Ticlid™

[Ticlopidine HCL]

Ticlid

Description / Properties

Ticlopidine is an inhibitor of platelet aggregation. It causes 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, but only in vivo-activity, however, there is no evidence for a circulating active metabolite.

Ticlopidine interferes with platelet aggregation by inhibiting ADP-dependent binding of fibrinogen to the platelet membrane; it does not involve cyclo-oxygenase inhibition, as does aspirin. Platelet cyclic-AMP does not seem to play a role in its mechanism of action.

Bleeding time with 40 mm Hg cuff pressure maintained as measured by the Ivy method is prolonged by greater than two-fold over baseline values. The uncuffed bleeding time prolongation is less pronounced.

Upon discontinuation of treatment, bleeding time and other platelet function tests return to normal within one week in the majority of patients.

Inhibition of platelet aggregation is detected within 2 days of administration with ticlopidine 250 mg bid. The maximum antiplatelet effect is obtained after 5 to 8 days of dosing at 250 mg bid.

At therapeutic dose, ticlopidine inhibits ADP-induced (2.5 mmol/l) platelet aggregation by 50 to 70%. Lower doses are associated with less platelet aggregation inhibition.

The effect of ticlopidine on the risk of vascular events was studied in several blinded, controlled clinical studies.

In a trial comparing ticlopidine and aspirin (the Ticlopidine Aspirin Stroke Study, or TASS), 3069 patients who had experienced transient ischemic attack or minor stroke were included and followed for at least 2 and up to 5 years. Over the duration of the study, ticlopidine significantly reduced the risk of fatal or nonfatal stroke by 27 % (p=0.011) compared to aspirin. During the first year, when the risk of stroke is greatest, the reduction in risk of stroke (fatal and non fatal) compared to aspirin was 48%. The reduction was similar in men and women.

In a trial comparing ticlopidine and placebo (The Canadian American Ticlopidine Study, or CATS), 1073 patients who had experienced a previous atherothrombotic stroke were treated for up to 3 years. Ticlid significantly reduced the overall risk of stroke by 34 % (p=0.017) compared to placebo. During the first year, the reduction in risk of fatal and non fatal stroke over placebo was 33%.

In a trial comparing ticlopidine and placebo (The Swedish Ticlopidine Multicentre Study, or STIMS), 687 patients with intermittent claudication were included. The median duration of patient observation, from entry to final evaluation, was 5.6 years.

Ticlid significantly reduced the total mortality by 29% (p=0.015). The incidence of cardio and cerebrovascular events (fatal and non fatal)) was reduced by 41% (p=0.007).

Pharmacokinetic Properties After oral administration of a single standard dose of ticlopidine, a rapid absorption occurs, with peak plasma levels occurring approximately 2 hours after dosing.

Absorption is practically complete. Administration of ticlopidine after meals improves bioavailability.

Steady-state plasma levels are obtained after 7 to 10 days of dosing at 250 mg bid. The average terminal elimination half-life of ticlopidine at steady state is approximately 30 to 50 hours. However, the inhibition of platelet aggregation does not correlate with plasma drug levels.

Ticlopidine is extensively metabolized by the liver. Following an oral dose of radio labelled product, 50 to 60% are recovered in the urine and the rest in the feces.

Indications

  • Reduction of risk of first and recurrent stroke for patients who have experienced at least one of the following events : complete thromboembolic or ischemic stroke, minor stroke, reversible ischemic neurological deficit (RIND), or transient ischemic attack (TIA) including transient monocular blindness (TMB).
  • Prevention of major ischemic accidents, particularly coronary, in patients presenting with chronic arterial disease of the lower limbs at the stage of intermittent claudication.
  • Prevention and correction of platelets function disorders caused by extracorporeal circuits:
         - surgery with extracorporeal circulation
         - chronic hemodialysis

    Contraindication

    Prevention of subacute occlusions following coronary STENT(s) implantation.
  • Haemorrhagic diathesis
  • Organic lesions which are liable to bleed i.e. active gastroduodenal ulcer or haemorrhagic cerebrovascular accident in the acute phase.
  • Blood disease involving prolonged bleeding time
  • History of allergy to ticlopidine
  • History of leucopenia, thrombocytopenia or agranulocytosis

    Drug Interactions

    COMBINATIONS WITH INCREASED HAEMORRHAGIC RISK :

    NSAIDs :

    Increase of haemorrhagic risk ( increase of platelet antiaggregant activity and NSAIDs effect on the gastro-duodenal mucous membrane). If such drugs are necessary, close clinical monitoring is required.

    ANTIPLATELET DRUGS :

    Increase of haemorrhagic risk ( increase of platelet antiaggregant activity). If such drugs are necessary, close clinical monitoring is required.

    SALICYLIC DERIVATIVES (by extrapolation from acetylsalicylic acid) :

    Increase of haemorrhagic risk ( increase of platelet antiaggregant activity and salicylic derivatives effect on the gastro-duodenal mucous membrane). If such drugs are necessary, close clinical monitoring is required. In case of STENT(s) implantation see 4-2 Posology and 4-4 Special Warnings and Special Precautions for use.

    ORAL ANTICOAGULANTS :

    Increase of haemorrhagic risk (combination of anticoagulant activity and platelet antiaggregant activity). If such drugs are necessary, close clinical and biological monitoring (INR) is required.

    HEPARINS :

    Increase of haemorrhagic risk (combination of anticoagulant activity and platelet antiaggregant activity). If such drugs are necessary, close clinical and biological monitoring (APTT) is required.

    COMBINATIONS REQUIRING SPECIAL PRECAUTIONS :

    THEOPHYLLINE

    Increase of plasma theophylline levels with risk of overdosage (decrease in total plasma theophylline clearance). Clinical monitoring, and if necessary plasma theophylline levels are required. Theophylline dosage must be adjusted during and after treatment with ticlopidine.

    DIGOXIN

    Co-administration of ticlopidine and digoxin leads to a slight decrease (approximately 15%) in plasma digoxin levels. This should not affect the therapeutic efficacy of digoxin.

    PHENOBARBITAL

    In healthy volunteers, the inhibitory effects of ticlopidine on platelet aggregation are not affected 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. There have been rare reports of increased phenytoin levels and phenytoin toxicity when ticlopidine is co-prescribed. Caution should be exercised in coadministering this drug with Ticlid and it may be useful to remesure phenytoin blood concentrations.

    OTHER CONCOMITANT THERAPIES :

    In clinical studies, ticlopidine was given concomitantly with beta-blockers, calcium channel blockers and diuretics : no clinically significant adverse interactions were reported.

    In-vitro studies demonstrate that ticlopidine is reversibly bound to plasma proteins (98%), but that it does not interact with plasma protein binding of propanolol, basic drug which is also highly protein bound.

    In very rare instances, lowering of cyclosporine blood level has been reported. Therefore, cyclosporine blood level should be monitored in case of coadministration.

    Side Effects

    The incidence rates of adverse effects are derived from two multicentre controlled clinical trials (CATS and TASS) conducted in 2048 TIA / stroke patients.

  • Haematological

    Cell blood counts were closely monitored in two large clinical studies conducted in 2,048 TIA/stroke patients treated with ticlopidine. A 2.4 % incidence of neutropenia was reported, which includes 0.8% of severe neutropenia (<450 neutrophils/mm3).In these clinical trials, as in most of the cases from the post-marketing surveillance studies, most cases of severe neutropenia or agranulocytosis (<300 neutrophils/mm3) developed in the first 3 months of ticlopidine treatment, and were not typically accompanied by signs of infection or other clinical symptoms (need for CBCs monitoring). In such cases, the bone marrow typically showed a decrease in myeloid precursors.

    There have been rare reports of bone marrow aplasia or pancytopenia.

    Uncommon cases of isolated thrombocytopenia ( < 80.000 / mm3) have been reported with ticlopidine treatment.

    There have been rare reports of thrombotic thrombocytopenic purpura (see 4-4 Special Warnings / Clinical monitoring).

  • Haemorrhagic

    Common haemorrhagic complications, mainly bruising or ecchymosis and epistaxis may occur with treatment. Peri- and postoperative bleedings have been reported.

  • Gastrointestinal

    Treatment with ticlopidine may cause gastrointestinal disturbances

    The most common was diarrhoea and the second was nausea. Diarrhoea is generally mild and transient, and occurs mainly during the first 3 months of treatment.

    These disturbances usually resolve within 1 to 2 weeks without discontinuation of treatment. Very rare cases of severe diarrhea with colitis (including lymphocytic colitis) have been reported. If the effect is severe and persistant, therapy should be discontinued.

  • Cutaneous

    Common skin rashes, particularly maculopapular or urticarial, often accompanied by pruritus have been reported. In general, skin rashes occur within the first 3 months of treatment, with a mean time to onset of 11 days. If treatment is discontinued, the symptoms disappear within a few days. These skin rashes may be generalized. There have been very rare reports of erythema multiforme and Stevens Johnson syndrome.

  • Hepatic

    There have been rare reports of hepatitis (cytolytic and cholestatic) during the first months of treatment. The course has generally been favourable after treatment was discontinued.

    Very rare cases of immunological reactions with different manifestations have been reported e.g. : allergic reactions, anaphylaxis, Quincke edema, arthralgia, vasculitis, lupus syndrome, hypersensitivity nephropathy, allergic pneumopathy.

    Altered laboratory findings

  • Haematological

    Neutropenia and rarely, pancytopenia as well as isolated thrombocytopenia or exceptionally accompanied by haemolytic anaemia, have been associated with Ticlid treatment.

  • Hepatic

    Ticlopidine treatment has been accompanied by an increase in hepatic enzymes. Common increase (either isolated or not), of alkaline phosphatases and transaminases (incidence greater than twice the upper limit of normal) was observed in both group (ticlopidine and placebo). Ticlopidine treatment has also been accompanied by a minor elevation of bilirubin..

  • Cholesterol

    Chronic ticlopidine therapy has been associated with increased serum cholesterol and triglyceride levels. Serum HDL-C, LDL-C, VLDL-C and triglyceride levelsmay increase 8 to 10 % after 1 to 4 months of treatment. No further elevations are seen with continued therapy. The ratios of the lipoprotein subfractions (especially the ratio of HDL to LDL) remain unchanged. The data in the clinical studies have shown that the effect does not depend on age, sex, alcohol consumption or diabetes, and has no influence on the cardiovascular risk.

    Warning and Precautions

    Haematological and haemorrhagic adverse effects can occur. These may be severe and sometimes fatal consequences have been observed.

    These severe effects could be associated with :

  • Inadequate monitoring, late diagnosis and inappropriate therapeutic measures for adverse effects

  • Concomitant administration of anticoagulants or antiplatelet agents such as aspirin and nonsteroidal anti-inflammatory drugs. However, in case of STENT implantation, ticlopidine should be combined with aspirin (100 to 325 mg per day) for about one month following implantation.

    IT IS ESSENTIAL TO COMPLY STRICTLY WITH THE INDICATIONS IN THE PRODUCT LICENCE, THE PRECAUTIONS AND CONTRA-INDICATIONS FOR TICLOPIDINE.

    Clinical Monitoring: All patients should be carefully monitored for clinical signs and symptoms of adverse drug reactions specially during the first three months of therapy.