Ticlopidine 250 mg

Ticlopidine is not eliminated by renal excretion, and routine dosage adjustments are not required in patients with renal impairment. Supplementary doses are not required after hemodialysis or peritoneal dialysis.

A wide range of hemorrhagic complications (post-traumatic bleeding, perioperative bleeding, ecchymosis, epistaxis, hematuria, conjunctival hemorrhage, petechiae, GI hemorrhage, hematemesis, gingival bleeding, melena, hemothorax, menorrhagia, and intracerebral hemorrhage) have been reported during treatment with ticlopidine.

Ticlopidine should be discontinued 14 days prior to elective surgery or dental extraction. For urgent surgery, the effects of ticlopidine may be reversed by transfusion of platelets, but not by administration of fresh frozen plasma.

The most serious hematologic adverse effects of ticlopidine include neutropenia, TTP, agranulocytosis, and aplastic anemia.

TTP is a rare but potentially fatal adverse event that manifests as a multisystem disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, renal dysfunction, neurologic abnormalities, and fever. Prompt institution of therapeutic plasma exchange enhances the likelihood of survival, especially if the onset of TTP occurs more than 2 weeks after initiation of therapy [J Am Coll Cardiol 2007;50(12):1138-43].

Severe neutropenia (absolute neutrophil count <0.45×10⁹ cells/L) may have a sudden onset, generally occurs during the first 3 to 12 weeks of treatment, and was reported in 0.8% of patients enrolled in clinical trials. Ticlopidine-associated neutropenia is generally reversible upon discontinuation of the drug, with recovery occurring within 1 to 3 weeks; however, the condition can be life threatening and deaths have occurred.

Thrombocytopenia, alone or in combination with neutropenia, has occurred during treatment with ticlopidine. The onset is generally within the first 3 to 12 weeks of treatment with the drug. Recovery of platelet counts generally occurs upon discontinuation of ticlopidine.

All patients should be monitored for signs and symptoms of bleeding during treatment with ticlopidine. Monitor complete blood count with differential prior to initiating ticlopidine therapy, every 2 weeks during the first three months of therapy and periodically thereafter. Monitor alkaline phosphatase and serum transaminase levels at baseline and during the first four months of therapy if liver dysfunction is suspected.

Total serum cholesterol and triglyceride concentrations increased by up to 8% to 10% during the first month of treatment with ticlopidine in clinical trials. Further increases in serum lipids did not generally occur in these studies.

Ticlopidine is a prodrug that is converted to its active form via hepatic metabolism. Use of the drug in patients with severe hepatic dysfunction is contraindicated.

Abnormal hepatic function tests were reported in 1% of patients enrolled in clinical trials of the drug; thus serum transaminase (ALT, AST) and alkaline phosphatase levels should be monitored during the first 4 months of therapy if liver dysfunction is suspected.

Category B. Ticlopidine was not teratogenic when administered to mice, rats and rabbits. It is not known whether the drug crosses the placenta and there is very limited experience with ticlopidine in human pregnancy; thus, it is not possible to make definitive statements regarding the safety of the drug in this setting.

The safety and efficacy of ticlopidine in children have not been established.

Ticlopidine is excreted in the breast milk of lactating rats; no human data are available. Given the potential hematologic complications associated with the drug it is best avoided during breastfeeding.

Peak plasma levels occur approximately 2 hours after oral administration.

Ticlopidine is rapidly absorbed from the gastrointestinal tract (> 80%) after oral administration.

Ticlopidine is an irreversible platelet aggregation inhibitor. The drug antagonizes the effects of ADP at P2Y12 receptors located on the platelet membrane, thereby inhibiting ADP-mediated platelet aggregation. The effect on platelet function is irreversible and persists for the life of the platelet, which is approximately 7 to 10 days.

The onset of platelet inhibition occurs within 24 to 48 hours, although maximal inhibition requires 5 to 7 days of administration.

Approximately 60% of a dose is excreted in urine, almost completely as metabolites. Clearance decreases with age. Steady-state trough values in elderly patients (mean age 70 years) are about twice those in younger populations.

Ticlopidine is a prodrug that is converted to an active metabolite by hepatic cytochrome P450 (CYP)-mediated metabolism. CYP2C19 is thought to be responsible for generation of the active metabolite. Ticlopidine is extensively metabolized in the liver and only trace amounts of intact drug are detected in the urine. The initial half-life is about 7 hours; with chronic dosing, the half-life increases to approximately 4 days.