiento del estándar durante la primera anualidad permitió su reducción a <0,5 EM por mil en los tres indicadores. En los EM de preparación se identificó un valor anómalo que implicó analizar sus causas y proponer propuestas de mejora. En el periodo postimplantación se redujeron los EM respecto al periodo preimplantación (p > 0,05). Conclusiones: El seguimiento de los indicadores de calidad permite medir y evaluar la seguridad farmacoterapéutica en el paciente oncológico. Tras la implantación del SGC en la UOF se han reducido los EM generados (AU)

Objective: To analyze continuous improvement in the safety of oncologic patients through the change of quality indicators established with the implementation of a quality management system (QMS) according to the ISO 9001-2008 regulation at a oncologic pharmacy unit (OPU). Method: Prospective and observational study carried out between January of 2008 and December of 2011. The ISO 9001-2008 certification of the OPU included the proceedings of electronic prescription, validation, preparation, delivery, and administration of the antineoplastic therapy. The following quality indicators were established: medication errors (ME), preparation and delivery errors not reaching the patient, and ME reaching the patient. The indicators were calculated quarterly through the Farmis-Oncofarm® software; the adherence standard was defined at < 1 ME per one thousand and the follow-up was done through control graphs. One "postimplementation" period (2008-2011) and one "pre-implementation" period (2007) were established and the U Mann Whitney test was used to compare the median of the indicator for both periods. The differences between the two periods were considered to be statistically significant when the p value was p < 0.05. Results: 140,440 preparations were made at the OPU, for 4,770 patients, corresponding to 52,906 patients-day. The adherence to the standard during the first one-year period allowed reducing the three indicators to < 0,5 ME per one thousand. For preparation ME an abnormal value was identified; the causes were analyzed and improvement measures were proposed. In the post-implementation period, ME were reduced during the post-implementation period as compared to the pre-implementation period (p<0.05). Conclusions: The follow-up of the quality indicators allows measuring and assessing the pharmacotherapy safety in the oncologic patient. After the implementation of the QMS at the OPU, the number of ME has been reduced (AU)

Exposición a fármacos citotóxicos en el personal sanitario / Exposure to cytotoxic drugs among health care professionals

Objetivo: Cuantificar los niveles de exposición del personal sanitario a fármacos citotóxicos con el fin de establecer el nivel umbral de exposición e implantar medidas para incrementar la protección y seguridad. Material y método La cuantificación de la contaminación de 5-fluorouracilo, gemcitabina y ciclofosfamida se llevó a cabo en las superficies de las siguientes áreas: cabina de seguridad biológica clase II tipo B3 (S1), mesa de preparación de tratamientos en antecámara (S2) y mesa de la sala de administración en hospital de día (S3). Se tomaron muestras de las superficies con un paño absorbente a tiempo t0, previo inicio de la sesión de trabajo, y t1, tras 3 h de trabajo mediante arrastre. En cada superficie se calculó el valor de la masa mediana respecto al valor basal y los percentiles 90, 75, 50 y 25 para cada citotóxico en μg/m2.Se comprobó la normalidad de la distribución con la prueba Shapiro-Wilk. El análisis estadístico incluyó las pruebas U de Mann-Whitney, Kruskal-Wallis y Wilcoxon. Se fijó el nivel de significación estadística para valores de p < 0,05.ResultadosSe recogieron un total de 90 muestras en total, 30 muestras por cada superficie de estudio. La masa media registrada de cualquier compuesto citotóxico fue superior en S1 y t1, con un valor de p = 0,017 y p = 0,004, respectivamente. Para cada fármaco citotóxico se fijó como valor objetivo el percentil 25 donde se obtuvieron valores de contaminación indetectables. Conclusiones La introducción de un programa de monitorización continua de superficies de diversos compuestos citotóxicos es esencial para fijar unos niveles aceptables de contaminación residual y reducir la exposición ocupacional (AU)

Objective: To quantify levels of exposure to cytotoxic drugs among health professionals in order to establish an exposure threshold and implement measures to increase protection and safety Material and method: Contamination with 5-fluorouracil, gemcitabine and cyclophosphamide was measured on work surfaces in the following areas: a class II type B3 biological safety cabinet(S1), a treatment prep table in an antechamber (S2) and a desk from the administrative room in the Outpatient Unit (S3). We took samples from the work surfaces by wiping them with an absorbent cloth at time t0, prior to the work session, and at t1 after three hours of work. For each surface, we calculated the median mass value with respect to the baseline value and the90th, 75th, 50th and 25th percentiles for each cytotoxin in g/m2.Distribution normality was assessed using the Shapiro-Wilk test. Statistical analysis included the Kruskal-Wallis and Mann-Whitney-Wilcoxon tests. Statistical significance was established for values of P<.05.Results: We gathered a total of 90 samples, 30 from each of the studied work surfaces. The mean recorded mass of any of the cytotoxic compounds was higher for S1 and t1, with values of P=.017 and P=.004 respectively. The target value for each cytotoxic drug was established at the 25th percentile, where undetectable contamination values were obtained. Conclusions: Introducing a continuous programme to monitor work surfaces for an array of cytotoxic compounds is fundamental in order to establish acceptable levels of residual contamination and reduce exposure in the workplace (AU)

[Exposure to cytotoxic drugs among health care professionals]. / Exposición a fármacos citotóxicos en el personal sanitario.

OBJECTIVE: To quantify levels of exposure to cytotoxic drugs among health professionals in order to establish an exposure threshold and implement measures to increase protection and safety. MATERIAL AND METHOD: Contamination with 5-fluorouracil, gemcitabine and cyclophosphamide was measured on work surfaces in the following areas: a class II type B3 biological safety cabinet (S(1)), a treatment prep table in an antechamber (S(2)) and a desk from the administrative room in the Outpatient Unit (S(3)). We took samples from the work surfaces by wiping them with an absorbent cloth at time t(0), prior to the work session, and at t(1) after three hours of work. For each surface, we calculated the median mass value with respect to the baseline value and the 90th, 75th, 50th and 25th percentiles for each cytotoxin in µg/m(2). Distribution normality was assessed using the Shapiro-Wilk test. Statistical analysis included the Kruskal-Wallis and Mann-Whitney-Wilcoxon tests. Statistical significance was established for values of P<.05. RESULTS: We gathered a total of 90 samples, 30 from each of the studied work surfaces. The mean recorded mass of any of the cytotoxic compounds was higher for S(1) and t(1), with values of P=.017 and P=.004 respectively. The target value for each cytotoxic drug was established at the 25th percentile, where undetectable contamination values were obtained. CONCLUSIONS: Introducing a continuous programme to monitor work surfaces for an array of cytotoxic compounds is fundamental in order to establish acceptable levels of residual contamination and reduce exposure in the workplace.

Perfil de toxicidad y adherencia del esquema farmacoterapéutico gemcitabina-carboplatino en cáncer de pulmón no microcítico / Toxicity Profile and Adherence to the Pharmacotherapeutic Regimen of Gemcitabine–carboplatin in Non-small Cell Lung Cancer

Objetivo Analizar la relación entre las dosis administradas de gemcitabina-carboplatino (GEM-CARBO) y la incidencia y grado de toxicidad, hematológica y renal, y la adherencia al tratamiento en pacientes con cáncer de pulmón no microcítico. Métodos Estudio retrospectivo de 37 meses de duración. El conjunto mínimo de datos para realizar el seguimiento de los pacientes se obtuvo con ayuda del programa informático Farmis-Oncofarm® y de las historias clínicas y farmacoterapéuticas. La toxicidad hematológica se evaluó de acuerdo con la Common Toxicity Criteria 3.0. La toxicidad renal se valoró a partir de los datos de concentración sérica de creatinina y el aclaramiento de creatinina. Resultados Se han incluido en el estudio 31 pacientes a los que se les administraron un total de 122 ciclos. La incidencia de anemia y neutropenia grado III fue de un 34,0 y un 30,8%, respectivamente, de trombocitopenia de grado III del 3,8% y de grado IV del 7,7%. No se ha identificado ningún caso de toxicidad renal. El 65,0% de los pacientes recibieron más del 85,0% de la dosis de carboplatino teórica planeada y el 58,0% de los pacientes recibieron más del 85,0% de la dosis de gemcitabina teórica planeada. Se retrasó la administración en el 18,0% de los ciclos prescritos. Conclusiones La indicación y prescripción del esquema GEM-CARBO se ha ajustado con unas evidencias científicas sólidas, pero su toxicidad hematológica ha limitado su uso y ha dificultado la administración de la intensidad de dosis prevista comprometiendo la efectividad del tratamiento (AU)

Objective To analyse the relationship between doses of gemcitabine–carboplatin (GEM-CARBO) administered and incidence and level of haematological and renal toxicity, and the adherence to the treatment in patients with non-small cell lung cancer. Methods Retrospective study, which lasted for 37 months. We were able to obtain the minimum set of data needed to carry out the follow-up with the help of Farmis-Oncofarm® software and the medical and pharmacotherapeutic records. The haematological toxicity was assessed in accordance with the Common Toxicity Criteria 3.0. Renal toxicity was evaluated using serum creatinine levels and creatinine clearance. Results Thirty-one patients were included in the study who were administered a total of 122 cycles. There was a 34.0% and 30.8% incidence of anaemia and grade 3 neutropenia, respectively. There was also a 3.8% and 7.7% incidence of grade 3 and grade 4 thrombocytopenia, respectively. No cases of renal toxicity were found. 65.0% of patients received more than 85.0% of the planned theoretical dosage of carboplatin and 58% of patients received more than 85.0% of the planned theoretical dosage of gemcitabine. Administration was delayed in 18.0% of the cycles prescribed. Conclusions The indication and prescription of the GEM-CARBO regimen was adjusted in accordance with solid scientific evidence, but its haematological toxicity limited its use and made it difficult to maintain the dose intensity foreseen in the study. This compromised the effectiveness of the treatment (AU)

Toxicity profile and adherence to the pharmacotherapeutic regimen of gemcitabine-carboplatin in non-small cell lung cancer.

OBJECTIVE: To analyse the relationship between doses of gemcitabine-carboplatin (GEM-CARBO) administered and incidence and level of haematological and renal toxicity, and the adherence to the treatment in patients with non-small cell lung cancer. METHODS: Retrospective study which lasted for 37 months. We were able to obtain the minimum set of data needed to carry out the follow-up with the help of Farmis-Oncofarm(®) software and the medical and pharmacotherapeutic records. The haematological toxicity was assessed in accordance with the Common Toxicity Criteria 3.0. Renal toxicity was evaluated using serum creatinine levels and creatinine clearance. RESULTS: Thirty-one patients were included in the study who were administered a total of 122 cycles. There was a 34.0% and 30.8% incidence of anaemia and grade 3 neutropaenia, respectively. There was also a 3.8% and 7.7% incidence of grade 3 and grade 4 thrombocytopaenia, respectively. No cases of renal toxicity were found. 65.0% of patients received more than 85.0% of the planned theoretical dosage of carboplatin and 58% of patients received more than 85.0% of the planned theoretical dosage of gemcitabine. Administration was delayed in 18.0% of the cycles prescribed. CONCLUSIONS: The indication and prescription of the GEM-CARBO regimen was adjusted in accordance with solid scientific evidence, but its haematological toxicity limited its use and made it difficult to maintain the dose intensity foreseen in the study. This compromised the effectiveness of the treatment.

[Antineoplastic oral agents and drug-nutrient interactions: a sistematic review]. / Interacción de los antineoplásicos orales con los alimentos: revisión sistemática.

INTRODUCTION: Studies on bioavailability are part of the clinical development of drugs for oral use in order to identify potential drug-food interactions. For oral antitumor drugs, their clinical importance is currently recognized although regrettably the information available presents variability concerning the scientific evidence. OBJECTIVES: To review the available scientific evidence about oral anti-tumor medications and establish the recommendations for their administration with foods. METHODS: We carried out a bibliographic search in Medline and The Cochrane Library for the period January of 1966 to March of 2008, focused on identifying those publications about drug-food interactions with oral antitumor medications. The bibliographical analysis was made in two steps. During the first phase, we excluded those articles in which the title or their content did not correspond with the objective settled; during the second phase, we deleted all the references duplicated in both databases. The inclusion criteria to select the articles were: design (systematic reviews, meta-analysis, Phase I and Phase II randomized clinical trials), population (adult patients; >19 years of age), intervention evaluated (administration of oral anti-tumor drugs under fasting conditions or with food) and measurement of the iFA results (calculation of the 90% CI of the odds ratio between the geometric mean of the values under the curve of the plasma concentrations (ABC) or the maximal plasma concentration (Cmax) with and without foods). We excluded those publications that did not make reference to the bioequivalence dictamen established by the Food and Drugs Administration (FDA) in their outcomes measurement. A critical appraisal of the selected articles was done according to the recommendations that the FDA established to be met by these studies. RESULTS: At the initial search we obtained 850 references (98.5% Medline + and 1.4% Cochrane). During the first phase, we excluded 87.7% (746) of the articles, 100% of them corresponding to the search in Medline. During the second phase, 40 studies remained (5.2% of the initial ones) for full-text critical appraisal, to which four studies were added not indexed in Medline. From the critical appraisal of the 44 final articles, 25 were excluded (20 original articles, 4 short communications, and 1 meta-analysis) because they did not include as an outcome measure the bioequivalence dictamen. The 19 (2.2%) remaining articles provided information on 19 oral anti-tumor drugs in 210 patients and 146 healthy volunteers. Of these 19 drugs, 63% did not present drug-food interactions, with the possibility of administering them either with or without food; 21% have to be administered with foods and only 16% present drug-food interactions, so they have to be administered without foods. DISCUSSION: Currently, the clinical importance of drug-food interactions with oral anti-tumor drugs is identified more directly with the patient's safety than with the efficacy of the therapy. Given the development of these oral agents, their incorporation into the oncologic strategy displacing parenteral therapy, with monthly costs of thousands of Euros, it is necessary to perform well-designed studies on pharmacokinetics and pharmacodynamics. Their goal has to be comparing their bioavailability in the presence or absence of foods with the clinical response. In the meanwhile, to establish recommendations for their administration in relation to foods is inconsistent for some of these drugs and their results is uncertain given the lack of studies based on the FDA bioequivalence dictamen.

Management of returned anti-neoplastic treatments and their reuse in oncology patients.

OBJECTIVE: Analyse the profile of parenteral preparation and treatment (anti-neoplastic and supplementary) that were dispensed and returned to the Pharmacy Department, the reasons why they were not administered, their reuse and the associated direct costs. METHOD: Longitudinal study over eight months (October 2004-May 2005) in a tertiary hospital with centre for preparing anti-neoplastic agents (including supplementary treatment) in its Pharmacy Department. The variables studied, downloaded from the Oncofarm® application, are as follows: (a) patients and diagnostics; (b) returned treatments, classified by reason returned, pharmaco-therapeutic scheme, cycle and day; (c) returned preparations (anti-neoplastic and supplementary) that were reused; and (d) direct costs. Data is presented with its absolute and relative frequencies and confidence intervals of 95% normalised at 1000 patients/day. RESULTS: 84 treatments were returned by 66 patients for a total of 139 preparations corresponding to 3,429 patients/day. This figure represents 24.5 (CI 95%, 19.6 to 30.2) treatments that were prepared and not administered per 1,000 patients/day, mainly due to clinical causes (n = 47). Colon neoplasia and treatment with 5-fluorouracil and levofolinic acid presented the highest number of returns. The returned preparations made up 1.45 % (CI 95%, 1.2 to 1.7) of those produced. The percentage of reuse is 98%, which results in savings of euro 10,432.55 (90% of the cost of the treatments that are returned). CONCLUSIONS: The application of quality, effectiveness and safety criteria to anti-neoplastic treatments that are prepared and returned to the Pharmacy Department allows a more efficient preparation process.

Gestión de la devolución de tratamientos antineoplásicos y de su reutilización en pacientes oncológicos / Management of returned anti-neoplastic treatments and their reuse in oncology patients

Objetivo: Analizar el perfil de tratamientos y preparaciones parenterales (antineoplásicas y de soporte) dispensados y devueltos al servicio de farmacia, las causas de no administración, su reutilización y los costes directos asociados. Método: Estudio longitudinal, prospectivo, durante 8 meses (octubre 2004-mayo 2005) en un hospital terciario con centralización de la preparación de esquemas antineoplásicos (incluye tratamiento de soporte) en el servicio de farmacia. Las variables estudiadas, descargadas del aplicativo Oncofarm®, fueron: a) pacientes y diagnósticos; b) tratamientos devueltos, diferenciando por causa, esquema farmacoterapéutico, ciclo y día; c) preparaciones devueltas (antineoplásicos y soporte) y reutilizadas, y d) costes directos. Los datos se presentan con sus frecuencias absolutas, relativas e intervalos de confianza (IC) del 95 %, normalizado a 1.000 pacientes/día. Resultados: 84 tratamientos devueltos de 66 pacientes con un total de 139 preparaciones correspondientes a 3.429 pacientes/día. Este dato representa 24,5 (IC del 95 %, 19,6 a 30,2) de tratamientos preparados y no administrados por 1.000 pacientes/día, debido, mayoritariamente, a causas clínicas (n = 47). La neoplasia de colon y el esquema de 5-fluorouracilo y ácido levofolínico presentan el mayor número de devoluciones. Las preparaciones devueltas suponen el 1,45 % (IC del 95 %, 1,2 a 1,7) de las elaboradas. El porcentaje de reutilización es del 98 %, con un coste ahorrado que asciende a 10.432,55 (90 % del coste de los tratamientos devueltos).Conclusiones: La aplicación de criterios de calidad, eficacia y seguridad a los tratamientos antineoplásicos preparados y devueltos al servicio de farmacia permite incrementar la eficiencia en el proceso de preparación (AU)

Objective: Analyse the profile of parenteral preparation and treatment (anti-neoplastic and supplementary) that were dispensed and returned to the Pharmacy Department, the reasons why they were not administered, their reuse and the associated direct costs. Method: Longitudinal study over eight months (October 2004-May 2005) in a tertiary hospital with centre for preparing anti-neoplastic agents (including supplementary treatment) in its Pharmacy Department. The variables studied, downloaded from the Oncofarm® application, are as follows: a) patients and diagnostics; b) returned treatments, classified by reason returned, pharmaco-therapeutic scheme, cycle and day; c) returned preparations (anti-neoplastic and supplementary) that were reused; and d) direct costs. Data is presented with its absolute and relative frequencies and confidence intervals of 95 % normalised at 1000 patients/day. Results: 84 treatments were returned by 66 patients for a total of 139 preparations corresponding to 3,429 patients/day. This figure represents 24.5 (CI 95 %, 19.6 to 30.2) treatments that were prepared and not administered per 1,000 patients/day, mainly due to clinical causes (n = 47). Colon neoplasia and treatment with 5-fluorouracil and levofolinic acid presented the highest number of returns. The returned preparations made up 1.45 % (CI 95 %, 1.2 to 1.7) of those produced. The percentage of reuse is 98 %, which results in savings of € 10,432.55 (90 % of the cost of the treatments that are returned).Conclusions: The application of quality, effectiveness and safety criteria to anti-neoplastic treatments that are prepared and returned to the Pharmacy Department allows a more efficient preparation process (AU)

Interacción de los antineoplásicos orales con los alimentos: revisión sistemática / Antineoplastic oral agents and drug-nutrient interactions: a sistematic review

Introducción: Los estudios de biodisponibilidad son parte integrante del desarrollo clínico de medicamentos para administración oral con el fin de identificar potenciales interacciones fármaco-alimento (iFA). Actualmente, para los antineoplásicos orales se empieza a reconocer su importancia clínica, aun cuando lamentablemente, la información disponible presenta variabilidad en su evidencia científica. Objetivos: Revisar la evidencia científica disponible sobre las interacciones de los alimentos con medicamentos antineoplásicos orales y establecer recomendaciones para su administración. Métodos: Se realizó una búsqueda bibliográfica en Medline y The Cochrane Library para el periodo comprendido entre enero de 1966 a marzo de 2008, enfocada a identificar las publicaciones sobre interacciones fármaco alimento con antineoplásicos orales. El análisis bibliográfico consta de dos fases. En la primera fase se excluyeron los artículos que por título y contenido del resumen no se correspondían con el objetivo planteado; en la segunda fase se eliminaron las referencias duplicadas en ambas bases de datos. Los criterios de inclusión para seleccionar los artículos fueron: diseño (revisiones sistemáticas, metaanálisis, ensayos clínicos randomizados Fase I y II), población (pacientes adultos; >19 años de edad), intervención evaluada (administración de antineoplásicos orales bajo condiciones de ayuno o con alimentos) y medida del resultado de la iFA (cálculo del IC90% de la razón entre la media geométrica de valores del área bajo la curva de concentraciones plasmáticas (ABC) o la concentración plasmática máxima (Cmax) con y sin alimentos). Se excluyeron las publicaciones que como medida de resultado no hacían referencia al dictamen de bioequivalencia establecido por la Food and Drugs Administration (FDA). La valoración crítica de los artículos seleccionados se realizó según las recomendaciones que de acuerdo con la FDA deben cumplir estos estudios. Resultados: En la búsqueda inicial se obtuvieron 850 referencias (98,5% Medline + y 1,4% Cochrane). En la primera fase se excluyeron el 87,7% (746) de los artículos, correspondiendo el 100% a la búsqueda en Medline. En la segunda fase, quedaron 40 artículos (5,2% de los iniciales) para su lectura crítica a texto completo, a los que se añadieron cuatro más no indexados en Medline. De la lectura crítica de los 44 artículos finales, se excluyeron 25 artículos (20 artículos originales, 4 comunicaciones cortas y 1 metanálisis) por no incluir como medida de resultado el dictamen de bioequivalencia. Los 19 (2,2%) artículos restantes proporcionaron información sobre 19 fármacos antineoplásicos orales, en 210 pacientes y 146 voluntarios sanos. De estos 19 fármacos, el 63% no presentan iFA o interacciones fármaco-alimento, pudiéndose administrar indistintamente con/sin alimentos; el 21% se deben administrar con alimentos y sólo el 16% presentan interacción fármaco alimento, por lo que se deben administrar sin alimentos. Discusión: Actualmente, la importancia clínica de las interacciones fármaco alimento con antineoplásicos orales se identifica más directamente con la seguridad del paciente que con la efectividad del tratamiento. Ante el desarrollo de estos agentes orales, su irrupción en la terapia oncológica desplazando a la terapia parenteral, con costes mensuales de miles de euros, hay necesidad de realizar estudios farmacocinéticos y farmacodinámicos bien diseñados. Su objetivo debe de ser comparar su biodisponibilidad en presencia o ausencia de alimentos con la respuesta clínica. Mientras tanto, establecer recomendaciones para su administración en relación con los alimentos, es inconsistente para algunos de estos fármacos y su resultado incierto por la falta de estudios fundamentados en el dictamen de bioequivalencia establecido por la FDA (AU)

Introduction: studies on bioavailability are part of the clinical development of drugs for oral use in order to identify potential drug-food interactions. For oral antitumor drugs, their clinical importance is currently recognized although regrettably the information available presents variability concerning the scientific evidence. Objectives: To review the available scientific evidence about oral anti-tumor medications and establish the recommendations for their administration with foods. Methods: We carried out a bibliographic search in Medline and The Cochrane Library for the period January of 1966 to March of 2008, focused on identifying those publications about drug-food interactions with oral antitumor medications. The bibliographical analysis was made in two steps. During the first phase, we excluded those articles in which the title or their content did not correspond with the objective settled; during the second phase, we deleted all the references duplicated in both databases. The inclusion criteria to select the articles were: design (systematic reviews, meta-analysis, Phase I and Phase II randomized clinical trials), population (adult patients; >19 years of age), intervention evaluated (administration of oral anti-tumor drugs under fasting conditions or with food) and measurement of the iFA results (calculation of the 90% CI of the odds ratio between the geometric mean of the values under the curve of the plasma concentrations (ABC) or the maximal plasma concentration (Cmax) with and without foods). We excluded those publications that did not make reference to the bioequivalence dictamen established by the Food and Drugs Administration (FDA) in their outcomes measurement. A critical appraisal of the selected articles was done according to the recommendations that the FDA established to be met by these studies. Results: At the initial search we obtained 850 references (98.5% Medline + and 1.4% Cochrane). During the first phase, we excluded 87.7% (746) of the articles, 100% of them corresponding to the search in Medline. During the second phase, 40 studies remained (5.2% of the initial ones) for full-text critical appraisal, to which four studies were added not indexed in Medline. From the critical appraisal of the 44 final articles, 25 were excluded (20 original articles, 4 short communications, and 1 meta-analysis) because they did not include as an outcome measure the bioequivalence dictamen. The 19 (2.2%) remaining articles provided information on 19 oral anti-tumor drugs in 210 patients and 146 healthy volunteers. Of these 19 drugs, 63% did not present drugfood interactions, with the possibility of administering them either with or without food; 21% have to be administered with foods and only 16% present drug-food interactions, so they have to be administered without foods. Discussion: Currently, the clinical importance of drugfood interactions with oral anti-tumor drugs is identified more directly with the patient's safety than with the efficacy of the therapy. Given the development of these oral agents, their incorporation into the oncologic strategy displacing parenteral therapy, with monthly costs of thousands of Euros, it is necessary to perform well-designed studies on pharmacokinetics and pharmacodynamics. Their goal has to be comparing their bioavailability in the presence or absence of foods with the clinical response. In the meanwhile, to establish recommendations for their administration in relation to foods is inconsistent for some of these drugs and their results is uncertain given the lack of studies based on the FDAbioequivalence dictamen (AU)

Cisplatin preparation error; patient management and morbidity.

INTRODUCTION: Antineoplastic drug therapy errors represent a high iatrogenic potential due to antineoplastic drugs narrow therapeutic ranges and the complexity of chemotherapy regimens that may increase the risk of morbidity and mortality for oncology patients. SETTING: We report a 57-year-old man with head and neck cancer who mistakenly received 180 mg/ m(2) of cisplatin overdose despite the safety measures and validations carried out during preparation. The patient developed moderate nausea and vomiting, acute renal failure, hearing difficulty (tinnitus), and severe myelodepression. PATIENT MANAGEMENT: Prophylactic and symptomatic treatments were applied in order to prevent and correct toxicity during the 9 days stay at hospital. RESULT: He recovered with mild tinnitus and mild renal impairment as the only sequelae. This case presents a hospital stay and treatment quite different to others used to reverse all cisplatin overdose toxicity and it shows the benefits of prompt management.