indication

Used to reduce the risk of thrombotic stroke (fatal or nonfatal) in patients who have experienced stroke precursors, and in patients who have had a completed thrombotic stroke.

pharmacology

Ticlopidine is a platelet aggregation inhibitor structurally and pharmacologically similar to clopidogrel. When taken orally, ticlopidine causes a time- and dose-dependent inhibition of both platelet aggregation and release of platelet granule constituents, as well as a prolongation of bleeding time. The intact drug has no significant in vitro activity at the concentrations attained in vivo; and, although analysis of urine and plasma indicates at least 20 metabolites, no metabolite which accounts for the activity of ticlopidine has been isolated.

mechanism of action

The active metabolite of ticlopidine prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. It is proposed that the inhibition involves a defect in the mobilization from the storage sites of the platelet granules to the outer membrane. No direct interference occurs with the GPIIb/IIIa receptor. As the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation. By blocking the amplification of platelet activation by released ADP, platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of ticlopidine.

toxicity

Single oral doses of ticlopidine at 1600 mg/kg and 500 mg/kg were lethal to rats and mice, respectively. Symptoms of acute toxicity were GI hemorrhage, convulsions, hypothermia, dyspnea, loss of equilibrium and abnormal gait.

biotransformation

Metabolized extensively by the liver; only trace amounts of intact drug are detected in the urine. At least 20 metabolites have been identified. It has been proposed that 1 or more active metabolites may account for ticlopidine's activity, because ticlopidine itself is an extremely weak platelet aggregation inhibitor in vitro at the concentrations achieved in vivo. However, no active metabolite has been identified.

absorption

Absorption is greater than 80%. Food increases absorption.

half life

Half-life following a single 250-mg dose is approximately 7.9 hours in subjects 20 to 43 years of age and 12.6 hours in subjects 65 to 76 years of age. With repeated dosing (250 mg twice a day), half-life is about 4 days in subjects 20 to 43 years of age and about 5 days in subjects 65 to 76 years of age.

route of elimination

Ticlopidine hydrochloride is metabolized extensively by the liver; only trace amounts of intact drug are detected in the urine. Approximately 1/3 of the dose excreted in the feces is intact ticlopidine hydrochloride, possibly excreted in the bile.

drug interactions

Acetylsalicylic acid: Increased effect of ticlopidine

Alteplase: Increased bleeding risk. Monitor for signs of bleeding.

Aminophylline: Ticlopidine increases the effect and toxicity of theophylline

Bortezomib: Ticlopidine may decrease the metabolism and clearance of Bortezomib. Consider alternate therapy or monitor for adverse/toxic effects of Bortezomib if Ticlopidine is initiated, discontinued or dose changed.

Carbamazepine: Ticlopidine increases the effect of carbamazepine

Carisoprodol: Ticlopidine may decrease the metabolism and clearance of Carisoprodol. Consider alternate therapy or monitor for adverse/toxic effects of Carisoprodol if Ticlopidine is initiated, discontinued or dose changed.

Cilostazol: Ticlopidine may decrease the metabolism and clearance of Cilostazol. Consider alternate therapy or monitor for adverse/toxic effects of Cilostazol if Ticlopidine is initiated, discontinued or dose changed.

Cimetidine: Cimetidine may increase Ticlopidine levels. Avoid concomitant therapy.

Citalopram: Ticlopidine may decrease the metabolism and clearance of Citalopram. Consider alternate therapy or monitor for adverse/toxic effects of Citalopram if Ticlopidine is initiated, discontinued or dose changed.

Clobazam: Ticlopidine may decrease the metabolism and clearance of Clobazam. Consider alternate therapy or monitor for adverse/toxic effects of Clobazam if Ticlopidine is initiated, discontinued or dose changed.

Clomipramine: Ticlopidine may decrease the metabolism and clearance of Clomipramine. Consider alternate therapy or monitor for adverse/toxic effects of Clomipramine if Ticlopidine is initiated, discontinued or dose changed.

Cyclosporine: Ticlopidine decreases the effect of cyclosporine

Diazepam: Ticlopidine may decrease the metabolism and clearance of Diazepam. Consider alternate therapy or monitor for adverse/toxic effects of Diazepam if Ticlopidine is initiated, discontinued or dose changed.

Digoxin: Ticlopidine may decrease Digoxin levels. Monitor for Digoxin levels with Ticlopidine is initiated, discontinued or dose changed.

Dyphylline: Ticlopidine increases the effect and toxicity of theophylline

Escitalopram: Ticlopidine may decrease the metabolism and clearance of Escitalopram. Consider alternate therapy or monitor for adverse/toxic effects of Ambrisentan if Escitalopram is initiated, discontinued or dose changed.

Ethotoin: Ticlopidine increases the effect of hydantoin

Fosphenytoin: Ticlopidine may decrease the metabolism and clearance of Fosphenytoin. Consider alternate therapy or monitor for adverse/toxic effects of Fosphenytoin if Ticlopidine is initiated, discontinued or dose changed.

Ginkgo biloba: Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.

Heparin: Increased bleeding risk. Monitor aPTT.

Ifosfamide: Ticlopidine may decrease the metabolism and clearance of Ifosfamide. Consider alternate therapy or monitor for adverse/toxic effects of Ifosfamide if Ticlopidine is initiated, discontinued or dose changed.

Imipramine: Ticlopidine may decrease the metabolism and clearance of Imipramine. Consider alternate therapy or monitor for adverse/toxic effects of Imipramine if Ticlopidine is initiated, discontinued or dose changed.

Mephenytoin: Ticlopidine increases the effect of hydantoin

Methsuximide: Ticlopidine may decrease the metabolism and clearance of Methsuximide. Consider alternate therapy or monitor for adverse/toxic effects of Methsuximide if Ticlopidine is initiated, discontinued or dose changed.

Moclobemide: Ticlopidine may decrease the metabolism and clearance of Moclobemide. Consider alternate therapy or monitor for adverse/toxic effects of Moclobemide if Ticlopidine is initiated, discontinued or dose changed.

Nilutamide: Ticlopidine may decrease the metabolism and clearance of Nilutamide. Consider alternate therapy or monitor for adverse/toxic effects of Nilutamide if Ticlopidine is initiated, discontinued or dose changed.

Oxtriphylline: Ticlopidine increases the effect and toxicity of theophylline

Pentamidine: Ticlopidine may decrease the metabolism and clearance of Pentamidine. Consider alternate therapy or monitor for adverse/toxic effects of Pentamidine if Ticlopidine is initiated, discontinued or dose changed.

Phenobarbital: Ticlopidine may decrease the metabolism and clearance of Phenobarbital. Consider alternate therapy or monitor for adverse/toxic effects of Phenobarbital if Ticlopidine is initiated, discontinued or dose changed.

Phenytoin: Ticlopidine may decrease the metabolism and clearance of phenytoin. Consider alternate therapy or monitor for adverse/toxic effects of phenytoin if ticlopidine is initiated, discontinued or dose changed.

Reteplase: Increased bleeding risk. Monitor for signs of bleeding.

Sodium bicarbonate: Sodium bicarbonate may decrease Ticlopidine levels. Administer agents 1 to 2 hours apart.

Streptokinase: Increased bleeding risk. Monitor for signs of bleeding.

Tamoxifen: Ticlopidine may decrease the therapeutic effect of tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tamsulosin: Ticlopidine, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Ticlopidine is initiated, discontinued, or dose changed.

Tenecteplase: Increased bleeding risk. Monitor for signs of bleeding.

Theophylline: Ticlopidine increases the effect and toxicity of theophylline

Thioridazine: Ticlopidine may decrease the metabolism of Thioridazine. Concomitant therapy is contraindicated.

Tizanidine: Ticlopidine may decrease the metabolism and clearance of Tizanidine. Consider alternate therapy or use caution during co-administration.

Tramadol: Ticlopidine may decrease the effect of Tramadol by decreasing active metabolite production.

Treprostinil: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Ticlopidine. Monitor for increased bleeding during concomitant thearpy.

Trimipramine: The strong CYP2C19 inhibitor, ticlopidine, may decrease the metabolism and clearance of trimipramine, a CYP2C19 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of trimipramine if ticlopidine is initiated, discontinued or dose changed.

Warfarin: Increased bleeding risk. Monitor INR.