VA Class:BL117
ATC Class:B01AC05
Ticlopidine, a thienopyridine derivative P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist, is a platelet-aggregation inhibitor.1, 2, 52, 71, 82
Prevention of Thrombotic Stroke
Ticlopidine is used to reduce the risk of fatal or nonfatal thrombotic stroke in patients who have had either a previous completed thrombotic stroke or stroke precursors (e.g., transient ischemic attack [TIA], transient monocular or partial blindness [amaurosis fugax], reversible ischemic neurologic deficit, minor stroke).1, 2, 71 Because of the risk of life-threatening adverse hematologic effects, including neutropenia and/or agranulocytosis, thrombotic thrombocytopenic purpura (TTP), and aplastic anemia, the manufacturer states that the drug should be reserved for patients who are unable to tolerate or are sensitive to aspirin or who have failed to respond to aspirin therapy where indicated to prevent stroke; the manufacturer further states that ticlopidine is contraindicated in patients with preexisting hematopoietic disorders such as neutropenia or thrombocytopenia or a history of either thrombotic thrombocytopenic purpura or aplastic anemia.1 The manufacturer also states that the drug should not be used in patients with a hemostatic disorder, active pathologic bleeding (e.g., bleeding peptic ulcer, intracranial bleeding), or severe hepatic impairment.1, 35, 36, 71 The American College of Chest Physicians (ACCP) states that use of ticlopidine for the secondary prevention of stroke has become severely limited because of the risk of serious adverse effects and the availability of safer antiplatelet agents (e.g., clopidogrel).1009
Ticlopidine has been shown in 2 randomized, double-blind studies to reduce the risk of stroke and other vascular outcomes compared with aspirin or placebo in patients with stroke precursors or in those who had experienced an atherothrombotic stroke.72, 73 Subgroup analyses of one of these studies suggested that the beneficial effects of ticlopidine relative to aspirin were more pronounced in nonwhite, predominantly African American patients.45 However, serious adverse effects, such as neutropenia and TTP, were reported with ticlopidine in these studies.72, 73
Prevention of Coronary Artery Stent Thrombosis
Ticlopidine also is used as an adjunct to aspirin therapy to reduce the incidence of subacute stent thrombosis after percutaneous coronary intervention (PCI) with successful coronary artery stent placement.1, 46, 71 Because of the risk of serious adverse effects (e.g., thrombocytopenia, neutropenia, thrombotic thrombocytopenic purpura) associated with ticlopidine, use of the drug for the prevention of coronary artery stent thrombosis largely has been replaced by other antiplatelet agents.1010 ACCP and other experts currently recommend dual-drug antiplatelet therapy with other P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonists (e.g., clopidogrel, prasugrel, ticagrelor) and aspirin in patients undergoing PCI with stent placement.994, 1010
In comparative clinical trials in patients undergoing stent implantation, therapy with ticlopidine hydrochloride (250 mg twice daily) plus aspirin (100 mg twice daily to 325 mg daily) was associated with a lower incidence of recurrent cardiovascular events (e.g., stent thrombosis resulting in death, myocardial infarction [MI], the need for repeat coronary angioplasty, or coronary artery bypass grafting [CABG]) than therapy with aspirin alone or combined with anticoagulants (e.g., warfarin).1, 46, 71
Ticlopidine hydrochloride is administered orally.1, 2, 71 The drug should be taken with food to maximize GI absorption and tolerance.1, 71
Prevention of Thrombotic Stroke
For reducing the risk of fatal or nonfatal stroke in adults, the usual dosage of ticlopidine hydrochloride is 250 mg twice daily.1, 71 The safety and efficacy of this dosage in geriatric patients appear to be similar to those in younger adults, and clinical trials establishing the efficacy of the usual dosage principally involved the elderly;1, 2, 71 however, the possibility that some geriatric patients may exhibit increased sensitivity to ticlopidine hydrochloride cannot be excluded.1, 71 The manufacturer states that the efficacy of dosages other than the usual adult dosage has not been studied in controlled clinical trials.1, 71
Therapy with ticlopidine hydrochloride has been continued for at least up to 5.8 years in some patients.1, 2, 71
Prevention of Coronary Artery Stent Thrombosis
When ticlopidine hydrochloride is used as an adjunct to aspirin to prevent subacute stent thrombosis in adults undergoing coronary stent placement, the usual initial dosage recommended by the manufacturer is 250 mg twice daily in conjunction with antiplatelet dosages of aspirin; therapy is initiated after successful stent implantation and continued for 30 days.1, 46, 71
If ticlopidine is used in combination with aspirin as the thienopyridine-derivative component of dual-drug antiplatelet therapy following drug-eluting stent (DES) implantation, it is critical that combined therapy with ticlopidine and aspirin be continued for at least 12 months to minimize the risk of potentially catastrophic stent thrombosis.70 (See Myocardial Infarction under Dosage: Acute Coronary Syndrome, in Dosage and Administration in Clopidogrel Bisulfate 20:12.18.)
Dosage in Renal and Hepatic Impairment
In patients with renal impairment, reduction of ticlopidine hydrochloride dosage or discontinuance of the drug may be necessary if hemorrhagic or hematopoietic complications occur.1, 71 In controlled clinical trials, no unexpected adverse effects were observed in patients with mild renal impairment receiving usual dosages of the drug, but the manufacturer states that there has been no experience in patients with more severe degrees of impairment.1, 71
The manufacturer currently states that use of ticlopidine hydrochloride in patients with severe hepatic impairment is contraindicated, since experience to date in such patients is limited and they may be at risk for bleeding diathesis.1, 71
Adverse effects of ticlopidine are relatively frequent,1, 3, 4, 5, 10, 11, 71 with more than 50% of patients in controlled clinical trials reporting at least one adverse effect while receiving the drug over study periods ranging up to 5.8 years.1, 3, 4, 10, 11, 71 Most adverse effects are mild in severity1, 4, 71 and occur early in the course of treatment (i.e., within the first 3 months);1, 4, 11, 71 however, some adverse effects may become evident for the first time only after several months of therapy.1, 11, 71 In comparative studies, ticlopidine generally appeared to be more poorly tolerated overall than aspirin, with diarrhea and rash occurring with ticlopidine at about twice the rates reported with aspirin; only adverse GI effects typically associated with nonsteroidal anti-inflammatory agent (NSAIA) therapy (e.g., GI pain or bleeding, peptic ulcer) occurred more frequently with aspirin than with ticlopidine.1, 4, 71
The most serious adverse effects of ticlopidine involve the hematologic system, principally neutropenia, which may be life-threatening.1, 4, 8, 9, 11, 71 The most frequently reported adverse effects of ticlopidine involve the GI tract.1, 4, 10, 11, 71 The most frequent adverse effects in controlled clinical trials were diarrhea, nausea, dyspepsia, and rash;1, 4, 11, 71 these effects occurred more often in whites and women.11 In controlled clinical trials, 21% of patients discontinued ticlopidine therapy because of adverse effects.1, 4, 8, 11, 71 The most common adverse effects resulting in drug discontinuance were nausea, vomiting, diarrhea, GI pain, rash, and neutropenia.1, 71
The most serious adverse hematologic effects of ticlopidine are neutropenia1, 3, 4, 7, 8, 9, 10, 11, 14, 71 (absolute neutrophil count [ANC] less than 1200 neutrophils/mm3), agranulocytosis,1, 7, 9, 10, 20, 71 thrombotic thrombocytopenic purpura (TTP),1, 7, 11, 23, 30, 32, 71 and aplastic anemia.1, 7, 16, 17, 20, 22, 24, 25, 26, 27, 71 The incidence of ticlopidine-induced neutropenia, TTP, or aplastic anemia peaks about 4-6, 3-4, or 4-8 weeks, respectively, following initiation of therapy; the incidence of these hematologic effects declines thereafter.1, 71 Only in a few instances have these hematologic adverse effects occurred more than 3 months after initiation of ticlopidine therapy.1, 71 Risk factors for development of these adverse hematologic effects have not been identified; however, data from a large clinical trial suggest that the risk of adverse effects, including severe neutropenia, with ticlopidine therapy may be reduced (and beneficial effects on stroke reduction more pronounced) in nonwhite (e.g., African American) patients.44, 45 (See Uses: Prevention of Thrombotic Stroke.) Fever may be a clinical manifestation indicative of neutropenia, TTP, or aplastic anemia.1, 71 Neutropenia occurred in 2.4% of stroke patients receiving the drug in controlled clinical trials.1, 71 Hematologic status must be carefully monitored in patients receiving ticlopidine.1, 4, 11, 71 (See Cautions: Precautions and Contraindications.)
The onset of neutropenia may be sudden.1, 71 Mild to moderate neutropenia1, 3, 4, 11, 71 (ANC of 451-1200 neutrophils/mm3) occurred in 1.6% of patients and severe neutropenia1, 3, 4, 7, 8, 11, 71 (ANC less than 450 neutrophils/mm3) in 0.8% of patients1, 8, 11, 71 receiving ticlopidine in controlled clinical trials.1, 71 In patients with mild to moderate neutropenia, neutrophil counts usually recover within a few days of discontinuing ticlopidine, but neutropenia may be transient and may not necessarily require discontinuance of the drug.1, 71 Severe neutropenia usually occurs within 3 weeks to 3 months after initiating ticlopidine therapy1, 4, 8, 10, 11, 71 (but may occur later),1, 71 may be idiosyncratic and not dose related,8 and can be detected with regular hematologic monitoring.1, 8, 11, 71 The bone marrow usually shows a reduction in myeloid precursors,1, 4, 71 principally those associated with arrest of maturation of the granulocytic cell line.4 Neutropenia usually is not severe, often being relieved by a temporary reduction in dosage,4 but discontinuance of ticlopidine therapy was required1, 3, 7, 8, 11, 71 in 1.3% of patients in controlled clinical trials.1, 71 Neutrophil counts usually return to normal within 1-3 weeks when ticlopidine therapy is immediately discontinued following detection of neutropenia.1, 4, 71 However, neutropenia has been reported rarely following ticlopidine discontinuance21 and rarely has been fatal.1, 4, 7, 14, 71
Thrombocytopenia1, 7, 10, 11, 14, 71 (platelet count less than 80,000 cells/mm3) may occur rarely in isolation or in conjunction with neutropenia, TTP, or aplastic anemia in patients receiving ticlopidine.1, 14, 71 If thrombocytopenia occurs, ticlopidine therapy should be discontinued.1, 71 (See Cautions: Precautions and Contraindications.) Rarely, immune thrombocytopenia1, 7, 11, 71 and thrombotic thrombocytopenic purpura1, 7, 11, 23, 30, 32, 71 have occurred and in some cases were fatal.1, 11, 32, 35, 36, 71 TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (fragmented red blood cells [schistocytes] on peripheral blood smear), neurologic changes, renal dysfunction, and fever.1, 71 Clinical symptoms may precede laboratory evidence of TTP, but manifestations of the adverse effect can occur in any order.1, 71 Based on an annual estimated patient exposure of 2-4 million and assuming an event reporting rate of 10%, the incidence of ticlopidine-associated TTP may be as high as one case in every 2000-4000 patients exposed.1, 71 However, in a retrospective postmarketing surveillance study in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) and coronary artery stenting, TTP was diagnosed in 0.02% of patients an average of 25 days after initiation of ticlopidine therapy in patients receiving the drug for an average of 22 days.35, 36
Purpura1, 4, 11, 26, 30, 71 is a common adverse hematologic effect of ticlopidine, occurring in 2.2% of patients receiving the drug in controlled clinical trials.1, 11, 71 Rarely, purpura has resulted in discontinuance of ticlopidine.1, 71
Adverse hematologic effects occurring occasionally with ticlopidine therapy include increased bleeding,1, 71 spontaneous posttraumatic bleeding,1, 71 perioperative bleeding1, 28, 71 (including perioperative GI bleeding),1, 71 ecchymosis,1, 5, 10, 71 epistaxis,1, 4, 5, 10, 11, 71 hematuria,1, 4, 71 conjunctival hemorrhage,1, 71 unspecified bleeding disorders,3, 9, 10 easy bruisability,4 petechiae,4 GI hemorrhage,4 gingival bleeding,5 menorrhagia,10 and intracerebral bleeding or hemorrhage.1, 3, 71 Intracerebral hemorrhage rarely has been fatal.3 Hemolytic anemia with reticulocytosis,1, 71 aplastic anemia1, 7, 16, 17, 20, 22, 24, 25, 26, 27, 71 (sometimes fatal),1, 16, 22, 26, 27, 71 agranulocytosis1, 7, 9, 10, 20, 71 (sometimes fatal),1, 71 eosinophilia,1, 71 pancytopenia1, 10, 17, 71 (sometimes fatal),1, 71 thrombocytosis,1, 71 leukemia,1, 71 and bone marrow depression1, 71 each have been reported rarely. Aplastic anemia is characterized by anemia, thrombocytopenia, and neutropenia together with evidence of depression of myeloid precursors on bone marrow examination.1, 71 Patients may exhibit manifestations suggestive of infection in association with low leukocyte and platelet counts.1, 71 The incidence of aplastic anemia usually peaks after about 4—8 weeks of therapy.1, 71 Based on an annual estimated patient exposure of 2-4 million and assuming an event reporting rate of 10%, the incidence of ticlopidine-associated aplastic anemia may be as high as one case in every 4000-8000 patients exposed.1, 71
Adverse GI effects accounted for 30-40% of reported adverse effects, and usually occurred within the first 3 months of ticlopidine therapy,1, 71 were usually mild in severity,1, 71 tended to occur more frequently in geriatric patients,11 and often disappeared within 1-2 weeks despite continued therapy.1, 71 The most common adverse GI effect of ticlopidine is diarrhea,1, 3, 4, 5, 7, 8, 9, 10, 11, 27, 71 which occurred in 12.5% of patients receiving the drug in controlled clinical trials.1, 11, 71 Diarrhea may be accompanied by abdominal cramps4, 7, 9 and is the most frequent adverse effect requiring discontinuance of therapy, resulting in ticlopidine discontinuance1, 4, 8, 71 in 6.3% of patients receiving the drug in controlled clinical trials.1, 4, 71 Diarrhea may be alleviated by a temporary reduction in dosage.4, 7, 8 If diarrhea is severe or persistent, ticlopidine therapy should be discontinued.1, 71 In some cases of severe or bloody diarrhea in clinical trials, colitis subsequently was diagnosed.1, 71
Other adverse GI effects of ticlopidine include nausea1, 5, 7, 9, 10, 11, 71 and dyspepsia,1, 7, 9, 11, 71 each of which occurred in 7% of patients receiving the drug in controlled clinical trials.1 GI pain1, 5, 10, 11, 71 occurred in 3.7% of patients receiving ticlopidine in controlled clinical trials.1, 71 Nausea, dyspepsia, and GI pain resulted in drug discontinuance in 2.6%, 1.1%, and 1.9%, respectively, of patients receiving the drug in controlled clinical trials.1, 71 Vomiting,1, 5, 9, 10, 71 which occurred in 1.9% of patients,1, 71 flatulence,1, 11, 71 which occurred in 1.5% of patients,1, 71 and anorexia,1, 10, 11, 71 which occurred in 1% of patients, also have been reported with ticlopidine therapy in controlled clinical trials.1, 71 Vomiting resulted in drug discontinuance in 1.4% of patients.1 Flatulence and anorexia occasionally have resulted in drug discontinuance.1, 71 GI fullness,1, 11, 71 gastritis,9 and peptic ulcer1, 4, 9, 71 have been reported rarely.1, 71
Dermatologic and Sensitivity Reactions
Rash1, 3, 4, 5, 7, 9, 11, 17, 19, 24, 71 is the most common adverse dermatologic effect of ticlopidine, occurring in approximately 5% of patients receiving the drug in controlled clinical trials.1, 11, 71 The rash may be maculopapular1, 17, 71 or urticarial1, 71 and often is associated with pruritus.1, 71 Pruritus1, 10, 11, 71 occurred in 1.3% of patients receiving ticlopidine in controlled clinical trials.1, 71 Rash resulted in discontinuance of ticlopidine therapy in 3.4% of patients1, 4, 11, 71 and pruritus in 0.8% of patients receiving the drug in controlled clinical trials.1, 71 Rash usually occurs within 3 months of initiating ticlopidine therapy (average onset of 11 days), and resolves within several days with drug discontinuance.1, 4, 11, 71 Ticlopidine therapy can often be reinstituted following resolution without rash recurrence.1, 11, 71 Urticaria1, 4, 10, 11, 71 has been reported occasionally.1, 71 Vasculitis,1, 71 erythema,10 angioedema,1, 71 allergic pneumonitis,1, 71 systemic lupus erythematosus with positive antinuclear antibody (ANA) titer,1, 71 serum sickness,1, 71 anaphylaxis,1, 71 and severe rashes, including Stevens-Johnson syndrome,1, 71 erythema multiforme,1, 71 and exfoliative dermatitis,1, 71 each have been reported rarely.
Elevations in serum alkaline phosphatase concentration1, 11, 18, 71 (to greater than 2 times the upper limit of normal) occurred in 7.6% of patients1, 71 and AST (SGOT) concentrations1, 11, 18, 29, 71 (to greater than 2 times the upper limit of normal) occurred in 3.1% of patients receiving ticlopidine in controlled clinical trials.1, 71 These elevations generally occurred within 1-4 months of therapy.1, 71 No progressive increases were observed, but most patients with these abnormalities discontinued therapy.1, 71 Elevations in serum transaminase and bilirubin concentrations (up to and exceeding 10 times the upper limit of normal) have been reported rarely during postmarketing experience.1, 71 Abnormal liver function test results1, 3, 7, 9, 10, 11, 18, 19, 25, 29, 31, 71 occurred in 1% of patients and resulted in discontinuance of ticlopidine therapy in 0.7% of patients in controlled clinical trials.1, 71 Increased1, 11, 18, 29, 71 or decreased11 serum bilirubin concentration, increased serum γ-glutamyltransferase (γ-glutamyltranspeptidase, GT, GGTP) concentration,11 hepatitis,1, 71 hepatocellular jaundice,1, 71 cholestatic jaundice,1, 7, 11, 13, 15, 29, 31, 71 severe cholestasis,18, 31 cholestatic hepatitis,29 hepatic failure,1, 71 and hepatic necrosis1, 71 each have been reported rarely. Granulomatous hepatitis also has been reported; a causal relationship to the drug has not been established.12
Dizziness1, 11, 71 occurred in approximately 1% of patients receiving ticlopidine in controlled clinical trials1, 71 and resulted in drug discontinuance in 0.4% of patients.1, 71 Headache1, 11, 32, 71 and asthenia1, 11 each occasionally occurred in patients receiving the drug in controlled clinical trials.1, 71 Peripheral neuropathy,1, 71 pain,1, 11, 32, 71 and tinnitus1, 11, 71 each have been reported rarely.
Increases in total serum cholesterol concentrations1, 4, 7, 9, 11, 71 usually occur with ticlopidine therapy.1, 4, 7, 11, 71 Serum total cholesterol concentrations increase by 8-10% within 1 month of initiating therapy1, 4, 11, 71 and persist for the duration of treatment.1, 11, 71 Such increases were not associated with liver dysfunction or an increase in vascular ischemic events.4 Increases in serum triglyceride concentrations also may occur with ticlopidine therapy.1, 71 Ratios of lipoprotein subfractions are unchanged.1, 4, 71
Renal failure,1, 71 nephrotic syndrome,1, 71 acute interstitial nephritis,19 hyponatremia,1, 71 sepsis,1, 11, 71 arthropathy,1, 71 and myositis1, 71 each have been reported rarely in patients receiving ticlopidine.
Precautions and Contraindications
Because ticlopidine may cause life-threatening adverse effects, the potential benefit of therapy with the drug must be carefully weighed against the possible risks involved, and the patient should be apprised of the risks.1, 11, 71 Ticlopidine should be reserved for patients who are unable to tolerate or do not respond adequately to aspirin therapy where indicated to prevent stroke.1, 11, 71
Because ticlopidine may cause severe neutropenia and/or agranulocytosis, as well as other hematologic abnormalities (see Cautions: Hematologic Effects), which may be life-threatening, it is essential that complete blood counts (including platelet count) and leukocyte differentials be performed prior to initiation of therapy and every 2 weeks to the end of the third month of therapy in patients receiving the drug.1, 4, 7, 8, 10, 71 The manufacturer states that more frequent monitoring, and monitoring after the first 3 months of therapy, is necessary only in patients with clinical manifestations (e.g., suggestive of or consistent with infection) or laboratory evidence (e.g., neutrophil count less than 70% of the baseline count, decrease in hematocrit or platelet count) that suggest incipient adverse hematologic effects.1, 71 The possibility of thrombotic thrombocytopenic purpura (TTP) should be considered in any patient receiving ticlopidine who develops fever, weakness, pallor, petechiae or purpura, dark urine, jaundice, neurologic changes, and/or acute, unexplained decreases in hemoglobin or platelet count, particularly during the 3 months following initiation of therapy.1, 71 In such patients, a peripheral blood smear revealing fragmented red blood cells (schistocytes) should be considered presumptive evidence of TTP.1, 71 The possibility of aplastic anemia should be investigated in any patient receiving ticlopidine who has evidence of a simultaneous decrease in platelet and leukocyte counts.1, 71 If laboratory testing confirms neutropenia (less than 1200 cells/mm3), TTP, aplastic anemia, or thrombocytopenia (less than 80,000 platelets/mm3), ticlopidine therapy should be discontinued immediately.1, 8, 11, 71 Because some cases of immune thrombocytopenia and TTP in patients receiving ticlopidine have been fatal, careful attention to diagnosis must be made to guide treatment.1, 71 With prompt treatment (often including plasmapheresis), 70-80% of patients with TTP will survive with minimal or no sequelae.1, 71 Prompt treatment of aplastic anemia, which may include use of hematopoietic agents, can minimize the mortality associated with aplastic anemia.1, 71 When ticlopidine therapy is immediately discontinued following detection of neutropenia, neutrophil counts usually return to normal within 1-3 weeks,1, 3, 11, 71 but fatalities have been reported rarely.1, 7, 14, 71 Because of the long plasma half-life of ticlopidine, the manufacturer recommends that complete blood counts (including platelet count) and leukocyte differential should be performed for at least 2 weeks following discontinuance of ticlopidine in any patient who discontinues the drug for any reason within the first 3 months of therapy.1, 71 Ticlopidine is contraindicated in patients with preexisting hematopoietic disorders such as neutropenia and thrombocytopenia or a history of either TTP or aplastic anemia.1, 9, 10, 11, 71
In patients with coronary artery stents, particularly those with drug-eluting stents, premature discontinuance of therapy with a thienopyridine derivative (e.g., clopidogrel, ticlopidine) and aspirin has been associated with stent thrombosis with potentially fatal sequelae.70, 74, 75, 76, 77, 78, 79, 80 Before implantation of a drug-eluting stent, patients should be assessed for likelihood of compliance with prolonged dual-drug antiplatelet therapy; strong consideration should be given to avoiding use of a drug-eluting stent in patients who are not expected to comply.70, 81 In patients who are likely to require invasive or surgical procedures within 12 months after drug-eluting stent implantation, implantation of a bare-metal stent or use of balloon angioplasty with provisional stent implantation should be considered instead.70 Clinicians performing invasive procedures must understand the consequences of premature discontinuance of thienopyridine derivative therapy in patients with drug-eluting stents.70 If issues about a patient's antiplatelet therapy are unclear (e.g., concern about periprocedural bleeding), such professionals should contact the patient's cardiologist.70 Elective procedures with substantial bleeding risk should be deferred until dual-drug antiplatelet therapy has been completed.70 For nonelective procedures that mandate discontinuance of thienopyridine-derivative therapy, aspirin therapy should be continued if at all possible, and the thienopyridine derivative restarted as soon as possible after the procedure.70
Because ticlopidine increases serum total cholesterol and triglyceride concentrations (see Cautions: Metabolic Effects), these effects should be considered when the drug is used in patients in whom such effects may be clinically important.1, 4, 7, 9, 11, 71
The tolerability and safety of concomitant therapy with ticlopidine and heparin, oral anticoagulants, or fibrinolytic agents have not been established.1, 71 If a patient receiving any of these agents is to be transferred to therapy with ticlopidine, these agents should be discontinued before ticlopidine is administered.1, 71
Ticlopidine should be used with caution in patients who may be at risk for increased bleeding from trauma, surgery, or other pathologic conditions.1, 71 If elective surgery is planned for patients receiving ticlopidine and it is desired that the platelet-aggregation inhibiting effects of the drug be avoided, ticlopidine should be discontinued 10-14 days prior to surgery to minimize excessive surgical bleeding.1, 28, 33, 71 In patients with prolonged bleeding time, IV methylprednisolone (20 mg) can normalize such prolongation within 2 hours of administration.1, 10, 28 Platelet transfusions also can be considered for reversing the effects of ticlopidine on bleeding;1, 33, 71 administration of platelets should be avoided in patients who developed thrombotic thrombocytopenic purpura secondary to ticlopidine therapy, as such transfusions may accelerate thrombosis in these patients.1, 33, 71
Because ticlopidine prolongs template bleeding time, the drug should be used with caution in patients who have lesions with a propensity to bleed (e.g., peptic ulcers).1, 71 In addition, drugs that may cause such lesions should be used with caution in patients receiving ticlopidine.1, 71 Aspirin reportedly does not appear to affect ticlopidine-mediated inhibition of adenosine diphosphate (ADP)-induced platelet aggregation, although ticlopidine can potentiate aspirin-mediated inhibition of collagen-induced platelet aggregation.1, 71 While one manufacturer states that long-term concomitant use of aspirin and ticlopidine is not recommended,1 a thienopyridine derivative (i.e., clopidogrel) has been used as an adjunct to aspirin therapy for at least 12 months following PCI and intracoronary stenting.994 (See Uses: Prevention of Coronary Artery Stent Thrombosis.) Ticlopidine is contraindicated in patients with a hemostatic disorder or active pathologic bleeding (e.g., bleeding peptic ulcer, intracranial bleeding).1, 9, 10, 11, 71
Because ticlopidine therapy may result in elevations of liver function test results,1, 3, 11, 71 including serum alkaline phosphatase, transaminase, and, rarely, bilirubin concentrations,1, 11, 71 monitoring of hepatic function, including ALT (SGPT), AST (SGOT), and γ-glutamyltransferase concentrations, should be considered when hepatic dysfunction is suspected, especially during the first 4 months of therapy.1, 71
Because clinical experience with ticlopidine in patients with concurrent systemic disease is limited, the drug should be used with caution in patients with any systemic disease or condition that may alter metabolism of the drug.1, 11, 71 Dosage of drugs metabolized by hepatic microsomal enzymes with low therapeutic ratios or being administered to patients with hepatic impairment may require adjustment when initiating or discontinuing concomitant therapy with ticlopidine.1, 71 Ticlopidine should be used with caution in patients with moderate to severe renal impairment, since decreased plasma clearance, increased AUC values, and prolonged bleeding times can occur in such patients.1, 71 Reduction of ticlopidine dosage or discontinuance of the drug in patients with renal impairment may be necessary if hemorrhagic or hematopoietic complications occur.1 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.) Because ticlopidine is metabolized in the liver, dosage of ticlopidine or concomitantly administered drugs that are metabolized in the liver may require adjustment when starting or stopping therapy.1 Ticlopidine is contraindicated in patients with severe hepatic impairment, since experience in these patients is limited and they may be at risk for bleeding diathesis.1, 6, 9, 11, 71
Patients receiving ticlopidine should be informed of the necessity of routine laboratory testing (e.g., complete blood counts, leukocyte differential, platelet counts) for the assessment of hematologic status.1, 3, 9, 11, 33, 71 Patients receiving ticlopidine should be informed that neutropenia, thrombotic thrombocytopenic purpura (TTP), aplastic anemia, or thrombocytopenia can occur with the drug, especially during the first 3 months of therapy, and that severe neutropenia can result in an increased risk of infection.1, 71 They also should be advised that it is critically important to undergo the scheduled hematologic tests in order to detect neutropenia, TTP, aplastic anemia, or thrombocytopenia.1, 71 Patients should be advised regarding manifestations of infection and to contact their clinician if any indication of infection such as fever, chills, and sore throat develops or worsens during therapy with the drug.1, 11, 71 Patients should be advised to discontinue ticlopidine therapy immediately and contact their clinician if any manifestations suggestive of aplastic anemia (e.g., fever, weakness, pallor, bruising, bleeding from gums or nose, excessive fatigue) or TTP (e.g., fever, weakness, difficulty speaking, seizures, jaundice, dark or bloody urine, pallor, petechiae) occur.1, 71 Patients also should be informed of the increased risk of bleeding and prolonged time to stop bleeding with ticlopidine and that they should report any unusual bleeding to their clinician.1, 71 Patients should inform their clinicians and dentists that they are receiving ticlopidine prior to scheduling of any surgery or prescription of any new drug.1, 9, 11, 71 Patients should be advised of possible adverse effects of ticlopidine including severe or persistent diarrhea, rash, subcutaneous bleeding, or any signs of cholestasis, including yellow skin or sclera, dark urine, or light colored stools, and should be advised to report the appearance of any of these signs or symptoms immediately to their clinician.1, 8, 9, 11, 71 Patients should be instructed to take ticlopidine with food to minimize GI discomfort.1, 71
Ticlopidine is contraindicated in patients with known hypersensitivity to the drug.1, 9, 11, 71
Safety and efficacy of ticlopidine hydrochloride in children younger than 18 years of age have not been established.1, 11, 71
The manufacturer states that total plasma clearance of ticlopidine is somewhat lower and trough plasma concentrations are increased in geriatric patients.1, 11, 71 A large proportion of patients studied in controlled clinical trials of ticlopidine for stroke prevention were geriatric; 45% were older than 65 years of age and 12% were older than 75 years of age.1, 71 Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.1, 11, 71 Except for dyspepsia, adverse GI effects of ticlopidine tend to occur more frequently in geriatric patients.11
Mutagenicity and Carcinogenicity
Ticlopidine was not mutagenic in vitro in the Ames test, rat hepatocyte DNA-repair assay, and Chinese hamster fibroblast chromosomal aberration test.1, 11, 71 The drug also was not mutagenic in vivo in the mouse spermatozoid morphology test, Chinese hamster micronucleus test, and Chinese hamster bone marrow cell sister chromatid exchange test.1, 11, 71
Ticlopidine hydrochloride was not tumorigenic when administered to rats for 2 years at dosages up to 100 mg/kg daily (610 mg/m2; 14 times the recommended clinical human dosage on a mg/kg basis for a 70-kg individual and 2 times the clinical human dosage on a mg/m2 basis for an individual with a body surface area of 1.73 m2).1, 9, 11, 71 Ticlopidine hydrochloride also was not tumorigenic when administered to mice for 78 weeks at dosages up to 275 mg/kg daily (1180 mg/m2; 40 times the recommended clinical human dosage on a mg/kg basis and 4 times the clinical human dosage on a mg/m2 basis).1, 9, 11, 71
Pregnancy, Fertility, and Lactation
In reproduction studies, ticlopidine hydrochloride dosages of 400 mg/kg daily in rats, 200 mg/kg daily in mice, and 100 mg/kg daily in rabbits produced maternal toxicity as well as fetal toxicity, but there was no evidence of teratogenicity.1, 9, 11, 71 There are no adequate and controlled studies to date using ticlopidine in pregnant women, and the drug should be used during pregnancy only when clearly needed.1, 9, 11, 71
Reproduction studies in male and female rats using oral ticlopidine hydrochloride dosages up to 400 mg/kg daily have not revealed evidence of impaired fertility.1, 11, 71
Ticlopidine is distributed into milk in rats.1, 11, 71 It is not known whether ticlopidine is distributed into human milk.1, 71 Because of the potential for serious adverse reactions to ticlopidine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1, 9, 11, 71
Ticlopidine, a thienopyridine-derivative P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist structurally and pharmacologically related to clopidogrel, is a platelet-aggregation inhibitor.1, 2, 46, 52, 53, 54, 55, 71, 82 While some in vitro data suggest that ticlopidine may be a prodrug, no specific metabolite(s) responsible for pharmacologic and therapeutic activity has been identified to date.1, 2, 71
Additional Information
SumMon® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications concerning potential drug interactions and/or laboratory test interferences and for information on acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 250 mg* | Ticlopidine Hydrochloride |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2022, Selected Revisions November 13, 2015. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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