Ticlopidine Hydrochloride
Drug Nomenclature
Pharmacopoeias. In China, Europe, and Japan.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Ticlopidine Hydrochloride). A white or almost white, crystalline powder. Sparingly soluble in water and in dehydrated alcohol; very slightly soluble in ethyl acetate. A 2.5% solution in water has apH of 3.5 to 4.0.
Adverse Effects and Precautions
Gastrointestinal disturbances, skin rashes, and bleeding are the most commonly reported adverse effects associated with ticlopidine therapy. Blood dyscrasias, including neutropenia, thrombotic thrombocytopenic purpura, and aplastic anaemia, have also occurred. There have been reports of hepatitis and cholestatic jaundice. Blood-lipid concentrations may increase during long-term therapy.
Ticlopidine should not be given to patients with haematopoietic disorders such as neutropenia or thrombocytopenia, haemorrhagic diathesis or other haemorrhagic disorders associated with a prolonged bleeding time, or conditions with an increased risk of bleeding such as peptic ulcer disease, acute cerebral haemorrhage, or severe liver dysfunction. Full blood counts should be performed before starting treatment and every 2 weeks during the first 3 months of therapy. If ticlopidine is stopped during this period, a full blood count should be performed within 2 weeks of stopping treatment. Consideration should be given to stopping ticlopidine therapy 10 to 14 days before elective surgery.
Effects on the blood. Severe neutropenia or agranulocytosis may occur in about 1% of patients given ticlopidine and fatal infection has been reported. Neutropenia usually develops within the first 3 months of therapy and is reversible on stopping ticlopidine, but there has been a report of a delayed reaction that occurred 18 days after ticlopidine was stopped. Isolated thrombocytopenia occurs in about 0.4% of patients and thrombotic thrombocytopenic purpura, sometimes fatal, has occurred. Conversely, good results have been achieved with ticlopidine as a treatment for thrombotic thrombocytopenic purpura, but it should only be used with extreme caution. Aplastic anaemia has also occurred rarely with ticlopidine.
Clopidogrel has also been associated with blood dyscrasias. Up to August 2004, the Australian Adverse Drug Reactions Advisory Committee (ADRAC) had received 80 reports of blood dyscrasias associated with clopidogrel, although ticlopidine was associated with a much higher rate of reports. Individual cases of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome, aplastic anaemia, leucopenia, and acquired haemophilia A, have also been reported. However the most frequently reported adverse effect of clopidogrel, as with other antithrombotics, is bleeding, particularly when given with other drugs affecting coagulation; ADRAC had received 130 reports of haemorrhagic events, leading to fatalities in 18 cases.
Effects on the gastrointestinal tract. Diarrhoea is a common adverse effect of ticlopidine therapy; it usually occurs during the first few months of therapy and resolves within 1 to 2 weeks without stopping therapy. However, there has been a report of diarrhoea and weight loss of 2 months duration that first presented 2 years after ticlopidine was started; diarrhoea resolved when ticlopidine was withdrawn.
Effects on the joints. Acute arthritis associated with a diffuse rash developed in a patient shortly after starting treatment with ticlopidine. Both the rash and the arthritis resolved on withdrawal, and it was suggested that a hypersensitivity reaction might be involved. One case of polyarthritis and 3 cases of arthralgia associated with ticlopidine had been reported to the UK CSM up to March 2001. Two cases of acute arthritis have also been reported with clopidogrel; symptoms developed 2 to 3 weeks after starting treatment and resolved after stopping.
Effects on the kidneys. A reversible deterioration in renal function has been reported in patients given ticlopidine after coronary stent implantation. There has also been a report of membranous nephropathy with nephrotic syndrome in a patient receiving clopidogrel.
Effects on the liver. Cholestatic hepatitis has been reported in patients receiving ticlopidine and is usually reversible when ticlopidine is stopped. However, there have been reports of persistent cholestasis after ticlopidine withdrawal. A case of granulomatous hepatitis has also been reported. Clopidogrel was substituted for ticlopidine in a patient who had developed raised liver enzymes during ticlopidine treatment; liver enzyme values returned to normal during continued clopidogrel therapy. However, there has been a report of hepatotoxicity with clopidogrel.
Effects on the lungs. Bronchiolitis obliterans-organising pneumonia developed in a 76-year-old woman receiving ticlopidine and prednisone for temporal arteritis. The condition resolved over several months when ticlopidine was withdrawn.
Interactions
Ticlopidine should be used with caution in patients receiving other drugs, such as anticoagulants and antiplatelets, that increase the risk of bleeding. Ticlopidine is an inhibitor of cytochrome P450, including the isoenzymes CYP2C19, CYP2D6, and CYP2B6, and may inhibit the metabolism of other drugs that are metabolised by this route. The clearance of ticlopidine may be reduced by cimetidine. Corticosteroids may antagonise the effect of ticlopidine on bleeding time.
Anticoagulants. Use of ticlopidine with anticoagulants may increase the risk of bleeding. However, ticlopidine has been reported to antagonise the effect of acenocoumarol (see Antiplatelets under Interactions of Warfarin).
Antiepileptics. For a report of acute phenytoin toxicity in a well-stabilised patient following addition of ticlopidine.
Xanthines. For reference to the effect of ticlopidine on theophylline half-life.
Pharmacokinetics
Ticlopidine is rapidly and almost completely absorbed from the gastrointestinal tract. It is about 98% bound to plasma proteins. The terminal half-life during chronic dosing is reported to be about 30 to 50 hours. Ticlopidine is extensively metabolised in the liver. About 60% of a dose is excreted in the urine as metabolites and 25% in the faeces.
Uses and Administration
Ticlopidine hydrochloride is a thienopyridine anti-platelet drug used in thromboembolic disorders. It appears to act by inhibiting adenosine diphosphate-mediated platelet aggregation. It may be given prophylactically as an alternative to aspirin in patients at risk of thrombotic stroke and in the management of intermittent claudication (see Peripheral Vascular Disease) and ischaemic heart disease. It is also licensed as an adjunct to aspirin for the prevention of subacute stent occlusion after intracoronary stenting (but see Reperfusion and Revascularisation Procedures, below). Ticlopidine may also be used to prevent occlusion and platelet loss during extracorporeal circulatory procedures.
In the prevention of thrombotic stroke, and in intermittent claudication, ticlopidine hydrochloride is given orally in a dose of 250 mg twice daily, with meals. For the prevention of subacute stent occlusion after in-tracoronary stenting ticlopidine hydrochloride is given in a dose of 250 mg twice daily for 4 weeks, starting at the time of stent placement.
Regular haematological monitoring is required during ticlopidine therapy (see Adverse Effects and Precautions, above).
Reperfusion and revascularisation procedures. Coronary stents are widely used as an adjunct to angioplasty to prevent acute vessel closure and to reduce restenosis (see Reperfusion and Revascularisation Procedures). Subacute thrombosis is a major complication of their use and patients were initially treated with an aggressive combination of anticoagulants and antiplatelets. However, it is now generally recognised that antiplatelet drugs alone are adequate in most patients.
Early studies found that ticlopidine for 4 to 6 weeks after stenting, given with long-term aspirin, was at least as effective as an oral anticoagulant with aspirin, with some studies showing benefit in terms of thrombosis or bleeding complications. However, the risk of neutropenia limits the use of ticlopidine, and clopidogrel is now generally preferred, although there is some evidence that shorter courses of ticlopidine (2 weeks) may be acceptable.
Ticlopidine has also been reported to improve the long-term patency of saphenous vein bypass grafts used to treat peripheral vascular disease in the legs.
Proprietary Preparations
Argentina: Dosier; Ticlid; Trombenal;
Australia: Ticlid; Tilodene;
Austria; Thrombodine; Ticlodone; Tiklid;
Belgium: Ticlid;
Brazil: Plaketar; Ticlid; Ticlobal;
Canada: Ticlid;
Chile: Aterodar; Piaquetil; Ticlid;
Czech Republic: Apiaket †; Apo-Tic; Ipaton; Platigren †; Tagren; Ticlid;
France: Ticlid; Ticlomed †;
Germany; Desiticlopiclin; Tiklyd;
Greece; Anchostam-100 †; Anghostam-100; Etfariol; Neo Fulvigal; Neoomnipen; Ruxicolan; Ticlid; Ticlodone;
Hong Kong; Aplaket; Ticlid; Tipidin;
Hungary: Aclotin; Aplatic; Ipaton; Placor; Ticlid;
India: Ticlobest; Ticlop; Ticlopid; Tikleen †; Tyklid;
Indonesia: Agulan; Cartrilet; Goclid; Nufaclapide; Picloclin; Ticard; Ticlid; Ticlon;Ticuring;
Italy: Anagregal †; Antigreg; Aplaket; Clox; Fluilast; Flupid; Fluxidin; Klodin; Opteron; Parsilid †; Ticlodone; Ticlogi †; Ticloproge †; Tiklid;
Japan: Panaldine;
Malaysia: Antigreg; Aplaket; Ticlid; Ticiopine; Tipidin;
Mexico: Ticlid;
Norway: Ticlid;
Philippines: Clotidone; Ticlid;
Poland: Aclotin; Apo-Clodin; Iclopid; Ifapidin; Ticlid; Ticio;
Portugal: Agregamina †; Aplaket; Betlife; Isaxion †; Klodipin; Movin; Opidina †; Plaquetal; Previta; Ticloclix; Ticlopat; Tiklyd; Tiropa; Trombopat;
Russia: Ticio; Tikleen;
South Africa: Ticlid †;
Singapore: Antigreg; Aplaket; Tacron †; Ticlid; Tipidin;
Spain: Ticlodone; Tiklid;
Sweden: Ticlid;
Thailand: Aplaket; Cenpidine; Siclot; Ticdine †; Ticlid; Ticio; Ticiopine; Tikol †; Tliopin; Tipidine; Viladil;
Turkey: Agretik; Ticlid; Ticlocard;
UAE: Ticopar;
United States of America (US and USA): Ticlid;
Venezuela: Ticlid; Ticlopin.
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