Inhibitor of Platelet Function
Action And Clinical Pharmacology: 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 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 hydrochloride. Upon discontinuation of ticlopidine hydrochloride 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 hydrochloride, rapid absorption occurs, with peak plasma levels occurring at approximately 2 hours after dosing. Absorption is at least 80% complete. Administration of ticlopidine hydrochloride 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.
Contra-Indications: Known hypersensitivity to drug or its excipients. Presence of hematopoietic disorders (such as neutropenia and/or thrombocytopenia). Presence of hemostatic disorder. Conditions associated with active bleeding, such as bleeding peptic ulcer or intracranial bleeding. Severe liver dysfunction.
Manufacturers’ Warnings In Clinical States: The following warnings were developed from clinical trial experience with over 2 000 patients with cerebrovascular disease who were treated with ticlopidine hydrochloride for as long as 5.8 years.
Hematological Complications: About 2.4% of ticlopidine patients in clinical trials developed neutropenia (defined as an absolute neutrophil count [ANC] below 1.2´ 10cells/L).
Thrombocytopenia occurs during the first 3 to 12 weeks of therapy, and recovery usually occurs after drug discontinuation. All patients should have a white blood cell count with a differential count 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.
All forms of hematological adverse reactions are potentially fatal. Rarely, cases of pancytopenia, aplastic anemia or thrombocytopenia have been reported. Most cases were reversible, but some of them have been fatal. Thrombocytopenia may occur in isolation or together with neutropenia. Thrombotic thrombocytopenic purpura (TTP) has been reported, therefore careful attention to diagnosis should be made to guide treatment; platelet transfusion may be harmful in these patients.
Hemorrhagic Complications: Prolongation of bleeding time occurs in subjects treated with ticlopidine hydrochloride. 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 Drugs: Anticoagulant drugs should be avoided as tolerance and safety of simultaneous administration with ticlopidine have not been established.
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.
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.
Precautions: 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 (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 WBC 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.
Elective Surgery: Ticlopidine should be discontinued 10 to 14 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 subjects, but there is no experience with ticlopidine hydrochloride 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 contraindications 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.
Drug Interactions: 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.
Other Concomitant Therapy: Although specific interaction studies were not performed, in clinical studies, ticlopidine was used concomitantly with b-blockers, calcium channel blockers and diuretics without evidence of clinically significant adverse interactions.
Adverse Reactions: Most adverse effects with ticlopidine 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 incidence rates of adverse reactions listed in Table II were derived from multicenter, controlled clinical trials comparing ticlopidine, placebo and ASA over study periods of up to 5 years. The rates are based on adverse reactions considered probably drug-related by the investigator.
The incidence of thrombocytopenia in these controlled studies was 0.4% in the ticlopidine and placebo groups of patients and 0.3% in the ASA patient population. The following rare events have been reported and their relationship to ticlopidine is uncertain. Pancytopenia, 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, fever, hyponatremia, bleeding increased (spontaneous, posttraumatic or postoperative), cholestatic jaundice, colitis, erythema multiforme, hepatic necrosis, hepatocellular jaundice, peptic ulcer, Stevens-Johnson syndrome, renal failure and sepsis.
Gastrointestinal: Ticlopidine therapy has been associated with a variety of gastrointestinal complaints including diarrhea and nausea. The majority of cases are mild and transient in nature and occur within 3 months of initiation of therapy. Typically, events are resolved within 1 to 2 weeks without discontinuation of therapy. If the effect is severe or persistent, therapy should be discontinued.
Hemorrhagic: Ticlopidine has been associated with a number of bleeding complications such as ecchymosis, epistaxis, hematuria, conjunctival hemorrhage, gastrointestinal bleeding and postoperative bleeding. 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, thrombocytopenia and thrombocytosis have been associated with ticlopidine administration (see Warnings).
Liver: Ticlopidine therapy has been associated with elevations of alkaline phosphatase (see Warnings). Maximal changes occur within 1 to 4 months of therapy initiation. No further progressive increases are seen with continuous therapy. Occasionally patients developed deviations in bilirubin, AST, ALT and GGTP.
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 are unchanged. The effect is not correlated with age, sex, alcohol use or diabetes.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: One 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 of ticlopidine is 250 mg twice daily with food. Ticlopidine should be taken with meals to minimize gastrointestinal intolerance.
Availability And Storage: Each oval, white, biconvex, film-coated tablet, engraved APO on one side and 250 on the other side, contains: ticlopidine HCl 250 mg. Nonmedicinal ingredients: carnauba wax, croscarmellose sodium, hydroxypropyl methylcellulose, mirocrystalline cellulose, polyethylene glycol, stearic acid and titanium dioxide. Bottles of 30 and 100. Two-and Four-Week Patient Packs of 28 (2 blister strips of 14 tablets each) and 56 (4 ´ 14) tablets, respectively. Store at room temperature (15 to 30°C) and protect from light.
For the first 3 months of therapy, only request or dispense the 14-day supply of tablets (see Precautions).
APO®-TICLOPIDINE Apotex Ticlopidine HCl Inhibitor of Platelet Function