Ticlopidine Hydrochloride (2 brand names, 1 dosage form, 1 route)
Available dosage forms: TABLET.
Routes of administration: ORAL.
Brand Names
- TICLID
- TICLOPIDINE HYDROCHLORIDE
Boxed Warning
Ticlopidine can cause life-threatening hematological adverse reactions, including neutropenia/agranulocytosis, thrombotic thrombocytopenic purpura (TTP) and aplastic anemia. Neutropenia/Agranulocytosis Among 2048 patients in clinical trials in stroke patients, there were 50 cases (2.4%) of neutropenia (less than 1200 neutrophils/mm ), and the neutrophil count was below 450/mm in 17 of these patients (0.8% of the total population). 3 3 TTP One case of thrombotic thrombocytopenic purpura was reported during clinical trials in stroke patients. Based on postmarketing data, US physicians reported about 100 cases between 1992 and 1997. Based on an estimated patient exposure of 2 million to 4 million, and assuming an event reporting rate of 10% (the true rate is not known), the incidence of ticlopidine-associated TTP may be as high as one case in every 2000 to 4000 patients exposed. Aplastic Anemia Aplastic anemia was not seen during clinical trials in stroke patients, but US physicians reported about 50 cases between 1992 and 1998. Based on an estimated patient exposure of 2 million to 4 million, and assuming an event reporting rate of 10% (the true rate is not known), the incidence of ticlopidine-associated aplastic anemia may be as high as one case in every 4000 to 8000 patients exposed. Monitoring of Clinical and Hematologic Status Severe hematological adverse reactions may occur within a few days of the start of therapy. The incidence of TTP peaks after about 3 to 4 weeks of therapy and neutropenia peaks at approximately 4 to 6 weeks. The incidence of aplastic anemia peaks after about 4 to 8 weeks of therapy. The incidence of the hematologic adverse reactions declines thereafter. Only a few cases of neutropenia, TTP, or aplastic anemia have arisen after more than 3 months of therapy. Hematological adverse reactions cannot be reliably predicted by any identified demographic or clinical characteristics. During the first 3 months of treatment, patients receiving ticlopid
Indications and Usage
Ticlopidine Hydrochloride Tablets USP are indicated: to reduce the risk of thrombotic stroke (fatal or nonfatal) in patients who have experienced stroke precursors, and in patients who have had a completed thrombotic stroke. Because ticlopidine is associated with a risk of life-threatening blood dyscrasias including thrombotic thrombocytopenic purpura (TTP), neutropenia/agranulocytosis and aplastic anemia (see and ), ticlopidine should be reserved for patients who are intolerant or allergic to aspirin therapy or who have failed aspirin therapy. BOXED WARNING WARNINGS as adjunctive therapy with aspirin to reduce the incidence of subacute stent thrombosis in patients undergoing successful coronary stent implantation (see ). CLINICAL TRIALS
Contraindications
The use of ticlopidine is contraindicated in the following conditions: Hypersensitivity to the drug Presence of hematopoietic disorders such as neutropenia and thrombocytopenia or a past history of either TTP or aplastic anemia Presence of a hemostatic disorder or active pathological bleeding (such as bleeding peptic ulcer or intracranial bleeding) Patients with severe liver impairment
Adverse Reactions
Adverse reactions in stroke patients were relatively frequent with over 50% of patients reporting at least one. Most (30% to 40%) involved the gastrointestinal tract. Most adverse effects are mild, but 21% of patients discontinued therapy because of an adverse event, principally diarrhea, rash, nausea, vomiting, GI pain and neutropenia. Most adverse effects occur early in the course of treatment, but a new onset of adverse effects can occur after several months. The incidence rates of adverse events listed in the following table were derived from multicenter, controlled clinical trials in stroke patients described above comparing ticlopidine, placebo and aspirin over study periods of up to 5.8 years. Adverse events considered by the investigator to be probably drug-related that occurred in at least 1% of patients treated with ticlopidine are shown in the following table: Percent of Patients with Adverse Events in Controlled Studies (TASS and CATS) Event Ticlopidine (n = 2048) Incidence Aspirin (n = 1527) Incidence Placebo (n = 536) Incidence Any Events 60.0 (20.9) 53.2 (14.5) 34.3 (6.1) Diarrhea 12.5 (6.3) 5.2 (1.8) 4.5 (1.7) Nausea 7.0 (2.6) 6.2 (1.9) 1.7 (0.9) Dyspepsia 7.0 (1.1) 9.0 (2.0) 0.9 (0.2) Rash 5.1 (3.4) 1.5 (0.8) 0.6 (0.9) GI Pain 3.7 (1.9) 5.6 (2.7) 1.3 (0.4) Neutropenia 2.4 (1.3) 0.8 (0.1) 1.1 (0.4) Purpura 2.2 (0.2) 1.6 (0.1) 0.0 (0.0) Vomiting 1.9 (1.4) 1.4 (0.9) 0.9 (0.4) Flatulence 1.5 (0.1) 1.4 (0.3) 0.0 (0.0) Pruritus 1.3 (0.8) 0.3 (0.1) 0.0 (0.0) Dizziness 1.1 (0.4) 0.5 (0.4) 0.0 (0.0) Anorexia 1.0 (0.4) 0.5 (0.3) 0.0 (0.0) Abnormal Liver Function Test 1.0 (0.7) 0.3 (0.3) 0.0 (0.0) Incidence of discontinuation, regardless of relationship to therapy, is shown in parentheses.
Drug Interactions
Therapeutic doses of ticlopidine caused a 30% increase in the plasma half-life of antipyrine and may cause analogous effects on similarly metabolized drugs. Therefore, the dose of drugs metabolized by hepatic microsomal enzymes with low therapeutic ratios or being given to patients with hepatic impairment may require adjustment to maintain optimal therapeutic blood levels when starting or stopping concomitant therapy with ticlopidine. Studies of specific drug interactions yielded the following results:
Overdosage
One case of deliberate overdosage with ticlopidine has been reported by a foreign postmarketing surveillance program. A 38-year-old male took a single 6000-mg dose of ticlopidine hydrochloride (equivalent to 24 standard 250-mg tablets). The only abnormalities reported were increased bleeding time and increased SGPT. No special therapy was instituted and the patient recovered without sequelae. Single oral doses of ticlopidine at 1600 mg/kg and 500 mg/kg were lethal to rats and mice, respectively. Symptoms of acute toxicity were GI hemorrhage, convulsions, hypothermia, dyspnea, loss of equilibrium and abnormal gait.