Professional Information — Ticlopidine Hydrochloride 93 154 00093 0154 01

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

Dosage and Administration

Stroke

The recommended dose of ticlopidine hydrochloride is 250 mg bid taken with food. Other doses have not been studied in controlled trials for these indications.

Coronary Artery Stenting

The recommended dose of ticlopidine hydrochloride is 250 mg bid taken with food together with antiplatelet doses of aspirin for up to 30 days of therapy following successful stent implantation.

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:

Incidence of discontinuation, regardless of relationship to therapy, is shown in parentheses.

Hematological

Neutropenia/thrombocytopenia, TTP, aplastic anemia (see and ), leukemia, agranulocytosis, eosinophilia, pancytopenia, thrombocytosis and bone-marrow depression have been reported. BOXED WARNING WARNINGS

Gastrointestinal

Ticlopidine therapy has been associated with a variety of gastrointestinal complaints including diarrhea and nausea. The majority of cases are mild, but about 13% of patients discontinued therapy because of these. They usually occur within 3 months of initiation of therapy and typically are resolved within 1 to 2 weeks without discontinuation of therapy. If the effect is severe or persistent, therapy should be discontinued. In some cases of severe or bloody diarrhea, colitis was later diagnosed.

Hemorrhagic

Ticlopidine has been associated with increased bleeding, spontaneous posttraumatic bleeding and perioperative bleeding including, but not limited to, gastrointestinal bleeding. It has also been associated with a number of bleeding complications such as ecchymosis, epistaxis, hematuria and conjunctival hemorrhage.

Intracerebral bleeding was rare in clinical trials in stroke patients with ticlopidine, with an incidence no greater than that seen with comparator agents (ticlopidine 0.5%, aspirin 0.6%, placebo 0.75%). It has also been reported postmarketing.

Rash

Ticlopidine has been associated with a maculopapular or urticarial rash (often with pruritus). Rash usually occurs within 3 months of initiation of therapy with a mean onset time of 11 days. If drug is discontinued, recovery occurs within several days. Many rashes do not recur on drug rechallenge. There have been rare reports of severe rashes, including Stevens-Johnson syndrome, erythema multiforme and exfoliative dermatitis.

Less Frequent Adverse Reactions (Probably Related)

Clinical adverse experiences occurring in 0.5% to 1.0% of stroke patients in controlled trials include:

Digestive System: GI fullness

Skin and Appendages: urticaria

Nervous System: headache

Body as a Whole: asthenia, pain

Hemostatic System: epistaxis

Special Senses: tinnitus

In addition, rarer, relatively serious and potentially fatal events associated with the use of ticlopidine have also been reported from postmarketing experience: Hemolytic anemia with reticulocytosis, immune thrombocytopenia, hepatitis, hepatocellular jaundice, cholestatic jaundice, hepatic necrosis, hepatic failure, peptic ulcer, renal failure, nephrotic syndrome, hyponatremia, vasculitis, sepsis, allergic reactions (including angioedema, allergic pneumonitis, and anaphylaxis), systemic lupus (positive ANA), peripheral neuropathy, serum sickness, arthropathy and myositis.

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:

Aspirin and other NSAIDs

Ticlopidine potentiates the effect of aspirin or other NSAIDs on platelet aggregation. The safety of concomitant use of ticlopidine and NSAIDs has not been established. The safety of concomitant use of ticlopidine and aspirin beyond 30 days has not been established (see : ). Aspirin did not modify the ticlopidine-mediated inhibition of ADP-induced platelet aggregation, but ticlopidine potentiated the effect of aspirin on collagen-induced platelet aggregation. Caution should be exercised in patients who have lesions with a propensity to bleed, such as ulcers. Long-term concomitant use of aspirin and ticlopidine is not recommended (see : ). CLINICAL TRIALS Stent Patients PRECAUTIONS GI Bleeding

Antacids

Administration of ticlopidine after antacids resulted in an 18% decrease in plasma levels of ticlopidine.

Cimetidine

Chronic administration of cimetidine reduced the clearance of a single dose of ticlopidine by 50%.

Digoxin

Coadministration of ticlopidine with digoxin resulted in a slight decrease (approximately 15%) in digoxin plasma levels. Little or no change in therapeutic efficacy of digoxin would be expected.

Theophylline

In normal volunteers, concomitant administration of ticlopidine resulted in a significant increase in the theophylline elimination half-life from 8.6 to 12.2 hours and a comparable reduction in total plasma clearance of theophylline.

Phenobarbital

In 6 normal volunteers, the inhibitory effects of ticlopidine on platelet aggregation were not altered by chronic administration of phenobarbital.

Phenytoin

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 . Several cases of elevated phenytoin plasma levels with associated somnolence and lethargy have been reported following coadministration with ticlopidine. Caution should be exercised in coadministering this drug with ticlopidine, and it may be useful to remeasure phenytoin blood concentrations. In vitro in vivo

Propranolol

studies demonstrated that ticlopidine does not alter the plasma protein binding of propranolol. However, the protein binding interactions of ticlopidine and its metabolites have not been studied . Caution should be exercised in coadministering this drug with ticlopidine. In vitro in vivo

Other Concomitant Therapy

Although specific interaction studies were not performed, in clinical studies ticlopidine was used concomitantly with beta blockers, calcium channel blockers and diuretics without evidence of clinically significant adverse interactions (see ). PRECAUTIONS

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.

Description

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: .

C H ClNS •HCl M.W. 300.25 _{14 14}

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.

Each tablet, for oral administration, contains 250 mg of ticlopidine hydrochloride. In addition, each tablet also contains the following inactive ingredients: butylated hydroxyanisole, corn starch, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, stearic acid, and titanium dioxide.

Clinical Pharmacology

Mechanism of Action

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 activity at the concentrations attained ; and, although analysis of urine and plasma indicates at least 20 metabolites, no metabolite which accounts for the activity of ticlopidine has been isolated. in vitro in vivo

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 and by inhibition of platelet aggregation after resuspension of platelets in buffered medium. ex vivo

Pharmacokinetics and Metabolism

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.

Hepatically Impaired Patients

The effect of decreased hepatic function on the pharmacokinetics of ticlopidine was studied in 17 patients with advanced cirrhosis. The average plasma concentration of ticlopidine in these subjects was slightly higher than that seen in older subjects in a separate trial (see ). CONTRAINDICATIONS

Renally Impaired Patients

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 ticlopidine (250 mg bid) for 11 days. Concentrations of unchanged ticlopidine 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.

Pharmacodynamics

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.

Clinical Studies

Stroke Patients

The effect of ticlopidine on the risk of stroke and cardiovascular events was studied in two multicenter, randomized, double-blind trials.

1. Study in Patients Experiencing Stroke Precursors

In a trial comparing ticlopidine and aspirin (The Ticlopidine Aspirin Stroke Study or TASS), 3069 patients (1987 men, 1082 women) who had experienced such stroke precursors as transient ischemic attack (TIA), transient monocular blindness (amaurosis fugax), reversible ischemic neurological deficit or minor stroke, were randomized to ticlopidine 250 mg bid or aspirin 650 mg bid. The study was designed to follow patients for at least 2 years and up to 5 years.

Over the duration of the study, ticlopidine significantly reduced the risk of fatal and nonfatal stroke by 24% (p =.011) from 18.1 to 13.8 per 100 patients followed for 5 years, compared to aspirin. During the first year, when the risk of stroke is greatest, the reduction in risk of stroke (fatal and nonfatal) compared to aspirin was 48%; the reduction was similar in men and women.

2. Study in Patients Who Had a Completed Atherothrombotic Stroke

In a trial comparing ticlopidine with placebo (The Canadian American Ticlopidine Study or CATS) 1073 patients who had experienced a previous atherothrombotic stroke were treated with ticlopidine 250 mg bid or placebo for up to 3 years.

Ticlopidine significantly reduced the overall risk of stroke by 24% (p=.017) from 24.6 to 18.6 per 100 patients followed for 3 years, compared to placebo. During the first year the reduction in risk of fatal and nonfatal stroke over placebo was 33%.

Stent Patients

The ability of ticlopidine 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.

How Supplied / Storage and Handling

NDC:68151-0079-0 in a BOTTLE of 1 TABLET, FILM COATEDS

Patient Counseling Information

Patients should be told that a decrease in the number of white blood cells (neutropenia) or platelets (thrombocytopenia) can occur with ticlopidine, 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 ticlopidine and that they should report any unusual bleeding to their physician. Patients should tell physicians and dentists that they are taking ticlopidine before any surgery is scheduled and before any new drug is prescribed.

Patients should be told to promptly report side effects of ticlopidine 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 ticlopidine with food or just after eating in order to minimize gastrointestinal discomfort.