Tiklopidin

Clinical Effects:

TICLOPIDINE
  • USES: Ticlopidine is used to reduce the risk of thrombotic stroke in patients that have had stroke precursors or completed thrombotic stroke. PHARMACOLOGY: Ticlopidine, a platelet aggregation inhibitor, interferes with platelet membrane function by inhibiting ADP-induced platelet binding and subsequent platelet-platelet interactions. EPIDEMIOLOGY: Cases of ticlopidine overdose are rare. OVERDOSE: Data limited. MILD TO MODERATE TOXICITY: Agitation, tachycardia, hypotension, hypoxia, metabolic acidosis, and bleeding were described in a 69-year-old man following an intentional ingestion of 10 g of ticlopidine. Following a single 6 g dose a 38-year-old developed an increased bleeding time and SGPT, but no clinical symptoms developed. SEVERE TOXICITY: Hypotension, hypoxia and mental status changes have been reported. Bleeding complications should be anticipated. ADVERSE EVENTS: COMMON: Gastrointestinal symptoms including diarrhea, nausea, dyspepsia, GI pain and vomiting have developed. Other clinical effects may include maculopapular or urticarial rash, cholestatic jaundice, and elevated liver enzymes. SEVERE: Life-threatening hematologic adverse events can develop suddenly within the first few days to weeks of therapy and may include neutropenia/agranulocytosis, thrombotic thrombocytopenic purpura (TTP), and aplastic anemia. The incidence of TTP usually peaks after 3 to 4 weeks of therapy, neutropenia generally peaks at 4 to 6 weeks, and aplastic anemia peaks at 4 to 8 weeks. Other hematologic events may also include bone-marrow suppression and an increased risk of bleeding including gastrointestinal bleeding. Intracerebral bleeding is rare. INFREQUENT: Urticaria, headache, asthenia, pain, epistaxis and tinnitus may develop.

Range of Toxicity:

TICLOPIDINE
  • TOXIC DOSE: Data limited. An adult developed agitation, confusion, tachycardia, lethargy, hypotension, metabolic acidosis and a prolonged bleeding time after ingesting 10 g of ticlopidine; recovery was uneventful. No clinical adverse effects, other than increased bleeding time and an elevated SGPT were reported following an overdose of 6 g in another adult. THERAPEUTIC DOSE: ADULT: STROKE: 500 mg/day. CORONARY ARTERY STENTING: 500 mg/day with antiplatelet doses of aspirin for up to 30 days following stenting. PEDIATRIC: Safety and efficacy have not been established.

Treatment:

TICLOPIDINE
  • Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Treatment is symptomatic and supportive. Limited overdose data. Monitor fluid and electrolyte status in patients with severe gastrointestinal loss; replace fluids and electrolytes as indicated. Monitor for bleeding (ie, gastrointestinal, epistaxis, hematuria and conjunctival hemorrhage). MANAGEMENT OF SEVERE TOXICITY: Treat hypotension with intravenous fluids. Add vasopressors if hypotension persists or transfuse if hypotension persists in the setting of clinical evidence of bleeding.
  • Decontamination: PREHOSPITAL: Activated charcoal may be considered following a recent ingestion in a patient that is able to protect the airway. HOSPITAL: Consider activated charcoal following a recent ingestion or if coingestions are suspected.
  • Airway management: Airway support is unlikely to be necessary following a minor exposure. Insure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression or seizure activity.
  • Monitoring of patient: Monitor vital signs and mental status. Monitor CBC with differential, serum electrolytes, renal function and liver enzymes following overdose. Monitor for clinical evidence of bleeding.
  • Hematologic toxicity: Hematologic toxicity has been reported after therapeutic use but not after overdose. Aplastic anemia, neutropenia, and thrombotic thrombocytopenia purpura (TTP) have been reported. NEUTROPENIA: Granulocyte colony-stimulating factor (G-CSF) has been used to treat severe neutropenia/leukopenia associated with ticlopidine therapy. Recommended dose of filgrastim for patients receiving myelosuppressive chemotherapy to decrease granulocytopenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor temperature and CBC with differential until recovery. Patients with severe neutropenia should be in protective isolation. Platelet and red cell transfusions may be necessary.
  • Plasmapheresis: Based on several retrospective case series it has been suggested that the mortality from ticlopidine-induced thrombotic thrombocytopenic purpura may be reduced by plasma exchange or plasmapheresis.
  • Patient disposition: HOME CRITERIA: A minor (1 to 2 tablets) inadvertent dose in a patient currently being treated with ticlopidine can likely be managed at home. An asymptomatic child with an inadvertent exposure (a single dose) can likely be monitored at home, if a responsible adult is present. OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions and any symptomatic patient should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility. ADMISSION CRITERIA: Patients with any evidence of persistent symptoms (ie, anemia, bleeding, myelosuppression or electrolyte imbalance) should be admitted. CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
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