Tagren

Tagren (ticlopidine hcl) est indiqué

• réduire le risque d'AVC thrombotique (fatal ou non fatal) chez les patients qui ont subi des précurseurs d'AVC et chez les patients qui ont subi un AVC thrombotique terminé. Parce que Tagren (ticlopidine hcl) est associé à un risque de dyscrasies sanguines potentiellement mortelles, y compris le purpura thrombocytopénique thrombotique (TTP), la neutropénie / agranulocytose et l'anémie aplasique (voir AVERTISSEMENT EN BOÎTE et AVERTISSEMENTS), Tagren (ticlopidine hcl) doit être réservé aux patients intolérants ou allergiques à la thérapie à l'aspirine ou qui ont échoué à la thérapie à l'aspirine.
• en tant que traitement d'appoint à l'aspirine pour réduire l'incidence de la thrombose de stent subaigu chez les patients subissant une implantation de stent coronaire réussie (voir Essais cliniques).

AVC: La dose recommandée de Tagren (ticlopidine hcl) est de 250 mg bid pris avec de la nourriture. D'autres doses n'ont pas été étudiées dans des essais contrôlés pour ces indications.

Stenting d'artère coronaire: La dose recommandée de Tagren (ticlopidine hcl) est de 250 mg bid pris avec de la nourriture avec des doses d'aspirine antiplaquettaires jusqu'à 30 jours de traitement après une implantation réussie du stent.

L'utilisation de Tagren (ticlopidine hcl) est contre-indiquée dans les conditions suivantes:

• Hypersensibilité au médicament
• Présence de troubles hématopoïétiques tels que neutropénie et thrombocytopénie ou antécédents de TTP ou d'anémie aplasique
• Présence d'un trouble hémostatique ou d'un saignement pathologique actif (comme un ulcère gastro-duodénal ou un saignement intracrânien)
• Patients atteints d'insuffisance hépatique sévère

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 Tagren (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 Tagren (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 Tagren (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: Tagren (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 Tagren (ticlopidine hcl) with heparin, oral anticoagulants or fibrinolytic agents have not been established. In trials for cardiac stenting, patients received heparin and Tagren (ticlopidine hcl) concomitantly for approximately 12 hours. If a patient is switched from an anticoagulant or fibrinolytic drug to Tagren (ticlopidine hcl) , the former drug should be discontinued prior to Tagren (ticlopidine hcl) administration.

PRECAUTIONS

General: Tagren (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 Tagren (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 Tagren (ticlopidine hcl) on bleeding. Because platelet transfusions may accelerate thrombosis in patients with TTP on ticlopidine, they should, if possible, be avoided.

GI Bleeding: Tagren (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 Tagren (see CONTRAINDICATIONS).

Use in Hepatically Impaired Patients: Since ticlopidine is metabolized by the liver, dosing of Tagren (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 Tagren (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 Tagren (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 Tagren (ticlopidine hcl) and that they should report any unusual bleeding to their physician. Patients should tell physicians and dentists that they are taking Tagren (ticlopidine hcl) before any surgery is scheduled and before any new drug is prescribed.

Patients should be told to promptly report side effects of Tagren (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 Tagren (ticlopidine hcl) with food or just after eating in order to minimize gastrointestinal discomfort.

Laboratory Tests: Liver Function: Tagren (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 Tagren (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.

Les effets indésirables chez les patients ayant subi un AVC étaient relativement fréquents, plus de 50% des patients ayant déclaré au moins un. La plupart (30% à 40%) impliquaient le tractus gastro-intestinal. La plupart des effets indésirables sont légers, mais 21% des patients ont arrêté le traitement en raison d'un événement indésirable, principalement diarrhée, éruption cutanée, nausées, vomissements, douleur gastro-intestinale et neutropénie. La plupart des effets indésirables surviennent au début du traitement, mais une nouvelle apparition d'effets indésirables peut survenir après plusieurs mois.

Les taux d'incidence des événements indésirables répertoriés dans le tableau suivant ont été dérivés d'essais cliniques multicentriques contrôlés chez des patients ayant subi un AVC décrits ci-dessus comparant Tagren (ticlopidine hcl), placebo et aspirine sur des périodes d'étude allant jusqu'à 5,8 ans. Les événements indésirables considérés par l'investigateur comme probablement liés à la drogue survenus chez au moins 1% des patients traités par Tagren (ticlopidine hcl) sont présentés dans le tableau suivant:

Pourcentage de patients présentant des événements indésirables dans des études contrôlées (TASS et CATS)

L'incidence de l'arrêt, quelle que soit la relation avec le traitement, est indiquée entre parenthèses.

Hématologique: Neutropénie / thrombocytopénie, TTP, anémie aplasique (voir AVERTISSEMENT EN BOÎTE et AVERTISSEMENTS), une leucémie, une agranulocytose, une éosinophilie, une pancytopénie, une thrombocytose et une dépression médullaire ont été rapportées.

Gastro-intestinal: Le traitement par Tagren (ticlopidine hcl) a été associé à diverses plaintes gastro-intestinales, notamment des diarrhées et des nausées. La majorité des cas sont légers, mais environ 13% des patients ont arrêté le traitement à cause de ceux-ci. Ils surviennent généralement dans les 3 mois suivant le début du traitement et sont généralement résolus dans les 1 à 2 semaines sans arrêt du traitement. Si l'effet est grave ou persistant, le traitement doit être interrompu. Dans certains cas de diarrhée sévère ou sanglante, une colite a ensuite été diagnostiquée.

Hémorragique: Tagren (ticlopidine hcl) a été associé à une augmentation des saignements, des saignements post-traumatiques spontanés et des saignements périopératoires, y compris, mais sans s'y limiter, des saignements gastro-intestinaux. Il a également été associé à un certain nombre de complications hémorragiques telles que l'ecchymose, l'épistaxis, l'hématurie et l'hémorragie conjonctivale.

Les saignements intracérébraux étaient rares dans les essais cliniques chez les patients ayant subi un AVC avec Tagren (ticlopidine hcl), avec une incidence non supérieure à celle observée avec les agents de comparaison (ticlopidine 0,5%, aspirine 0,6%, placebo 0,75%). Il a également été signalé après la commercialisation.

Éruption cutanée: La ticlopidine a été associée à une éruption maculopapulaire ou urticariale (souvent avec prurit). L'éruption survient généralement dans les 3 mois suivant le début du traitement avec un temps d'apparition moyen de 11 jours. Si le médicament est arrêté, la récupération se produit dans quelques jours. De nombreuses éruptions cutanées ne se reproduisent pas lors de la réapparition du médicament. Il y a eu de rares cas d'éruptions cutanées graves, notamment le syndrome de Stevens-Johnson, l'érythème polymorphe et la dermatite exfoliative.

Effets indésirables moins fréquents (probablement liés): Les expériences indésirables cliniques survenant chez 0,5% à 1,0% des patients ayant subi un AVC dans les essais contrôlés comprennent: Système digestif: Plénitude GI

Peau et appendices: urticaire

Système nerveux: mal de crâne

Corps dans son ensemble : asthénie, douleur

Système hémostatique: épistaxis

Sens spéciaux: acouphènes

En plus, plus rare, événements relativement graves et potentiellement mortels associés à l'utilisation de Tagren (ticlopidine hcl) ont également été rapportés par expérience post-commercialisation: anémie hémolytique avec réticulocytose, thrombocytopénie immunitaire, hépatite, jaunisse hépatocellulaire, jaunisse cholestatique, nécrose hépatique, insuffisance hépatique, ulcère gastro-duodénal, insuffisance rénale, syndrome néphrotique, hyponatrémie, vascularite, septicémie, réactions allergiques (y compris l'œdème de Quincke, pneumonite allergique, et l'anaphylaxie) lupus systémique (ANA positif) neuropathie périphérique, maladie sérique, arthropathie et myosite.

Un cas de surdosage délibéré avec Tagren (ticlopidine hcl) a été signalé par un programme de surveillance post-commercialisation à l'étranger. Un homme de 38 ans a pris une dose unique de 6000 mg de Tagren (ticlopidine hcl) (équivalent à 24 comprimés standard de 250 mg). Les seules anomalies signalées étaient une augmentation du temps de saignement et une augmentation du SGPT. Aucun traitement spécial n'a été instauré et le patient s'est rétabli sans séquelles.

Des doses orales uniques de ticlopidine à 1600 mg / kg et 500 mg / kg étaient mortelles pour les rats et les souris, respectivement. Les symptômes de la toxicité aiguë étaient l'hémorragie gastro-intestinale, les convulsions, l'hypothermie, la dyspnée, la perte d'équilibre et la marche anormale.