Ticlopidine

Uses

Ticlopidine is 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. Because Ticlopidine is associated with a risk of life-threatening blood dyscrasias including thrombotic thrombocytopenic purpura (TTP), neutropenia/ agranulocytosis and aplastic anemia. Ticlopidine should be reserved for patients who are intolerant or allergic to aspirin therapy or who have failed aspirin therapy.

Ticlopidine is also used as an adjunctive therapy with aspirin to reduce the incidence of subacute stent thrombosis in patients undergoing successful coronary stent implantation

Ticlopidine is also used to associated treatment for these conditions: Stent Thrombosis, Stroke

How Ticlopidine works

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.

Dosage

Ticlopidine dosage

Stroke:The recommended dose of Ticlopidine is 250 mg bid taken with food. Other doses have not been studied in controlled trials for these indications.

Coronary Artery Stenting:The recommended dose of Ticlopidine is 250 mg bid taken with food together with antiplatelet doses of aspirin for up to 30 days of therapy following successful stent implantation.

Side Effects

Diarrhoea, nausea, dyspepsia, bleeding, pupura, skin rash, increase in serum cholesterol concentration, elevation of LFTs, hepatitis, cholestatic jaundice.

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. The FDA label includes a black-box warning of neutropenia, aplastic anemia, thrombotic thrombocytopenia purpura, and agranulocytosis, so it is necessary to monitor patients' WBC and platelets when they are taking ticlopidine.

Precaution

Patients with increased risk of bleeding from trauma, surgery or pathological disorder. Moderate to severe renal impairment. May need to stop therapy 10-14 days before elective surgery. Full blood counts should be performed prior to therapy and every 2 wk during the first 3 mth of treatment. Pregnancy.

Interaction

Reduced clearance with cimetidine; corticosteroid may antagonise effects on bleeding time. Avoid concurrent use with clopidogrel.

Food Interaction

• Take with a high fat meal. High fat meals will increase ticlopidine absorption.
• Take with food. Food can help ticlopidine-induced stomach upset.

[Moderate] ADJUST DOSING INTERVAL: The bioavailability and gastrointestinal tolerance of ticlopidine is enhanced by food.br> br> MANAGEMENT: Patients may be advised to take ticlopidine with meals.

Ticlopidine Cholesterol interaction

[Moderate] Ticlopidine can induce increases in serum cholesterol and triglycerides.

Serum total cholesterol levels have increased 8% to 10% in some patients within 1 month of initiation of ticlopidine therapy and have persisted at those levels.

Clinical monitoring of lipid profiles is recommended during ticlopidine therapy in patients at risk for hyperlipidemia-associated adverse events.

Ticlopidine Drug Interaction

Moderate: aspirin, aluminum hydroxide / aspirin / calcium carbonate / magnesium hydroxide, aspirin, warfarin, duloxetineMinor: donepezilUnknown: pioglitazone, amoxicillin / clavulanate, rosuvastatin, ethanol, furosemide, esomeprazole, niacin, pantoprazole, tramadol, cyanocobalamin, cholecalciferol, phytonadione, ezetimibe, ondansetron

Ticlopidine Disease Interaction

Major: bleeding risks, hepatic dysfunction, myelosuppressionModerate: hyperlipidemia, renal dysfunction

Volume of Distribution

The volume of distribution was not quantified.

Elimination Route

Absorption is greater than 80%. Food increases absorption by approximately 20%.

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.

Clearance

Ticlopidine clearance was not quantified, but clearance decreases with age.

Elimination Route

Ticlopidine is eliminated mostly in the urine (60%) and somewhat in the feces (23%).

Pregnancy & Breastfeeding use

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.

Contraindication

The use of Ticlopidine 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

Special Warning

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 Ticlopidine 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.

Renal Impairment: Dose reduction or discontinuance if haemorrhagic or haematopoietic complications occur.

Hepatic Impairment: Severe: contraindicated.

Acute Overdose

One case of deliberate overdosage with Ticlopidine has been reported by a foreign postmarketing surveillance program. A 38-year-old male took a single 6000-mg dose of Ticlopidine (equivalent to 24 standard 250-mg tablets). The only abnormalities reported were increased bleeding time and increased SGPT. No special therapy was instituted and the patient recovered without sequelae.

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.

Storage Condition

Store at 15° to 30° C

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