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Active ingredient: Ticlopidine - Brands, Medical Use, Clinical Data

Brands, Medical Use, Clinical Data

Drug Category

  • Fibrinolytic Agents
  • Platelet Aggregation Inhibitors

Dosage Forms

  • Tablets (for oral administration, containing 250 mg of ticlopidine hydrochloride)

Brands / Synonyms

Ticlid; Ticlopidine; Ticlopidine HCL; Ticlopidine Hydrochloride

Indications

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.

Absorption

Absorption is greater than 80%. Food increases absorption.

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.

Biotrnasformation / Drug Metabolism

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.

Contraindications

The use of TICLID is contraindicated in the following conditions:

· Hypersensitivity to the drug

· Presence of hematopoietic disorders such as neutropenia and thrombocytopenia or a past history of either TTP or aplastic anemia

· Presence of a hemostatic disorder or active pathological bleeding (such as bleeding peptic ulcer or intracranial bleeding)

· Patients with severe liver impairment

Drug Interactions

Therapeutic doses of TICLID caused a 30% increase in the plasma half-life of antipyrine and may cause analogous effects on similarly metabolized drugs. Therefore, the dose of drugs metabolized by hepatic microsomal enzymes with low therapeutic ratios or being given to patients with hepatic impairment may require adjustment to maintain optimal therapeutic blood levels when starting or stopping concomitant therapy with ticlopidine. Studies of specific drug interactions yielded the following results:

Aspirin and Other NSAIDs: Ticlopidine potentiates the effect of aspirin or other NSAIDs on platelet aggregation. The safety of concomitant use of ticlopidine and NSAIDs has not been established. The safety of concomitantuse of ticlopidine and aspirin beyond 30 days has not been established. Aspirin did not modify the ticlopidine-mediated inhibition of ADP-induced platelet aggregation, but ticlopidine potentiated the effect of aspirin on collagen-induced platelet aggregation. Caution should be exercised in patients who have lesions with a propensity to bleed, such as ulcers. Long-term concomitant use of aspirin and ticlopidine is not recommended.

Antacids: Administration of TICLID after antacids resulted in an 18% decrease in plasma levels of ticlopidine.

Cimetidine: Chronic administration of cimetidine reduced the clearance of a single dose of TICLID by 50%.

Digoxin: Coadministration of TICLID with digoxin resulted in a slight decrease (approximately 15%) in digoxin plasma levels. Little or no change in therapeutic efficacy of digoxin would be expected.

Theophylline: In normal volunteers, concomitant administration of TICLID resulted in a significant increase in the theophylline elimination half-life from 8.6 to 12.2 hours and a comparable reduction in total plasma clearance of theophylline.

Phenobarbital: In 6 normal volunteers, the inhibitory effects of TICLID on platelet aggregation were not altered by chronic administration of phenobarbital.

Phenytoin: In vitro studies demonstrated that ticlopidine does not alter the plasma protein binding of phenytoin. However, the protein binding interactions of ticlopidine and its metabolites have not been studied in vivo. Several cases of elevated phenytoin plasma levels with associated somnolence and lethargy have been reported following coadministration with TICLID. Caution should be exercised in coadministering this drug with TICLID, and it may be useful to remeasure phenytoin blood concentrations.

Propranolol: In vitro studies demonstrated that ticlopidine does not alter the plasma protein binding of propranolol. However, the protein binding interactions of ticlopidine and its metabolites have not been studied in vivo. Caution should be exercised in coadministering this drug with TICLID.

Other Concomitant Therapy: Although specific interaction studies were not performed, in clinical studies TICLID was used concomitantly with beta blockers, calcium channel blockers and diuretics without evidence of clinically significant adverse interactions.

Food Interaction: The oral bioavailability of ticlopidine is increased by 20% when taken after a meal. Administration of TICLID with food is recommended to maximize gastrointestinal tolerance. In controlled trials in stroke patients, TICLID was taken with meals.

 

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