Inhibitor of Platelet Function
Action and Clinical Uses:
Ticlopidine is an inhibitor of platelet aggregation. It causes a time and dose-dependent inhibition of platelet aggregation and release of platelet factors, as well as a prolongation of bleeding time. The drug has no significant in vitro activity.
The exact mechanism of action is not fully characterized, but does not involve inhibition of the prostacyclin/thromboxane pathways or platelet CAMP.
Ticlopidine interferes with platelet membrane function by inhibiting ADP-induced platelet-fibrinogen binding and subsequent platelet-platelet interactions. The effect of ticlopidine on platelet function is irreversible.
Template bleeding time is usually prolonged by 2- to 5-fold of baseline values with the therapeutic dose of ticlopidine.
Upon discontinuation of ticlopidine dosing, bleeding time and other platelet function tests return to normal within 1 week in the majority of patients.
The correlation between ticlopidine plasma levels and activity is still under investigation. Much of the following data was obtained from older patients corresponding to the age of patients participating in clinical trials (mean age: 63 years).
After oral administration of the therapeutic dose of ticlopidine, rapid absorption occurs, with peak plasma levels occurring at approximately 2 hours after dosing. Absorption is at least 80% complete. Administration of ticlopidine after meals results in an increased (20%) level of ticlopidine in plasma.
Steady-state plasma levels of ticlopidine in plasma are obtained after approximately 14 days of dosing at 250 mg b.i.d. The terminal elimination half-life is 4 to 5 days. However, inhibition of platelet aggregation is not correlated with plasma drug levels.
Ticlopidine binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins in a nonsaturable manner.
Ticlopidine is metabolized extensively by the liver; no intact ticlopidine is detected in the urine. Unmetabolized ticlopidine is a minor component in plasma after a single dose, but at steady state, ticlopidine is the major component.
Impaired hepatic function resulted in higher than normal plasma levels of unchanged ticlopidine after single doses or after multiple doses.
Inhibition of platelet aggregation is detected within 2 days of administration with 250 mg b.i.d. Maximum platelet aggregation inhibition is achieved 8 to 11 days following dosing with 250 mg b.i.d.
Indications And Clinical Uses:
For reduction of the risk of first or recurrent stroke for patients who have experienced at least one of the following events: complete thromboembolic stroke, minor stroke, reversible ischemic neurological deficit (RIND), or transient ischemic attack (TIA) including transient monocular blindness (TMB).
Considerations in the selection of stroke prevention therapy should include the patients’ current medical status and history, and their ability to comply with the required blood monitoring instructions concerning the use of ticlopidine.
The following conditions: known hypersensitivity to drug or its excipients; presence or history of hematopoietic disorders (such as neutropenia, thrombocytopenia or agranulocytosis); hemorrhagic diathesis, presence of hemostatic disorder; conditions associated with active bleeding, such as bleeding peptic ulcer or intracranial bleeding; severe liver dysfunction.WarningWarnings
Warnings in Clinical States:
Severe, sometimes fatal, hematological and hemorrhagic adverse effects can occur with administration of ticlopidine (see below). Therefore frequent monitoring to assure early diagnosis and prompt therapeutic measures to minimize the consequences of these adverse effects are recommended. The following warnings were developed from clinical trial experience with over 2 000 patients with cerebrovascular disease who were treated with ticlopidine for as long as 5.8 years and from spontaneous worldwide postmarketing experience.
Hematological Complications: All forms of hematological adverse reactions are potentially fatal. Rarely, cases of pancytopenia, aplastic anemia or thrombocytopenia have been reported. Thrombotic thrombocytopenic purpura (TTP) was not seen during clinical trials, but 152 cases (52 fatal) have been reported to date through spontaneous worldwide postmarketing reporting. The median time to occurrence was 3 to 4 weeks from the start of therapy, but a few cases occurred as soon as the same day of therapy, or more than 12 weeks after drug administration. Treatment consists of discontinuation of ticlopidine and plasmapheresis. Platelet transfusion is not recommended and could be harmful to the patient.
About 2.4% of ticlopidine treated patients in clinical trials developed neutropenia (defined as an absolute neutrophil count (ANC) below 1.2´.
All patients should have a white blood cell count with a differential and platelet count performed every 2 weeks starting at baseline, before treatment is initiated, to the end of the third month of therapy with ticlopidine. When the neutrophil count shows a declining trend or the neutrophil numbers have fallen below 30% of the baseline, the values should be confirmed.
Hemorrhagic Complications: Prolongation of bleeding time occurs in subjects treated with ticlopidine. Purpura and a few cases of more serious hemorrhagic events such as hematemesis, melena, hemothorax and intracranial bleeding have been reported. Patients must be instructed to watch for signs of bleeding disorders and to report any abnormality to their physician immediately. Ticlopidine therapy has to be stopped by the patient if a physician is not immediately available for consultation.
Anticoagulant/Antiplatelet Drugs: The use of heparins, oral anticoagulants and antiplatelet agents should be avoided as tolerance and safety of simultaneous administration with ticlopidine have not been established (see Precautions, Drug Interactions). However, in exceptional cases of concomitant treatment, close clinical and laboratory monitoring is required.
Hepatic Abnormalities: Most patients receiving ticlopidine showed some increase of their alkaline phosphatase values above their baseline and in one-third the increase exceeded the upper reference range. In 6% the value was greater than twice the upper reference range. These increases in alkaline phosphatase were nonprogressive and asymptomatic. In clinical trials, 2 cases (0.1%) of cholestatic jaundice accompanied by elevated transaminases alkaline phosphatase, and bilirubin levels above 43 mol/L have been observed. Both patients recovered promptly upon drug discontinuation. There have been rare reports of hepatitis during the first months of treatment from postmarketing experience. The course has generally been favorable after treatment was discontinued with recovery periods ranging from 4 to 239 days and a median of 30 days.
Pregnancy: The safety of ticlopidine in pregnancy has not been established. It should not be used in pregnant patients.
Children: Safety in children has not been studied. Do not use in pediatric patients.
Selection of Patients: Ticlopidine should be used only for the established indications (see Indications) and should not be given to patients with hematopoietic disorders, hemostatic disorders, patients suffering from conditions associated with active bleeding (see Contraindications) and patients anticipating elective surgery. In clinical trials elderly patients tolerated the drug well, but safety in children and pregnant women have not been established.
Clinical Monitoring: All patients have to be carefully monitored for clinical signs and symptoms of adverse drug reactions, especially during the first 3 months of therapy (see Adverse Effects). The signs and symptoms possibly related to neutropenia (fever, chills, sore throat, ulcerations in oral cavity), thrombocytopenia and abnormal hemostasis (prolonged or unusual bleeding, bruising, purpura, dark stool), jaundice (including dark urine, light colored stool) and allergic reactions should be explained to the patients who should be advised to stop medication and consult their physician immediately if any of these occur.
Laboratory Monitoring: All patients should have a white blood cell count with a differential and platelet count performed every 2 weeks starting at baseline, before treatment is initiated, to the end of the third month of therapy with ticlopidine. When the neutrophil count shows a declining trend or the neutrophil numbers have fallen below 30% of the baseline, the value should be confirmed.
Liver function tests should be conducted during therapy with ticlopidine in response to signs and symptoms suggestive of hepatic dysfunction.
Elective Surgery: Ticlopidine should be discontinued 10Â to 14Â days prior to elective surgery or dental extraction and bleeding time and thrombocyte count performed before the procedure if clinically indicated.
Emergency Surgery: Prolonged bleeding during surgery may be a problem in ticlopidine treated patients. Transfusions of fresh platelets would be expected to improve hemostasis in such patients, but there are no data from clinical trials to confirm this expectation. There are data from clinical pharmacology trials that indicate treatment with glucocorticosteroids can normalize bleeding time in ticlopidine treated subjects, but there is no experience with ticlopidine treated surgical patients to show that such treatment improves hemostasis.
Specific Precautions: Liver: Ticlopidine is contraindicated in patients with severe liver dysfunction or cholestatic jaundice. Mild increase of alkaline phosphatase may be seen for the duration of the treatment and is inconsequential in the majority of patients (see Warnings and Contraindications).
Kidneys: Ticlopidine has been well tolerated in patients with moderately decreased renal function. In severe renal disease, caution and close monitoring are recommended.
Gastrointestinal: Conditions associated with active bleeding, such as bleeding ulcers, constitute contraindication for ticlopidine. Clinical judgment and monitoring of stool for occult blood are required for patients with a history of ulcerative lesions.
Trauma: Ticlopidine should be discontinued temporarily until the danger of abnormal bleeding is eliminated. A single fatal case of intracranial bleeding following head trauma has been reported. The extent to which ticlopidine may have contributed to the severity of the bleeding is unknown.
Since ticlopidine is metabolized by the liver, dosing of ticlopidine or other drugs metabolized in the liver may require adjustment upon starting or stopping therapy.
Agents Observed Interaction
NSAIDs including ASA The combined antithrombotic effect of ticlopidine and ASA or NSAIDs can lead to increased risk of hemorrhagic complications. If concomitant use of these drugs is necessary, close clinical and laboratory monitoring is required.
Heparins Increased hemorrhagic risk due to combination of anticoagulant and platelet antiaggregant activity. If such drugs are necessary, close clinical and laboratory monitoring is required.
Antipyrine and products metabolized by hepatic microsomal enzymes 30% increase in t 1/2 of antipyrine. Dose of products metabolized by hepatic microsomal enzymes to be adjusted when starting or stopping concomitant therapy with ticlopidine.
Theophylline t 1/2 of theophylline increased from 8.6 to 12.2 hours along with a comparable reduction in its total plasma clearance. Monitoring of plasma levels of theophylline followed by the theophylline dose adjustment is mandatory when treating patients concomitantly with ticlopidine and theophylline.
Digoxin Approximately 15% reduction in digoxin plasma levels, (little or no change in digoxin’s efficacy expected).
Cimetidine Chronic administration of cimetidine induced a 50% reduction in clearance of a single dose of ticlopidine.
Antacids 20% decrease in ticlopidine plasma level when administered after antacids.
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. Caution should be exercised in coadministering this drug with ticlopidine and it may be useful to remeasure phenytoin blood concentrations.
Phenobarbital No interaction reported.
Other Concomitant Therapy: Although specific interaction studies were not performed, in clinical studies, ticlopidine was used concomitantly with beta-blockers, calcium channel blockers and diuretics without evidence of clinically significant adverse interactions.
In vitro studies demonstrated that ticlopidine is reversibly bound to plasma proteins (98%), but that it does not interact with plasma protein binding of propranolol, which is also highly protein bound in its basic form.
Cyclosporine blood levels should be monitored in case of coadministration with ticlopidine. In very rare instances, lowering of cyclosporine blood levels has been reported.
Pregnancy: The safety of ticlopidine in pregnant women has not been established. Unless absolutely indicated, ticlopidine should not be prescribed to a pregnant woman (see Warnings).
Lactation: Studies in rats have shown that ticlopidine is excreted in milk. Unless absolutely indicated, ticlopidine should not be prescribed to a lactating woman.
Most adverse effects are mild, transient and occur early in the course of treatment.
In controlled clinical trials of 1 to 5 years’ duration, discontinuation of ticlopidine due to one or more adverse effects was required in 20.9% of patients. In these same trials, ASA and placebo led to discontinuation in 14.5 and 6.7% of patients respectively.
The following rare events have been reported: Pancytopenia, bone marrow aplasia, hemolytic anemia with reticulocytosis, thrombocytopenic thrombotic purpura, jaundice, allergic pneumonitis, systemic lupus (positive ANA), peripheral neuropathy, vasculitis, serum sickness, arthropathy, hepatitis, nephrotic syndrome, myositis angioedema (Quincke edema), fever, hyponatremia, bleeding increased (spontaneous, post-traumatic or postoperative), cholestatic jaundice, colitis, erythema multiforme, hepatic necrosis, hepatocellular jaundice, peptic ulcer, Stevens-Johnson syndrome, renal failure, sepsis and hypersensitivity nephropathy.
Gastrointestinal: Ticlopidine therapy has been associated with a variety of gastrointestinal complaints including diarrhea and nausea. While most are mild and transient, when chronic or severe or accompanied by weight loss, fatigue and/or anorexia, it can also be indicative of colitis. The majority of the cases occur within the first 3 months of therapy. If the effect is persistent or severe, the therapy should be discontinued. Typically, events are resolved within 1 to 2 weeks thereafter.
Hemorrhagic: Ticlopidine has been associated with a number of bleeding complications such as ecchymosis, epistaxis, hematuria, conjunctival hemorrhage, gastrointestinal bleeding and peri- and postoperative bleeding (see Precautions, Emergency Surgery).
Intracerebral bleeding was rare in clinical trials with ticlopidine and was no more than that seen with comparator agents (ASA, placebo).
Rash: Ticlopidine has been associated with a maculopapular or urticarial rash (often with pruritus). Rash usually occurs within 3 months of initiation of therapy, with a mean time to onset of 11 days. If drug is discontinued, recovery should occur within several days. Many rashes do not recur on drug rechallenge. There have been rare reports of more severe rashes.
Altered Laboratory Findings: Hematological: agranulocytosis, eosinophilia, neutropenia, pancytopenia, isolated thrombocytopenia (rarely accompanied by hemolytic anemia), and thrombocytosis have been associated with ticlopidine administration (see Warnings).
Liver: Ticlopidine therapy has been accompanied by an increase in hepatic enzymes. In clinical trials, increases of alkaline phosphatase and transaminase levels (incidence greater than twice the upper limit of normal) were observed in both ticlopidine and placebo groups. Maximal changes occur within 1 to 4 months of therapy initiation (see Warnings). No progressive increases were observed in closely monitored clinical trials, but most patients with these abnormalities had therapy discontinued. Ticlopidine therapy has also been accompanied by a minor elevation of bilirubin and deviations in GGTP. One case of significant increase in gGT in an elderly patient was reported in the literature. gGT returned to normal upon discontinuation of ticlopidine therapy.
Cholesterol: Chronic ticlopidine therapy has been associated with increased serum cholesterol and triglycerides. Serum levels of HDL-C, LDL-C, VLDL-C, and triglycerides are increased 8 to 10% after 1 to 4 months of therapy. No further progressive elevations are seen with continuous therapy. The ratios of the lipoprotein subfractions (especially the ratio of HDL to LDL) remain unchanged. The effect is not correlated with age, sex, alcohol use or diabetes.
Symptoms And Treatment Of Overdose :
OverdoseOne case of deliberate overdosage with ticlopidine has been reported in a foreign postmarketing surveillance program. A 38-year-old male took a single 6 000 mg dose of ticlopidine (equivalent to 24 standard 250 mg tablets). The only abnormalities reported were increased bleeding time and increased ALT. No special therapy was instituted and the patient recovered without sequelae. Based on animal studies, overdosage may result in severe gastrointestinal intolerance.:
In the case of excessive bleeding after injury or surgery, standard supportive measures should be carried out if indicated, including gastric lavage, platelet transfusion and use of corticosteroids.
Dosage And Administration:
The recommended dose is 250 mg twice daily with food.
Ticlopidine should be taken with meals to minimize gastrointestinal intolerance.
Availability And Storage:
Each oval, white, film-coated tablet, printed using blue ink with Ticlid above half an arrow on one side, “250” above half an arrow on the other side, contains: ticlopidine HCl 250 mg. Nonmedicinal ingredients: citric acid, cornstarch, FD&C blue No. 1 aluminum lake, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, povidone, stearic acid powder, titanium dioxide, polyethylene glycol and water. Gluten- and tartrazine-free. Fold-over cards of 28 (2 blisters of 14 tablets). Boxes of 56 (4´14).
For the first 3 months of therapy, only request or dispense the 14 days’ supply of tablets (see Precautions).
Store at room temperature. Dispense in light-resistant containers. Blister packs should not be exposed to light.
TICLID® Roche Ticlopidine HCl Inhibitor of Platelet Function