Ticlid Information
Ticlid (Ticlopidine hcl) Warning:
Ticlid (Ticlopidine hcl) can cause life-threatening hematological adverse reactions, including neutropenia/agranulocytosis, thrombotic thrombocytopenic purpura (TTP) and aplastic anemia.
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).
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 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.
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 Ticlid (Ticlopidine hcl) must, therefore, be hematologically and clinically monitored for evidence of neutropenia or TTP. If any such evidence is seen, Ticlid (Ticlopidine hcl) should be immediately discontinued.
The detection and treatment of ticlopidine-associated hematological adverse reactions are further described under WARNINGS.
Ticlid (Ticlopidine hcl) Description:
Ticlid (Ticlopidine hcl) (ticlopidine hydrochloride) is a platelet aggregation inhibitor. Chemically it is 5-[(2-chlorophenyl)methyl]-4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride. The structural formula is:
Ticlopidine hydrochloride is a white crystalline solid. It is freely soluble in water and self-buffers to a pH of 3.6. It also dissolves freely in methanol, is sparingly soluble in methylene chloride and ethanol, slightly soluble in acetone and insoluble in a buffer solution of pH 6.3. It has a molecular weight of 300.25.
Ticlid (Ticlopidine hcl) tablets for oral administration are provided as white, oval, film-coated, blue-imprinted tablets containing 250 mg of ticlopidine hydrochloride. Each tablet also contains citric acid, magnesium stearate, microcrystalline cellulose, povidone, starch and stearic acid as inactive ingredients. The white film-coating contains hydroxypropylmethyl cellulose, polyethylene glycol and titanium dioxide. Each tablet is printed with blue ink, which includes FD&C Blue #1 aluminum lake as the colorant. The tablets are identified with Ticlid (Ticlopidine hcl) on one side and 250 on the reverse side.
Ticlid (Ticlopidine hcl) Clinical Pharmacology:
When taken orally, ticlopidine hydrochloride causes a time- and dose-dependent inhibition of both platelet aggregation and release of platelet granule constituents, as well as a prolongation of bleeding time. The intact drug has no significant in vitro activity at the concentrations attained in vivo; and, although analysis of urine and plasma indicates at least 20 metabolites, no metabolite which accounts for the activity of ticlopidine has been isolated.
Ticlopidine hydrochloride, after oral ingestion, interferes with platelet membrane function by inhibiting ADP-induced platelet-fibrinogen binding and subsequent platelet-platelet interactions. The effect on platelet function is irreversible for the life of the platelet, as shown both by persistent inhibition of fibrinogen binding after washing platelets ex vivo and by inhibition of platelet aggregation after resuspension of platelets in buffered medium.
After oral administration of a single 250-mg dose, ticlopidine hydrochloride is rapidly absorbed with peak plasma levels occurring at approximately 2 hours after dosing and is extensively metabolized. Absorption is greater than 80%. Administration after meals results in a 20% increase in the AUC of ticlopidine.
Ticlopidine hydrochloride displays nonlinear pharmacokinetics and clearance decreases markedly on repeated dosing. In older volunteers the apparent half-life of ticlopidine after a single 250-mg dose is about 12.6 hours; with repeat dosing at 250 mg bid, the terminal elimination half-life rises to 4 to 5 days and steady-state levels of ticlopidine hydrochloride in plasma are obtained after approximately 14 to 21 days.
Ticlopidine hydrochloride binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein. At concentrations attained with the recommended dose, only 15% or less ticlopidine in plasma is bound to this protein.
Ticlopidine hydrochloride is metabolized extensively by the liver; only trace amounts of intact drug are detected in the urine. Following an oral dose of radioactive ticlopidine hydrochloride administered in solution, 60% of the radioactivity is recovered in the urine and 23% in the feces. Approximately 1/3 of the dose excreted in the feces is intact ticlopidine hydrochloride, possibly excreted in the bile. Ticlopidine hydrochloride is a minor component in plasma (5%) after a single dose, but at steady-state is the major component (15%). Approximately 40% to 50% of the radioactive metabolites circulating in plasma are covalently bound to plasma proteins, probably by acylation.
Clearance of ticlopidine decreases with age. Steady-state trough values in elderly patients (mean age 70 years) are about twice those in younger volunteer populations.
Patients with mildly (Ccr 50 to 80 mL/min) or moderately (Ccr 20 to 50 mL/min) impaired renal function were compared to normal subjects (Ccr 80 to 150 mL/min) in a study of the pharmacokinetic and platelet pharmacodynamic effects of Ticlid (Ticlopidine hcl) (250 mg bid) for 11 days. Concentrations of unchanged Ticlid (Ticlopidine hcl) were measured after a single 250-mg dose and after the final 250-mg dose on Day 11.
AUC values of ticlopidine increased by 28% and 60% in mild and moderately impaired patients, respectively, and plasma clearance decreased by 37% and 52%, respectively, but there were no statistically significant differences in ADP-induced platelet aggregation. In this small study (26 patients), bleeding times showed significant prolongation only in the moderately impaired patients.
In healthy volunteers over the age of 50, substantial inhibition (over 50%) of ADP-induced platelet aggregation is detected within 4 days after administration of ticlopidine hydrochloride 250 mg bid, and maximum platelet aggregation inhibition (60% to 70%) is achieved after 8 to 11 days. Lower doses cause less, and more delayed, platelet aggregation inhibition, while doses above 250 mg bid give little additional effect on platelet aggregation but an increased rate of adverse effects. The dose of 250 mg bid is the only dose that has been evaluated in controlled clinical trials.
After discontinuation of ticlopidine hydrochloride, bleeding time and other platelet function tests return to normal within 2 weeks, in the majority of patients.
At the recommended therapeutic dose (250 mg bid), ticlopidine hydrochloride has no known significant pharmacological actions in man other than inhibition of platelet function and prolongation of the bleeding time.
Ticlid (Ticlopidine hcl) Clinical Trials:
The ability of Ticlid (Ticlopidine hcl) to reduce the rate of thrombotic events after the placement of coronary artery stents has been studied in five randomized trials, one of substantial size (Stent Anticoagulation Restenosis Study or STARS) described below, and four smaller studies. In these trials, ticlopidine 250 mg bid with ASA (dose range from 100 mg bid to 325 mg qd) was compared to aspirin alone or to anticoagulant therapy plus aspirin. The trials enrolled patients undergoing both planned (elective) and unplanned coronary stent placement. The types of stents used, the use of intravascular ultrasound, and the use of high-pressure stent deployment varied among the trials, although all patients in STARS received a Palmaz-Schatz stent. The primary efficacy endpoints of the trials were similar, and included death, myocardial infarction and the need for repeat coronary angioplasty or CABG. All trials followed patients for at least 30 days.
In STARS, patients were randomized to receive one of three regimens for 4 weeks: aspirin alone, aspirin plus coumadin, or aspirin plus ticlopidine. Therapy was initiated following successful coronary stent placement. The primary endpoint was the incidence of stent thrombosis, defined as death, Q-Wave MI, or angiographic thrombus within the stented vessel demonstrated at the time of documented ischemia requiring emergent revascularization. The incidence rates for the primary endpoint and its components at 30 days are shown in the table below.
The use of ticlopidine plus aspirin did not affect the rate of non-Q-wave MIs when compared with aspirin alone or aspirin plus anticoagulants in STARS.
The use of ticlopidine plus aspirin was associated with a lower rate of recurrent cardiovascular events when compared with aspirin alone or aspirin plus anticoagulants in the other four randomized trials.
The rate of serious bleeding complications and neutropenia in STARS are shown in the table below. There were no cases of thrombotic thrombocytopenic purpura (TTP) or aplastic anemia reported in 1346 patients who received ticlopidine plus aspirin in the five randomized trials.
Ticlid (Ticlopidine hcl) Indications And Usage:
Ticlid (Ticlopidine hcl) is indicated:
Ticlid (Ticlopidine hcl) Contraindications:
The use of Ticlid (Ticlopidine hcl) is contraindicated in the following conditions:
Ticlid (Ticlopidine hcl) Precautions:
Ticlid (Ticlopidine hcl) should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or pathological conditions. If it is desired to eliminate the antiplatelet effects of Ticlid (Ticlopidine hcl) prior to elective surgery, the drug should be discontinued 10 to 14 days prior to surgery. Several controlled clinical studies have found increased surgical blood loss in patients undergoing surgery during treatment with ticlopidine. In TASS and CATS it was recommended that patients have ticlopidine discontinued prior to elective surgery. Several hundred patients underwent surgery during the trials, and no excessive surgical bleeding was reported.
Prolonged bleeding time is normalized within 2 hours after administration of 20 mg methylprednisolone IV. Platelet transfusions may also be used to reverse the effect of Ticlid (Ticlopidine hcl) on bleeding. Because platelet transfusions may accelerate thrombosis in patients with TTP on ticlopidine, they should, if possible, be avoided.
Patients should be told that a decrease in the number of white blood cells (neutropenia) or platelets (thrombocytopenia) can occur with Ticlid (Ticlopidine hcl) , especially during the first 3 months of treatment and that neutropenia, if it is severe, can result in an increased risk of infection. They should be told it is critically important to obtain the scheduled blood tests to detect neutropenia or thrombocytopenia. Patients should also be reminded to contact their physicians if they experience any indication of infection such as fever, chills, or sore throat, any of which might be a consequence of neutropenia. Thrombocytopenia may be part of a syndrome called TTP. Symptoms and signs of TTP, such as fever, weakness, difficulty speaking, seizures, yellowing of skin or eyes, dark or bloody urine, pallor or petechiae (pinpoint hemorrhagic spots on the skin), should be reported immediately.
All patients should be told that it may take them longer than usual to stop bleeding when they take Ticlid (Ticlopidine hcl) and that they should report any unusual bleeding to their physician. Patients should tell physicians and dentists that they are taking Ticlid (Ticlopidine hcl) before any surgery is scheduled and before any new drug is prescribed.
Patients should be told to promptly report side effects of Ticlid (Ticlopidine hcl) such as severe or persistent diarrhea, skin rashes or subcutaneous bleeding or any signs of cholestasis, such as yellow skin or sclera, dark urine, or light-colored stools.
Patients should be told to take Ticlid (Ticlopidine hcl) with food or just after eating in order to minimize gastrointestinal discomfort.
In a 2-year oral carcinogenicity study in rats, ticlopidine at daily doses of up to 100 mg/kg (610 mg/m) was not tumorigenic. For a 70-kg person (1.73 m body surface area) the dose represents 14 times the recommended clinical dose on a mg/kg basis and two times the clinical dose on body surface area basis. In a 78-week oral carcinogenicity study in mice, ticlopidine at daily doses up to 275 mg/kg (1180 mg/m) was not tumorigenic. The dose represents 40 times the recommended clinical dose on a mg/kg basis and four times the clinical dose on body surface area basis.
Ticlopidine was not mutagenic in vitro in the Ames test, the rat hepatocyte DNA-repair assay, or the Chinese-hamster fibroblast chromosomal aberration test; or in vivo in the mouse spermatozoid morphology test, the Chinese-hamster micronucleus test, or the Chinese-hamster bone-marrow-cell sister-chromatid exchange test. Ticlopidine was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg/day.
Ticlid (Ticlopidine hcl) 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 Ticlid (Ticlopidine hcl) , 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 Ticlid (Ticlopidine hcl) are shown in the following table:
Incidence of discontinuation, regardless of relationship to therapy, is shown in parentheses.
Ticlid (Ticlopidine hcl) Overdosage:
One case of deliberate overdosage with Ticlid (Ticlopidine hcl) has been reported by a foreign postmarketing surveillance program. A 38-year-old male took a single 6000-mg dose of Ticlid (Ticlopidine hcl) (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.
Ticlid (Ticlopidine hcl) How Supplied:
Ticlid (Ticlopidine hcl) is available in white, oval, film-coated 250-mg tablets, printed in blue with Ticlid (Ticlopidine hcl) on one side and 250 on the other. They are provided in unit of use bottles of 30 tablets (NDC 0004-0018-23) and 60 tablets (NDC 0004-0018-22) and 500 tablets (NDC 0004-0018-14).
Store at 15° to 30°C (59° to 86°F).
Ticlid (Ticlopidine hcl)
