EPIRUBICINA EN VADEMECUM

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	EPIRUBICINA
	DESCRIPCION La epirubicina es un agente quimioterépico de la familia de las antraciclinas y es el 4'-epimero de la doxorrubicina y un derivado semisintético de la daunorrubicina. La epirubicina tiene un espectro similar de actividad y de toxicidad a los de la doxorrubicina . En dos ensayos europeos de fase III que compararon la epirrubicina (FEC) yla doxorrubicina (CAF) en combinación con ciclofosfamida y fluorouracilo para el tratamiento del cáncer de mama, los pacientes tratados con epirubicina mostraron una respuesta similar y unas tasas de supervivencia iguales a los pacientes tratados con doxorrubicina. La combinación de ciclofosfamida , fluorouracilo y epirrubicina en dos dosis diferentes en los pacientes con cancer de mama con nódulos positivos mostró una supervivencia libre de enfermedad mayor que lsa combinacion de metotrexato, ciclofosfamida y fluorouracilo (CMF). Mecanismo de acción: la epirubicina y otras antraciclinas inducen citotoxicidad a través de varios mecanismos diferentes. La epirubicina complejos con el ADN intercalandose entre pares de bases del ADN, causando cambios en la conformación de la hélice lo que interfiere con el alargamiento del filamento inhibiendo la ADN polimerasa y la síntesis de proteínas debido a los efectos de la ARN polimerasa. La epirubicina también puede formar complejos con el hierro o el cobre. Estos complejos tienen constantes de asociación alta y pueden contribuir a la cardiotoxicidad inducida por epirubicina aumentando el ciclo redox para producir lesiones en la membrana y daño en las mitocondrias. La epirubicina también afecta a la topoisomerasa II, enzima responsable de roturas del filamento de ADN durante la transcripción. La epirubicina estabiliza el complejo enzima-ADN inicial que conduce a la rotura del ADN de doble cadena. La epirubicina también sufre reducción de un electrón para formar intermedios del radical libre de oxígeno. En presencia de oxígeno y catalizadores metálicos como Fe2 +, epirubicina experimenta una e reducción del radicalsemiquona. En presencia de oxígeno, el radical semiquona puede formar un superperoxido que en presencia de peróxido de hidrógeno forma un radical hidroxilo. Los radicales libres derivados de la epirubicina pueden inducir la peroxidación de lípidos de membrana, la escisión del filamento de ADN y la oxidación directa de las bases de purina o pirimidina, de los tioles y aminas. La epirubicina se considera inespecífica sobre el ciclo celular. La resistencia a la epirubicina puede ocurrir a través de varios mecanismos. Uno de los mecanismos de resistencia más importantes es el mecanismo de resistencia multifármaco (MDR) que se media a través de una sobreexpresión de una Glicoproteína P170. Esta proteína de membrana funciona como una bomba de eflujo de fármaco dependiente de la energía en células resistentes. Varios compuestos incluyendo ciclosporina, los análogos de ciclosporina y el verapamilo pueden bloquear esta proteína y revertir la resistencia. Otros mecanismos de resistencia incluyen cambios en la actividad de la topoisomerasa II y el glutatión. La formación de radicales libres inducida por epirubicina contribuye a su cardiotoxicidad. Una vez que la epirubicina entra en las células cardíacas, se reduce a un radical libre de antraciclina que se oxida rápidamente para formar el fármaco original y aniones de superóxido. Normalmente, estos radicales superóxido se convierten de nuevo en oxígeno a través de glutatión peroxidasa (GP); sin embargo, el corazón está esencialmente desprovisto de esta enzima. La administración de epirubicina destruye cualquier actividad de GP presente en las células cardíacas. En consecuencia, H2O2 se ve obligado a reaccionar con iones ferrosos (Fe2+) para formar el radical libre de superhidroóxido altamente tóxico que causa peroxidación lipídica grave y conduce a la destrucción mitocondrial extensa. Tanto las células cardíacas como las malignas son ricas en mitocondrias. Además, los radicales libres reticulan los grupos de sulfhidrilo de los canales de liberación de calcio e inhiben Ca-ATPase que conduce a un agotamiento extenso de las reservas de calcio del retículo sarcoplasmático (SR) y previene la restauración de las reservas de calcio en el SR, respectivamente. La disminución de la incidencia de toxicidad cardíaca clínicamente significativa asociada con epirubicina en comparación con la doxorubicina se debe al aclaramiento más rápido de la epirubicina y, posiblemente, a la glucuronidación de la epirubicina. Farmacocinética: La epirubicina se administra por vía intravenosa. Tras la administración intravenosa, la epirubicina se distribuye ampliamente en los tejidos. La epirubicina se une aproximadamente en un 77% a las proteínas plasmáticas, principalmente a la albúmina. La epirubicina tiene un aclaramiento trifásico con semi-vida media para las fases alfa, beta y terminal de 3 minutos, 1 hora y 30 horas, respectivamente. La epirubicina es rápida y extensamente metabolizada por el hígado y otros tejidos, incluyendo los glóbulos rojos. El metabolismo de la epirubicina se produce a través de cuatro rutas principales: 1) reducción del cetogrupo C-13 con la formación del derivado 13(S)-dihidro-epirubicinol, 2) conjugación tanto del fármaco inalterado como del epirubicinol con ácido glucurónico, 3) pérdida de la mitad del aminoazúcar a través de un proceso hidrolítico con la formación de doxorubicina y alcoholes doxorubicinoles, y 4) pérdida de la mitad del azúcar a través de un proceso de redox con la formación de 7-deoxy-doxorubicina aglucona. El epirubicinol tiene la décima parte de la actividad citotóxica de la epirubicina y no es probable que contribuya a la actividad citotóxica general de la epirubicina. Los metabolitos de glucurónido de epirubicina y epirubicinol no son activos, pero el metabolismo de glucurónido desvía la epirubicina de la formación de radicales libres, lo que puede reducir la cardiotoxicidad. No se ha notificado actividad significativa para los otros metabolitos. La epirubicina y sus principales metabolitos se excretan a través de la excreción biliar y en menor medida la excreción urinaria. El metabolismo y la eliminación de la epirubicina disminuyen en pacientes con disfunción hepática; la mediana del aclaramiento de epirubicina se reduce en un 30% en pacientes con niveles elevados de AST (SGOT) y en un 50% en pacientes con niveles elevados de bilirrubina y AST (SGOT). Se ha notificado una reducción del 50% en el aclaramiento plasmático de epirubicina en 4 pacientes con creatinina sérica > 5 mg/dl. Se requieren ajustes de dosis en pacientes con disfunción hepática o renal La edad afecta el aclaramiento de la epirubicina en pacientes mujeres. El aclaramiento plasmático pronosticado de las mujeres > 70 años de edad es aproximadamente un 35% menor que el de las pacientes femeninas de 25 años. Un número insuficiente de hombres > 50 años de edad se han estudiado para sacar conclusiones. La reducciones de dosis no se recomiendan para las mujeres > 70 años, pero estas mujeres deben ser monitorizadas de cerca.
	INDICACIONES Y POSOLOGÍA Para el tratamiento adyuvante del cáncer de mama: NOTA: Epirubicina ha sido designado un medicamento huérfano por la FDA para esta indicación. •en pacientes con evidencia de afectación del ganglio axilar tras la resección del tumor primario en combinación con ciclofosfamida y fluorouracilo: Administracion intravenosa: Adultos: 100 mg/m2 IV el día 1 en combinación con fluorouracilo IV y ciclofosfamida IV cada 21 días durante 6 ciclos o 60 mg/m2 IV en los días 1 y 8 en combinación con ciclofosfamida oral y fluorouracilo IV cada 28 días durante 6 ciclos. Los pacientes con supresión preexistente de la médula ósea o afectación tumoral de la médula ósea pueden requerir dosis iniciales más bajas (por ejemplo, 75—90 mg/m2). Epirubicina también se ha estudiado en combinación con vinorelbbina y como una terapia de un solo agente. •en combinación con taxanos: Dosis intravenosa: Adultos: Epirubicina 90 mg/m2 IV y docetaxel (75 mg/m2 IV) se somete a estudios de fase II. La combinación de epirubicina 60 mg/m2 y paclitaxel (175 mg/m2 IV durante 3 horas) ha mostrado tasas de respuesta del 68% en pacientes con cáncer de mama metastásico y se está comparando en un ensayo de fase III con epirubicina y ciclofosfamida. [2526] Un régimen semanal de epirubicina 25 mg/m2 IV y paclitaxel (80 mg/m2 IV durante 1 hora) tenía una tasa de respuesta del 51% en pacientes con cáncer de mama metastásico pretratado. Se observaron neutropenia grave en sólo el 18% de los pacientes. [2527] •en combinación con ciclofosfamida como terapia intensiva de dosis con soporte de progenitor de sangre periférica: Dosis intravenosa: Adultos: En pacientes con mal pronóstico cáncer de mama o cáncer de mama metastásico, se han administrado epirubicinas 200 mg/m2 y ciclofosfamida con protección de células progenitoras de sangre periférica y factor estimulante de colonias. Otro régimen ha incluido epirubicina 120 mg/m2 IV, ciclofosfamida y tiotepa apoyada por células progenitoras de sangre periférica y factores estimulantes de colonias. •para el tratamiento neoadyuvante de cáncer de mama localmente avanzado y recurrente: Dosis intraarterial: Adultos: En un estudio, epirubicina 30 mg/m2 por vía intraarterial a través de la arteria mamaria interna durante 30 minutos con fluorouracilo y mitomicina se administró y repitió cada 2 semanas durante 3 ciclos. La tasa de respuesta global en 13 pacientes tratados fue del 62% (tasa de respuesta de los pacientes IIIB en estadio 100% y pacientes recurrentes 25%). La mayoría de los pacientes pudieron entonces someterse a una resección quirúrgica. Para el tratamiento del cáncer de pulmón: •para el tratamiento del cáncer de pulmón de células no pequeñas (NSCLC): Dosis intravenosa: Adultos: La mayoría de los ensayos clínicos de quimioterapia combinada que contiene epirubicina para NSCLC muestran resultados similares de respuesta y supervivencia que otros regímenes combinados para NSCLC. En un ensayo de comparación, epirubicina 120 mg/m2 IV en el día 1 en combinación con cisplatino (60 mg/m2 IV el día 1) cada 21 días durante 12 ciclos dio lugar a una tasa de respuesta, duración de respuesta y supervivencia similares a la combinación de vinorelbina y cisplatino. La combinación de epirubicina fue significativamente más mielosupresora. [2529] •para el tratamiento del cáncer de pulmón de células pequeñas (SCLC): Dosis intravenosa: Adultos: En un pequeño estudio epirubicina 80 mg/m2 IV en el día 1 y etopósido (200 mg de PO días diarios 1-4) administrado cada 3 semanas mostró actividad y fue bien tolerado por pacientes con SCLC en estadio limitado y extenso. [2530] Epirubicina 50 mg/m2 IV en combinación con etopósido, ifosfamida y cisplatino (VIP-E) con apoyo de factor estimulante de colonias dio lugar a tasas de respuesta del 81% y 77% en pacientes con etapa limitada y etapa extensa de SCLC, respectivamente. Los pacientes calificados que respondieron a este tratamiento fueron tratados con quimioterapia en dosis altas con trasplante de células madre sanguíneas periféricas después de la epirubicina 150 mg/m2 IV en combinación con etopósido, ifosfamida y carboplatino (VIC-E). La mortalidad relacionada con el tratamiento fue del 13%. Todos los pacientes sobrevivientes mejoraron o mantuvieron sus respuestas previas después de una terapia de dosis altas. La supervivencia global después de ambos regímenes no fue superior a otros tratamientos. Además, hubo una alta incidencia de neoplasias malignas secundarias. [2531] Para el tratamiento del sarcoma de tejido blando: Dosis intravenosa: Adultos: Adultos con sarcoma de tejido blando localmente avanzado o metastásico tratados con epirubicina 45 mg/m2/día como perfusión intravenosa continua en los días 2—3 en combinación con ifosfamida (perfusión continua IV) cada 3 semanas tuvieron una tasa de respuesta global del 52% (22% de respuesta completa). El tratamiento requería apoyo al factor estimulante de colonias. [2532] Para el tratamiento del mieloma múltiple: Dosis intravenosa: Adultos: Epirubicina 20 mg/m2 IV en los días 1 y 2 con vincristina (1,5 mg IV el día 1), ciclofosfamida (200 mg/m2 IV días 1-3) y dexametasona (20 mg/m2 PO días 1—5). Este régimen se estudió en 15 pacientes previamente no tratados y 25 pacientes recidivados o refractarios con mieloma múltiple y dio lugar a tasas de respuesta del 53% y el 44%, respectivamente. [2533] Para el tratamiento del cáncer de ovario: Dosis intravenosa: Adultos: Varios ensayos de fase I/II han examinado el papel de la epirubicina en el cáncer de ovario. Una combinación de epirubicina 60 mg/m2 IV, paclitaxel (175 mg/m2 IV durante 3 horas) y carboplatino (AUC 5) ha demostrado estar activa y se está considerando para ensayos de fase III. [2534] Epirubicina 120 mg/m2 IV y paclitaxel (150 mg/m2 IV) ha mostrado tasas de respuesta del 34% en el tratamiento de segunda línea de un pequeño número de pacientes con cáncer de ovario resistente al platino. [2 Para el tratamiento del cáncer gástrico y el cáncer de cabeza y cuello: Dosis intravenosa: Adultos: En un ensayo aleatorizado, la combinación de epirubicina 50 mg/m2 IV y cisplatino cada 3 semanas en combinación con una prolongada perfusión continua de fluorouracilo (ECF) se ha comparado con la terapia estándar de fluorouracilo, doxorubicina y metotrexato (FAM). El régimen de ECF dio lugar a un aumento de la respuesta y el beneficio de supervivencia para los pacientes con cáncer gástrico no tratado previamente o cáncer de cabeza y cuello. [2536] Para el tratamiento del cáncer hepatocelular: Dosis intravenosa: Adultos: Epirubicina 40 mg/m2 IV el día 1 en combinación con etopósido (120 mg/m2 IV en los días 1, 3 y 5) cada 28 días se ha estudiado en un ensayo de fase II. Se notificó una respuesta objetiva del 39% en 36 pacientes que no eran candidatos a procedimientos quirúrgicos o locoregionales. [2537] Dosis de quimioembolización arterial hepática: Adultos: En una comparación de epirubicina 72 mg/m2 o doxorubicina en Lipiodol® intra arterialmente como quimioembolización, no hubo diferencia significativa en la supervivencia entre los 2 agentes. [2538] Para el tratamiento del cáncer de vejiga: Dosis intravesícula: Adultos: La dosis común para la profilaxis del cáncer de vejiga después de TUR es epirubicina 50 mg en 50 ml de solución salina normal estéril inculcado en la vejiga una vez por semana durante 4 semanas y luego tratamiento de mantenimiento de la misma dosis mensual durante 11 meses. Para el tratamiento del cáncer de vejiga, epirubicina 50 mg en 50 ml se inculca una vez por semana durante 8 semanas; la dosis puede aumentarse a 80 mg en 50 ml en pacientes con carcinoma in situ, dependiendo de la tolerabilidad individual. Los pacientes que ya hayan recibido la dosis acumulada máxima de antraciclinas no deben recibir epirubicina intravesicle. En los ensayos comparativos, la terapia con epirubicina se asoció con intervalos más largos libres de recurrencia y recurrencias menos invasivas en comparación con la doxorubicina. En general, las tasas de recurrencia con epirubicina o BCG intravesical son similares, excepto en pacientes con tumores mal diferenciados (G3) o tumor restringidos a la lámina propria de la vejiga (T1) donde la epirubicina está asociada con una mayor tasa de recurrencia. Límites máximos de dosis: La dosis máxima tolerada sugerida (MTD) para la epirubicina, que depende del estado de rendimiento, otros agentes de quimioterapia o radiación administrados en combinación, y el estado de la enfermedad, es la siguiente: NOTA: La dosis correcta de epirubicina variará de un protocolo a otro. Los médicos deben consultar las referencias apropiadas para verificar la dosis. •Adultos: 150 mg/m2/dosis como agente único; en combinación con otra quimioterapia mielosupresora, la dosis única máxima puede ser menor. La dosis acumulada máxima de epirubicina es de 900 mg/m2. •Niños: La dosis acumulada máxima de epirubicina es de 900 mg/m2. La dosis debe basarse en el peso corporal de los niños con una BSA < 0,5 m2. Los niños son más susceptibles a la cardiotoxicidad y requieren un seguimiento a largo plazo (ver Precauciones). Ajustes de dosis basados en toxicidades hematológicas y no hematológicas: Recuentos de plaquetas de Nadir <50.000/mm3, recuento absoluto de neutrófilos (ANC) <250/mm3, fiebre neutropénica o Toxicidades no hematológicas de grado 3/4: la dosis del día 1 en ciclos posteriores debe reducirse en un 25% de la dosis anterior. Adición de factores estimulantes de colonias, Si no ya se ha dado, puede considerarse antes de la reducción de la dosis. Para los pacientes que reciben epirubicina dividida (es decir, los días 1 y 8): la dosis del día 8 debe reducirse en un 25% de la dosis del día 1 si el recuento de plaquetas es de 75.000 a 100.000/mm3 y el ANC es 1000—1499/mm3. Si el recuento de plaquetas del día 8 es de <75.000/mm3, ANC <1000/mm3, o se ha producido toxicidad no hematológica de grado 3/4, omita la dosis del día 8. Pacientes con insuficiencia renal: No existen pautas específicas para pacientes con insuficiencia renal; Pacientes con insuficiencia hepática: Bilirrubina 1,2—3,0 mg/dl o AST 2—4 veces el límite superior de lo normal: 50% reducción de la dosis inicial. Bilirrubina > 3,0 mg/dl o AST > 4 veces el límite superior de lo normal: 75% reducción de la dosis inicial. Indicación no aprobada por la FDA
	Contraindications Epirubicin is contraindicated in patients with severe neutropenia (<1500 cell/mm3) and thrombocytopenia, unless bone marrow suppression is due to tumor involvement and may improve following treatment (e.g., multiple myeloma and lymphoma). Therapy with epirubicin should not be initiated until patients recover normal hematopoiesis after bone marrow suppression. Epirubicin should be used cautiously in patients who have had previous myelosuppressive therapy such as chemotherapy or radiotherapy. During treatment with epirubicin, the hematologic status of the patient should be closely monitored. Patients should be treated for any infection prior to receiving epirubicin. Patients who receive epirubicin regimens containing >= 120 mg/m2 should also receive prophylactic antibiotic therapy with an appropriate regimen, which may include trimethoprim-sulfamethoxazole or a quinolone. Patients with a history of varicella zoster, other herpes infections (e.g., herpes simplex), or other viral infections are at risk for reactivation of the infection when treated with chemotherapy. Patients who have had previous radiation therapy may experience radiation recall reactions during epirubicin therapy. Epirubicin is a radiation sensitizer and should be used with caution in patients receiving concurrent radiation therapy; although in some cases this may be a benefit. Myelosuppressive effects of epirubicin can increase the risk of infection or bleeding; therefore, dental work should be delayed until blood counts have returned to normal. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks. Epirubicin is a severe vesicant. Extravasation of epirubicin infusions should be avoided. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Patients should be closely monitored during IV infusions for signs and symptoms of extravasation such as poor blood return, burning, stinging, and swelling at the injection site. If extravasation occurs, stop the infusion and remove the tubing. Attempt to aspirate the drug prior to removing the needle. Elevate the affected area and treat with ice packs. As this can be a progressive injury, appropriate long-term follow-up is required. Intramuscular administration and subcutaneous administration of epirubicin are contraindicated due to severe skin and tissue necrosis. Intramuscular injections should not be administered to patients with platelet counts < 50,000/mm3 who are receiving epirubicin. IM injections may cause bleeding, bruising, or hematomas due to epirubicin-induced thrombocytopenia. Epirubicin causes acute and chronic cardiotoxicity and should be used with caution in patients with cardiac disease. Lower doses of epirubicin are probably associated with less damage or isolated right or left ventricular dysfunction, and may not be apparent clinically without monitoring. At higher epirubicin doses more severe biventricular damage and/or failure will occur. Patients with preexisting heart failure, angina, hypertension, or cardiac arrhythmias are at increased risk to develop cardiotoxicity during or following epirubicin therapy. Angina and arrhythmias are relative contraindications to the use of epirubicin, depending on the degree of clinical impairment. Other risk factors for the development of epirubicin-induced cardiotoxicity include previous mediastinal radiation, cumulative dose, higher rates of administration, and age > 60 years. Females and children may be more sensitive to the cardiotoxic effects of anthracyclines.[1001] Children treated with anthracyclines may develop late cardiotoxicity (see Adverse Reactions). Due to the risk of long-term cardiotoxicity, it has been recommended that children treated with anthracyclines should undergo screening with ECGs and echocardiograms every 2 years and 24-hour continuous ECGs and radionucleide angiograms every 5 years.[2017] Generally, patients with a left ventricular ejection fraction < 50% are not considered candidates for anthracycline therapy; the risks versus benefits of anthracycline therapy must be carefully considered in these patients. Patients should be observed closely for signs of epirubicin-inudced cardiotoxicity; early recognition is essential for successful treatment. Establishment of baseline left ventricular function and periodic monitoring are recommended. Patients currently receiving epirubicin should wait at least 4 weeks following the last dose before undergoing periodic cardiac evaluation to allow cardiac function to return to baseline. Although the most definitive technique for assessing anthracycline-induced cardiotoxicity is endomyocardial biopsy, echocardiograms or serial gated cardiography (MUGA) scans may also indicate if a patient is developing cardiotoxicity. A left ventricular ejection fraction < 50% or an absolute decrease of 10ï¿½20% in left ventricular heart function are indications to discontinue anthracycline therapy. A total lifetime dose of 900 mg/m2 is generally regarded as the maximum dose of epirubicin. However, some patients may tolerate a higher cumulative dose while other patients may develop clinical cardiotoxicity at a much lower cumulative dose. Epirubicin should not be given to patients who have previously received the maximum cumulative dose of another anthracycline. The clearance of epirbucin is decreased in elderly women. The predicted plasma clearance of epirubicin is about 35% lower for a 70 year old woman as compared to a 25 year old woman. An insufficient number of men > 50 years of age have been studied to make any conclusions regarding age-related changes in men. A dosage reduction of epirubicin is not recommended for women >= 70 years of age, however these women should be closely monitored during epirubicin treatment. Patients with severe hepatic disease and/or jaundice should not receive epirubicin. The dose of epirubicin should be adjusted for elevations in the total bilirubin or AST because these patients will have a decreased clearance of epirubicin with an increase in overall toxicity (see Dosage). Serum bilirubin and AST levels should be evaluated before and during treatment with epirubicin. Patients with severe renal impairment (serum creatinine > 5 mg/dl) or renal failure require dosage adjustment of epirubicin (see Dosage). Serum creatinine levels should be assessed before and during epirubicin treatment.
	Epirubicin should not be administered during pregnancy because of the possibility of teratogenic effects. Epirubicin is a FDA pregnancy category D agent. Women of childbearing potential should be warned against getting pregnant. If a woman becomes pregnant during therapy, she should be advised of the potential risks to the fetus. Two pregnancies have been reported in women receiving epirubicin. In one case, a woman was 28 weeks pregnant at her diagnosis of breast cancer and was treated with cyclophosphamide and epirubicin every 3 weeks for 3 cycles. She received the last dose at 34 weeks of the pregnancy and delivered a healthy baby at 35 weeks. A second woman with breast cancer metastatic to the liver received fluorouracil, cyclophosphamide and epirubicin but was removed from the trial due to the pregnancy. She experienced a spontaneous abortion. Breast-feeding is contraindicated during epirubicin therapy. It is not known if epirubicin is excreted in human breast milk but has been detected in breast milk of animals.
	Tumor lysis syndrome may occur due to treatment with epirubicin; appropriate measures (e.g., aggressive hydration and allopurinol) must be taken to prevent hyperuricemia in patients with large chemosensitive tumors. The resulting hyperuricemia could aggravate gout or urate nephrolithiasis. Generally, this is not a problem in patients with breast cancer, but clinicians should closely monitor susceptible patients (i.e., those with leukemia, lymphoma, or extensive small cell lung cancer). Use care to avoid accidental exposure to epirubicin during preparation, handling, and administration. The use of protective gowns, gloves and goggles is recommended. Following skin or ocular exposure, skin and eyes should be thoroughly rinsed. Vaccination during chemotherapy or radiation therapy should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.
	Cyclosporine, valspodar (PSC-833), trifluoperazine, tamoxifen, toremifene, and verapamil all block the multidrug resistance (MDR) glycoprotein, which is a mechanism of resistance to naturally occurring (non-synthetic) chemotherapy agents. These agents could enhance epirubicin's activity. Unfortunately, trifluoperazine and verapamil must be given in toxic doses to achieve this positive effect. Studies examining the use of the r-isomer of verapamil to block MDR, which has less cardiac effects, are underway. Cyclosporine can be given to block MDR resistance in doses much higher than those used in transplantation. Valspodar is an investigational cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to epirubicin therapy may result in increases in AUC for both epirubicin and epirubicinol possibly due to a decrease in clearance of parent drug, a decrease in metabolism of epirubicinol, or an increase in intracellular epirubicin concentrations. Concurrent administration of cimetidine (400 mg twice daily for 5 days before chemotherapy) increased the mean AUC of epirubicin by 50% and decreased its clearance by 30%. Cimetidine therapy should be stopped during epirubicin therapy. Other agents that inhibit hepatic isoenzymes may also affect epirubicin metabolism, efficacy, and/or toxicity. Concurrent use of epirubicin with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects. The immune response of the immunocompromised patient to vaccines is decreased and higher doses or more frequent boosters may be required. Despite these dose increases, the immune response may still be suboptimal. Live virus vaccines are contraindicated during therapy with antineoplastic agents due to the potentiation of virus replication, adverse reactions to the virus, and the immunocompromised status of the patient. Those undergoing antineoplastic therapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Estimates for postponing vaccination vary from 3 months to 1 year following discontinuation of treatment depending of the type of antineoplastic agent used and the disease state of the patient. The coadministration of paclitaxel or docetaxel did not affect the pharmacokinetics of epirubicin when epirubicin was given immediately following the taxane. Due to the thrombocytopenic effects of epirubicin, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. Large doses of salicylates (>= 6 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Due to rapid lysis of chemosensitive cells by epirubicin, serum uric acid levels may increase. This may compromise the efficacy of the uricosuric agents probenecid and sulfinpyrazone. Dosage adjustments of antigout agents may be necessary to control hyperuricemia. To prevent uric acid nephropathy in epirubicin-induced hyperuricemia, allopurinol is preferred over uricosuric agents. Because antineoplastic agents exert their toxic effects against rapidly growing cells, such as hematopoietic progenitor cells, sargramostim, GM-CSF, and filgrastim, G-CSF, are contraindicated for use in patients within 24 hours of treatment with antineoplastic agents. Administration of epirubicin to patients who have received the maximum cumulative dose of other anthracycline agents (e.g., daunorubicin, doxorubicin, or idarubicin) is contraindicated because of the increased risk of cardiotoxicity. Patients who have received prior mitoxantrone therapy may also experience increased cardiotoxicity. Dexrazoxane (900ï¿½1200 mg/m 2 ) administered in combination with epirubicin (135 mg/m 2 ) leads to increased epirubicin clearance and AUC. In addition, increasing the epirubicin dose from 60 to 100 mg/m 2 resulted in a 30% increase in the elimination half-life and decreased clearance of dexrazoxane. However, when epirubicin (60ï¿½100 mg/m 2 ) was given in combination with lower doses of dexrazoxane (600ï¿½1000 mg/m 2 ), no pharmacokinetic interactions were noted.[2128] The clinical significance of these interactions has not been determined. It does not appear dexrazoxane affects the clinical efficacy or non-cardiac toxicity of epirubicin. Dexrazoxane does appear to limit epirubicin-induced cardiotoxicity. Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; no significant change was seen with digoxin capsules, and the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. Digoxin capsules (Lanoxicapsï¿½) may be utilized to avoid this interaction in patients receiving antineoplastic agents and digoxin tablets. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy. An increased incidence of ventricular dysfunction and congestive heart failure has been associated with the concurrent use of trastuzumab with anthracyclines (e.g., doxorubicin, epirubicin, or mitoxantrone) and cyclophosphamide. Patients with prior treatment with radiation therapy or anthracyclines may have decreased ability to tolerate trastuzumab therapy
	Adverse Reactions Bone marrow suppression is the acute dose-limiting toxicity of epirubicin. The severity of the suppression depends on the dose of the drug and the regenerative capacity of the patient's bone marrow. Signs of myelosuppression include pancytopenia, leukopenia, neutropenia, thrombocytopenia, and anemia. The white blood cell count nadirs within 10ï¿½14 days of administration, and usually recovers within 7 days following the nadir. Infection was seen in 15ï¿½22% of breast cancer patients treated with epirubicin combination chemotherapy. Neutropenic fevers occurred in 6% of the patients who received epirubicin >= 100 mg/m2 in combination with cyclophosphamide and fluorouracil. Patients receiving epirubicin >= 100 mg/m2 alone or in combination with other myelosuppressive chemotherapy may require colony-stimulating factor support. Prophylactic antibiotic therapy is recommended for patients who receive regimens containing >= 120 mg/m2 of epirubicin. Acute cardiotoxicity can occur during administration of epirubicin; a cumulative, dose-dependent cardiomyopathy may also occur. Acute cardiac toxicity of epirubicin consists mainly of sinus tachycardia and/or ECG changes such as non-specific ST-T wave changes, but other arrhythmias such as sinus bradycardia, ventricular tachycardia, premature ventricular contractions (PVCs), AV block, and bundle-branch block have been reported. These changes do not necessitate dose modification or discontinuation and are not predictive of delayed cardiotoxicity. Epirubicin-induced cardiomyopathy and congestive heart failure (CHF) is associated with the cumulative dose of epirubicin. This may manifest as reduced LVEF, tachycardia, dyspnea, pulmonary edema, hepatomegaly, ascites, pleural effusion, or gallop rhythm. Delayed cardiotoxicity usually develops late in the course of therapy with epirubicin or within 2ï¿½3 months of completing treatment. However, later events (several months to years after ending treatment) have been reported. The estimated risk of developing epirubicin-induced CHF is 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 700 mg/m2, 3.3% at 900 mg/m2 and 15% at 1000 mg/m2. Previous irradiation to the left chest is associated with an increased risk of developing CHF and an accelerated mortality.[2539] Cancer survivors, especially pediatric patients, may have an increased cardiac morbidity and mortality due to previous anthracycline therapy. Up to 15 years after treatment with anthracyclines, cumulative doxorubicin doses of 228 mg/m2 have been associated with increased afterload, decreased contractility, or both in 65% of children treated for leukemia, which may be associated with progressive clinical injury. In addition, heart failure and an increased incidence of ECG abnormalities with 3ï¿½5% of patients experiencing non-sustained ventricular tachycardia were reported.[764] Similar effects may occur with epirubicin. It is thought that myocardial damage and ventricular dysfunction progress and lead to late-onset cardiac dysfunction following treatment with anthracyclines. Moderate to severe nausea/vomiting can occur during epirubicin chemotherapy, and scheduled antiemetics are required to alleviate these symptoms. Delayed emesis usually does not occur with epirubicin. Stomatitis and esophagitis can occur in 2 to 3 days following initiation of chemotherapy and is characterized by oral bleeding, burning, erythema, infections, and oral ulceration. Most patients recover by the third week of therapy. Hyperpigmentation of the oral mucosa may also occur. Diarrhea and anorexia may also occur. Alopecia occurs in almost all patients receiving epirubicin therapy. The hair loss can be sudden and total. Regrowth of hair usually resumes 3 weeks after therapy has been discontinued. Nail discoloration, photosensitivity, and skin discoloration have been reported. Conjunctivitis and keratitis have been reported with epirubicin chemotherapy. Administration of epirubicin causes urine discoloration, and patients should be warned in advance of this effect. The red urine should not be confused with hematuria. Epirubicin is a vesicant, and administration into soft tissue can cause pain, burning, tissue necrosis and skin ulcer. Venous sclerosis may result from the injection of epirubicin into small vessels or repeated injection into the same vein. Patients should be monitored carefully for any injection site reaction, especially severe pain, swelling and poor blood return. Symptoms of extravasation are usually immediate although extravasations into chest wall tissue are less acutely symptomatic. Application of ice packs has been shown to be effective in reducing skin lesions associated with anthracycline extravasation. Topical cooling does not reduce anthracycline skin concentrations but decreases cellular uptake of anthracyclines thereby decreasing the cytotoxic effect.[765] Other antidotes to anthracycline extravasation including corticosteroids, sodium bicarbonate, antihistamines, lidocaine and dimethylsulfoxide (DMSO) have been studied in both animal and clinical settings and are not effective. Surgical follow-up is indicated if pain and swelling at the site continues 2 weeks after the extravasation. A venous flare reaction has been noted in patients who receive epirubicin. It is characterized by facial flushing and delayed erythematous streaking along the vein. These reactions may lead to phlebitis. Symptoms may last up to an hour and may be treated with steroids, antihistamines and ice packs. These reactions are associated with excessively rapid administration and do not contraindicate further use. Anaphylactoid reactions and urticaria may occur following epirubicin administration. Signs and symptoms of anaphylactic reactions include skin rash (unspecified), pruritus, fever, chills and anaphylactic shock. A radiation recall reaction can occur after epirubicin administration at the sites of prior radiation. This reaction causes erythema, exfoliative dermatitis, pain, and burning, similar to that experienced with the original radiation therapy. The esophagus can be especially sensitive. Occurrence of secondary malignancy, usually acute myeloid leukemia with or without a preleukemic phase, has been reported following epirubicin. The latency period may be as short as 1ï¿½3 years. Patients who have received adjuvant epirubicin in clinical trials show a cumulative risk of secondary acute myelogenous leukemia of about 0.2% at 3 years and 0.8% at 5 years. Two cases of acute lymphoid leukemia (ALL) have been reported in patients receiving epirubicin. Epirubicin may contribute to gonadal suppression seen during cancer chemotherapy. Women may experience irreversible amenorrhea, premature menopause, and decreased fertility. Hot flashes have been reported in about 40% of women treated with epirubicin for breast cancer. Men may experience spermatogenesis inhibition. These effects are usually temporary. When administered to pediatric patients, doxorubicin may contribute to prepubertal growth inhibition.
	PRESENTACION Epirubicin Ellenceï¿½
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