Kersyn

Kersyn (ticlopidina hcl) está indicado

• para reducir el riesgo de accidente cerebrovascular trombótico (fatal o no fatal) en pacientes que han experimentado precursores de accidente cerebrovascular, y en pacientes que han tenido un accidente cerebrovascular trombótico completo. Debido a que Kersyn (ticlopidina hcl) está asociado con un riesgo de discrasias sanguíneas potencialmente mortales, incluida la púrpura trombocitopénica trombótica (TPT), neutropenia / agranulocitosis y anemia aplásica (ver ADVERTENCIA A BORRADO y ADVERTENCIAS), Kersyn (ticlopidina hcl) debe reservarse para pacientes intolerantes o alérgicos a la terapia con aspirina o que hayan fallado en la terapia con aspirina.
• como terapia complementaria con aspirina para reducir la incidencia de trombosis del stent subagudo en pacientes sometidos a implantación exitosa del stent coronario (ver Ensayos clínicos).

Carrera: La dosis recomendada de Kersyn (ticlopidina hcl) es de 250 mg dos veces al día con los alimentos. No se han estudiado otras dosis en ensayos controlados para estas indicaciones.

Aroma de la arteria coronaria: La dosis recomendada de Kersyn (ticlopidina hcl) es de 250 mg dos veces al día con alimentos junto con dosis antiplaquetarias de aspirina durante un máximo de 30 días de tratamiento después de una implantación exitosa del stent.

El uso de Kersyn (ticlopidina hcl) está contraindicado en las siguientes condiciones:

• Hipersensibilidad a la droga
• Presencia de trastornos hematopoyéticos como neutropenia y trombocitopenia o antecedentes de TTP o anemia aplásica
• Presencia de un trastorno hemostático o hemorragia patológica activa (como úlcera péptica hemorrágica o hemorragia intracraneal)
• Pacientes con insuficiencia hepática grave

WARNINGS

Hematological Adverse Reactions: Neutropenia: Neutropenia may occur suddenly. Bone-marrow examination typically shows a reduction in white blood cell precursors. After withdrawal of ticlopidine, the neutrophil count usually rises to !1200/mm³ within 1 to 3 weeks.

Thrombocytopenia: Rarely, thrombocytopenia may occur in isolation or together with neutropenia.

Thrombotic Thrombocytopenic Purpura (TTP): TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever. The signs and symptoms can occur in any order, in particular, clinical symptoms may precede laboratory findings by hours or days. With prompt treatment (often including plasmapheresis), 70% to 80% of patients will survive with minimal or no sequelae. Because platelet transfusions may accelerate thrombosis in patients with TTP on ticlopidine, they should, if possible, be avoided.

Aplastic Anemia: Aplastic anemia is characterized by anemia, thrombocytopenia and neutropenia together with a bone marrow examination that shows decreases in the precursor cells for red blood cells, white blood cells, and platelets. Patients may present with signs or symptoms suggestive of infection, in association with low white blood cell and platelet counts. Prompt treatment, which may include the use of drugs to stimulate the bone marrow, can minimize the mortality associated with aplastic anemia.

Monitoring for Hematologic Adverse Reactions: Starting just before initiating treatment and continuing through the third month of therapy, patients receiving Kersyn (ticlopidine hcl) must be monitored every 2 weeks. Because of discontinue ticlopidine during this 3-month period should continue to be monitored for 2 weeks after discontinuation. More frequent monitoring, and monitoring after the first 3 months of therapy, is necessary only in patients with clinical signs (eg, signs or symptoms suggestive of infection) or laboratory signs (eg, neutrophil count less than 70% of the baseline count, decrease in hematocrit or platelet count) that suggest incipient hematological adverse reactions.

Clinically, fever might suggest neutropenia, TTP, or aplastic anemia; TTP might also be suggested by weakness, pallor, petechiae or purpura, dark urine (due to blood, bile pigments, or hemoglobin) or jaundice, or neurological changes. Patients should be told to discontinue Kersyn (ticlopidine hcl) and to contact the physician immediately upon the occurrence of any of these findings.

Laboratory monitoring should include a complete blood count, with special attention to the absolute neutrophil count (WBC x % neutrophils), platelet count, and the appearance of the peripheral smear. Ticlopidine is occasionally associated with thrombocytopenia unrelated to TTP or aplastic anemia. Any acute, unexplained reduction in hemoglobin or platelet count should prompt further investigation for a diagnosis of TTP, and the appearance of schistocytes (fragmented RBCs) on the smear should be treated as presumptive evidence of TTP. A simultaneous decrease in platelet count and WBC count should prompt further investigation for a diagnosis of aplastic anemia. If there are laboratory signs of TTP or aplastic anemia, or if the neutrophil count is confirmed to be < 1200/mm³, then Kersyn (ticlopidine hcl) should be discontinued immediately.

Other Hematological Effects: Rare cases of agranulocytosis, pancytopenia, or leukemia have been reported in postmarketing experience, some of which have been fatal. All forms of hematological adverse reactions are potentially fatal.

Cholesterol Elevation: Kersyn (ticlopidine hcl) therapy causes increased serum cholesterol and triglycerides. Serum total cholesterol levels are increased 8% to 10% within 1 month of therapy and persist at that level. The ratios of the lipoprotein subfractions are unchanged.

Anticoagulant Drugs: The tolerance and long-term safety of coadministration of Kersyn (ticlopidine hcl) with heparin, oral anticoagulants or fibrinolytic agents have not been established. In trials for cardiac stenting, patients received heparin and Kersyn (ticlopidine hcl) concomitantly for approximately 12 hours. If a patient is switched from an anticoagulant or fibrinolytic drug to Kersyn (ticlopidine hcl) , the former drug should be discontinued prior to Kersyn (ticlopidine hcl) administration.

PRECAUTIONS

General: Kersyn (ticlopidine hcl) should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or pathological conditions. If it is desired to eliminate the antiplatelet effects of Kersyn (ticlopidine hcl) prior to elective surgery, the drug should be discontinued 10 to 14 days prior to surgery. Several controlled clinical studies have found increased surgical blood loss in patients undergoing surgery during treatment with ticlopidine. In TASS and CATS it was recommended that patients have ticlopidine discontinued prior to elective surgery. Several hundred patients underwent surgery during the trials, and no excessive surgical bleeding was reported.

Prolonged bleeding time is normalized within 2 hours after administration of 20 mg methylprednisolone IV. Platelet transfusions may also be used to reverse the effect of Kersyn (ticlopidine hcl) on bleeding. Because platelet transfusions may accelerate thrombosis in patients with TTP on ticlopidine, they should, if possible, be avoided.

GI Bleeding: Kersyn (ticlopidine hcl) prolongs template bleeding time. The drug should be used with caution in patients who have lesions with a propensity to bleed (such as ulcers). Drugs that might induce such lesions should be used with caution in patients on Kersyn (see CONTRAINDICATIONS).

Use in Hepatically Impaired Patients: Since ticlopidine is metabolized by the liver, dosing of Kersyn (ticlopidine hcl) or other drugs metabolized in the liver may require adjustment upon starting or stopping concomitant therapy. Because of limited experience in patients with severe hepatic disease, who may have bleeding diatheses, the use of Kersyn (ticlopidine hcl) is not recommended in this population (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).

Use in Renally Impaired Patients: There is limited experience in patients with renal impairment. Decreased plasma clearance, increased AUC values and prolonged bleeding times can occur in renally impaired patients. In controlled clinical trials no unexpected problems have been encountered in patients having mild renal impairment, and there is no experience with dosage adjustment in patients with greater degrees of renal impairment. Nevertheless, for renally impaired patients, it may be necessary to reduce the dosage of ticlopidine or discontinue it altogether if hemorrhagic or hematopoietic problems are encountered (see CLINICAL PHARMACOLOGY).

Information for the Patient

(See Patient Leaflet) Patients should be told that a decrease in the number of white blood cells (neutropenia) or platelets (thrombocytopenia) can occur with Kersyn (ticlopidine hcl) , especially during the first 3 months of treatment and that neutropenia, if it is severe, can result in an increased risk of infection. They should be told it is critically important to obtain the scheduled blood tests to detect neutropenia or thrombocytopenia. Patients should also be reminded to contact their physicians if they experience any indication of infection such as fever, chills, or sore throat, any of which might be a consequence of neutropenia. Thrombocytopenia may be part of a syndrome called TTP. Symptoms and signs of TTP, such as fever, weakness, difficulty speaking, seizures, yellowing of skin or eyes, dark or bloody urine, pallor or petechiae (pinpoint hemorrhagic spots on the skin), should be reported immediately.

All patients should be told that it may take them longer than usual to stop bleeding when they take Kersyn (ticlopidine hcl) and that they should report any unusual bleeding to their physician. Patients should tell physicians and dentists that they are taking Kersyn (ticlopidine hcl) before any surgery is scheduled and before any new drug is prescribed.

Patients should be told to promptly report side effects of Kersyn (ticlopidine hcl) such as severe or persistent diarrhea, skin rashes or subcutaneous bleeding or any signs of cholestasis, such as yellow skin or sclera, dark urine, or light-colored stools.

Patients should be told to take Kersyn (ticlopidine hcl) with food or just after eating in order to minimize gastrointestinal discomfort.

Laboratory Tests: Liver Function: Kersyn (ticlopidine hcl) therapy has been associated with elevations of alkaline phosphatase, bilirubin, and transaminases, which generally occurred within 1 to 4 months of therapy initiation. In controlled clinical trials in stroke patients, the incidence of elevated alkaline phosphatase (greater than two times upper limit of normal) was 7.6% in ticlopidine patients, 6% in placebo patients and 2.5% in aspirin patients. The incidence of elevated AST (SGOT) (greater than two times upper limit of normal) was 3.1% in ticlopidine patients, 4% in placebo patients and 2.1% in aspirin patients. No progressive increases were observed in closely monitored clinical trials (eg, no transaminase greater than 10 times the upper limit of normal was seen), but most patients with these abnormalities had therapy discontinued. Occasionally patients had developed minor elevations in bilirubin.

Postmarketing experience includes rare individuals with elevations in their transaminases and bilirubin to > 10X above the upper limits of normal. Based on postmarketing and clinical trial experience, liver function testing, including ALT, AST, and GGT, should be considered whenever liver dysfunction is suspected, particularly during the first 4 months of treatment.

Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 2-year oral carcinogenicity study in rats, ticlopidine at daily doses of up to 100 mg/kg (610 mg/m²) was not tumorigenic. For a 70-kg person (1.73 m² body surface area) the dose represents 14 times the recommended clinical dose on a mg/kg basis and two times the clinical dose on body surface area basis. In a 78-week oral carcinogenicity study in mice, ticlopidine at daily doses up to 275 mg/kg (1180 mg/m²) was not tumorigenic. The dose represents 40 times the recommended clinical dose on a mg/kg basis and four times the clinical dose on body surface area basis.

Ticlopidine was not mutagenic in vitro in the Ames test, the rat hepatocyte DNA-repair assay, or the Chinese-hamster fibroblast chromosomal aberration test; or in vivo in the mouse spermatozoid morphology test, the Chinese-hamster micronucleus test, or the Chinese-hamster bone-marrow-cell sister-chromatid exchange test. Ticlopidine was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg/day.

Pregnancy:Teratogenic Effects: Pregnancy: Category B. Teratology studies have been conducted in mice (doses up to 200 mg/kg/day), rats (doses up to 400 mg/kg/day) and rabbits (doses up to 200 mg/kg/day). Doses of 400 mg/kg in rats, 200 mg/kg/day in mice and 100 mg/kg in rabbits produced maternal toxicity, as well as fetal toxicity, but there was no evidence of a teratogenic potential of ticlopidine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers: Studies in rats have shown ticlopidine is excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ticlopidine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Clearance of ticlopidine is somewhat lower in elderly patients and trough levels are increased. The major clinical trials with Kersyn (ticlopidine hcl) in stroke patients were conducted in an elderly population with an average age of 64 years. Of the total number of patients in the therapeutic trials, 45% of patients were over 65 years old and 12% were over 75 years old. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Las reacciones adversas en pacientes con accidente cerebrovascular fueron relativamente frecuentes, con más del 50% de los pacientes que informaron al menos uno. La mayoría (30% a 40%) involucraba el tracto gastrointestinal. La mayoría de los efectos adversos son leves, pero el 21% de los pacientes interrumpieron la terapia debido a un evento adverso, principalmente diarrea, erupción cutánea, náuseas, vómitos, dolor gastrointestinal y neutropenia. La mayoría de los efectos adversos ocurren temprano en el curso del tratamiento, pero puede ocurrir un nuevo inicio de efectos adversos después de varios meses.

Las tasas de incidencia de eventos adversos enumerados en la siguiente tabla se derivaron de ensayos clínicos controlados multicéntricos en pacientes con accidente cerebrovascular descritos anteriormente que comparan Kersyn (ticlopidina hcl), placebo y aspirina durante períodos de estudio de hasta 5,8 años. Los eventos adversos considerados por el investigador probablemente relacionados con el fármaco que ocurrieron en al menos el 1% de los pacientes tratados con Kersyn (ticlopidina hcl) se muestran en la siguiente tabla:

Porcentaje de pacientes con eventos adversos en estudios controlados (TASS y CATS)

La incidencia de interrupción, independientemente de la relación con la terapia, se muestra entre paréntesis.

Hematológico: Neutropenia / trombocitopenia, TTP, anemia aplásica (ver ADVERTENCIA A BORRADO y ADVERTENCIAS), se han informado leucemia, agranulocitosis, eosinofilia, pancitopenia, trombocitosis y depresión de la médula ósea.

Gastrointestinal: La terapia con Kersyn (ticlopidina hcl) se ha asociado con una variedad de quejas gastrointestinales que incluyen diarrea y náuseas. La mayoría de los casos son leves, pero aproximadamente el 13% de los pacientes interrumpieron la terapia debido a estos. Por lo general, ocurren dentro de los 3 meses posteriores al inicio de la terapia y generalmente se resuelven dentro de 1 a 2 semanas sin la interrupción de la terapia. Si el efecto es severo o persistente, la terapia debe suspenderse. En algunos casos de diarrea severa o con sangre, la colitis fue diagnosticada más tarde.

Hemorrágico: Kersyn (ticlopidina hcl) se ha asociado con un aumento del sangrado, sangrado postraumático espontáneo y sangrado perioperatorio, incluido, entre otros, sangrado gastrointestinal. También se ha asociado con una serie de complicaciones hemorrágicas, como equimosis, epistaxis, hematuria y hemorragia conjuntival.

El sangrado intracerebral fue raro en ensayos clínicos en pacientes con accidente cerebrovascular con Kersyn (ticlopidina hcl), con una incidencia no mayor que la observada con agentes de comparación (ticlopidina 0.5%, aspirina 0.6%, placebo 0.75%). También se ha informado postmarketing.

Sarpullido: La ticlopidina se ha asociado con una erupción maculopapular o urticarial (a menudo con prurito). La erupción generalmente ocurre dentro de los 3 meses posteriores al inicio de la terapia con un tiempo medio de inicio de 11 días. Si se suspende el medicamento, la recuperación ocurre dentro de varios días. Muchas erupciones no se repiten en el desafío de drogas. Ha habido informes poco frecuentes de erupciones cutáneas graves, incluido el síndrome de Stevens-Johnson, eritema multiforme y dermatitis exfoliativa.

Reacciones adversas menos frecuentes (probablemente relacionadas): Las experiencias clínicas adversas que ocurren en 0.5% a 1.0% de los pacientes con accidente cerebrovascular en ensayos controlados incluyen: Sistema digestivo: GI plenitud

Piel y apéndices : urticaria

Sistema nervioso: dolor de cabeza

Cuerpo en su conjunto: astenia, dolor

Sistema hemostático : epistaxis

Sentidos especiales: tinnitus

Además, más raro, eventos relativamente graves y potencialmente fatales asociados con el uso de Kersyn (ticlopidina hcl) También se han informado de la experiencia posterior a la comercialización: anemia hemolítica con reticulocitosis, trombocitopenia inmune, hepatitis, ictericia hepatocelular, ictericia colestática, necrosis hepática, insuficiencia hepática, úlcera péptica, insuficiencia renal, síndrome nefrótico, hiponatremia, vasculitis, sepsis, reacciones alérgicas (incluyendo angioedema, neumonitis alérgica, y anafilaxia) lupus sistémico (ANA positivo) neuropatía periférica, enfermedad del suero, artropatía y miositis.

Un programa de vigilancia posterior a la comercialización en el extranjero ha informado de un caso de sobredosis deliberada con Kersyn (ticlopidina hcl). Un hombre de 38 años tomó una dosis única de 6000 mg de Kersyn (ticlopidina hcl) (equivalente a 24 tabletas estándar de 250 mg). Las únicas anormalidades reportadas fueron el aumento del tiempo de sangrado y el aumento del SGPT. No se instituyó una terapia especial y el paciente se recuperó sin secuelas.

Las dosis orales únicas de ticlopidina a 1600 mg / kg y 500 mg / kg fueron letales para ratas y ratones, respectivamente. Los síntomas de toxicidad aguda fueron hemorragia gastrointestinal, convulsiones, hipotermia, disnea, pérdida de equilibrio y marcha anormal.