Ticlid

Generic Name: Ticlopidine Hydrochloride
Class: Platelet-Aggregation Inhibitors
Chemical Name: 5-[(2-Chlorophenyl)methyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride
Molecular Formula: C14H14ClNS•ClH
CAS Number: 53885-35-1

Warning(s)

  • Possible life-threatening adverse hematologic effects (e.g., neutropenia1 3 4 7 8 9 10 11 14 71 and/or agranulocytosis,1 7 9 10 20 71 thrombotic thrombocytopenic purpura [TTP],1 7 11 23 30 32 71 aplastic anemia1 7 16 17 20 22 24 25 26 27 71 ).

  • Neutropenia occurred in 2.4% of stroke patients in clinical trials;1 71 TTP and aplastic anemia reported rarely.1 71

  • Incidence of neutropenia, TTP, or aplastic anemia peaks about 4–6, 3–4, or 4–8 weeks, respectively, following initiation of therapy and declines thereafter.1 71 Adverse hematologic effects occur infrequently >3 months after initiation of therapy.1 71

  • Risk factors for development of adverse hematologic effects not identified.1 71

  • Careful clinical and hematologic monitoring required, especially during the first 3 months of therapy.1 4 11 71 Discontinue therapy immediately if adverse hematologic effects occur.1 71 (See Hematologic Toxicity under Cautions.)

Introduction

Platelet-aggregation inhibitor;1 2 thienopyridine derivative.1 2 52 71

Uses for Ticlid

Prevention of Thrombotic Stroke

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., TIA, transient monocular or partial blindness [amaurosis fugax], reversible ischemic neurologic deficit, minor stroke).1 2 71 72 73

Because of potentially life-threatening adverse effects (see Boxed Warning), reserve for patients who are unable to tolerate or have hypersensitivity to aspirin or those who have failed to respond to aspirin therapy where indicated to prevent stroke.1 71 72 73

Slideshow: HealthQuiz: Basics About Stroke Signs and Symptoms

The American College of Chest Physicians (ACCP) states that use of ticlopidine for secondary prevention of stroke has become severely limited because of the risk of serious adverse effects and the availability of safer antiplatelet agents.1009

Prevention of Coronary Artery Stent Thrombosis

Used as an adjunct to aspirin therapy to reduce the incidence of subacute stent thrombosis after PCI with successful coronary artery stent placement.1 46 71

ACCP and other experts currently recommend dual-drug antiplatelet therapy with a P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist (e.g., clopidogrel) and aspirin in patients undergoing PCI with stent placement.994 1010 Use of ticlopidine for this indication largely has been replaced by clopidogrel.1010

Acute Coronary Syndromes

Has been used as an alternative to aspirin in patients with unstable angina or non-ST-segment-elevation MI 991 (i.e., non-ST-segment-elevation acute coronary syndrome) when aspirin therapy has failed, cannot be tolerated, or is contraindicated; however, clopidogrel generally is preferred in these situations.37 991

May be used as an alternative to aspirin therapy in patients with ST-segment-elevation MI (i.e., ST-segment elevation acute coronary syndrome) who have true aspirin allergy (hives, nasal polyps, bronchospasm, or anaphylaxis); however, clopidogrel generally is preferred in such patients.57

Ticlid Dosage and Administration

General

Prevention of Coronary Artery Stent Thrombosis

  • Initiate therapy after successful stent implantation.1 46 71

Administration

Oral Administration

Administer orally with food to maximize GI absorption and tolerance.1 2 71

Dosage

Available as ticlopidine hydrochloride; dosage expressed in terms of the salt.1 71

Adults

Prevention of Thrombotic Stroke
Oral

250 mg twice daily.1 71 Has been continued for at least up to 5.8 years in some patients.1 2 71

Prevention of Coronary Artery Stent Thrombosis
Oral

Manufacturer recommends 250 mg twice daily, beginning after stent implantation and continuing for up to 30 days in conjunction with antiplatelet dosages of aspirin.1 46 71

If ticlopidine is used in combination with aspirin following drug-eluting stent (DES) implantation, combined therapy with ticlopidine and aspirin must be continued for ≥12 months to minimize the risk of potentially catastrophic stent thrombosis.70 (See Compliance with Therapy in Patients with Drug-eluting Stents under Cautions.)

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time;1 71 contraindicated in patients with severe hepatic impairment.1 71 (See Hepatic Impairment under Cautions.)

Renal Impairment

Reduce dosage or discontinue therapy if hemorrhagic or hematopoietic complications occur.1 71

Geriatric Patients

No specific dosage recommendations at this time.1 71

Cautions for Ticlid

Contraindications

  • Known hypersensitivity to ticlopidine.1 9 11 71

  • Preexisting hematopoietic disorders (e.g., neutropenia, thrombocytopenia, history of TTP or aplastic anemia).1 9 10 11 71 (See Hematologic Toxicity under Cautions.)

  • Hemostatic disorders or active pathologic bleeding (e.g., bleeding peptic ulcer, intracranial bleeding).1 9 10 11 71 (See Conditions Predisposing to Bleeding under Cautions.)

  • Severe hepatic impairment.1 6 9 11 71

Warnings/Precautions

Warnings

Concomitant Anticoagulant Therapy

Tolerance and long-term safety of concomitant heparin, oral anticoagulants, or fibrinolytic agents not established; manufacturer recommends discontinuing anticoagulants and fibrinolytic drugs prior to initiating ticlopidine.1 71

Metabolic Effects

Possible increased total serum cholesterol concentrations without changes in lipoprotein subfractions;1 4 7 9 11 71 not associated with liver dysfunction or an increase in vascular ischemic events.4 Also, possible increases in triglyceride concentrations.1 71

Major Toxicities

Possible life-threatening adverse effects; carefully weigh potential benefit of therapy against possible risks involved.1 11 71 All adverse hematologic effects potentially fatal.1 71 Reserve therapy for patients who are unable to tolerate or do not respond adequately to aspirin therapy where indicated to prevent stroke.1 11 71

Hematologic Toxicity

Possible life-threatening adverse hematologic effects including neutropenia (ANC <1200/mm3)1 3 4 7 8 9 10 11 14 71 and/or agranulocytosis,1 7 9 10 20 71 thrombocytopenia (platelet count <80,000/mm3),1 7 10 11 14 71 TTP (i.e., fever, weakness, pallor, petechiae or purpura, dark urine, jaundice, neurologic changes, and/or acute, unexplained decreases in hemoglobin or platelet count),1 7 11 23 30 32 71 and aplastic anemia (i.e., anemia, thrombocytopenia, and neutropenia together with evidence of depression of myeloid precursors on bone marrow examination).1 7 16 17 20 22 24 25 26 27 71

Pancytopenia or leukemia, sometimes fatal, reported rarely during postmarketing experience.1 71

Perform CBCs (including platelet count) and leukocyte differentials prior to initiation of therapy and every 2 weeks to the end of the third month of therapy;1 4 7 8 10 71 continue monitoring for at least two weeks following discontinuance of ticlopidine within the first 3 months of therapy.1 71 Monitor more frequently or continue monitoring after the first 3 months of therapy if clinical manifestations (e.g., suggestive of or consistent with infection) or laboratory evidence (e.g., neutrophil count <70% of baseline count, decrease in hematocrit or platelet count) suggest incipient adverse hematologic effects.1 71 Discontinue therapy immediately if laboratory testing confirms neutropenia (<1200/mm3), TTP, aplastic anemia, or thrombocytopenia (platelet count <80,000/mm3).1 8 11 71 Initiate prompt treatment for TTP (e.g., plasmapheresis) and aplastic anemia (i.e., hematopoietic agents).1 71

Use 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

Compliance with Therapy in Patients with Drug-eluting Stents

Stent thrombosis with potentially fatal sequelae, particularly with DES, associated with premature discontinuance of therapy with a thienopyridine derivative and aspirin.70 74 75 76 77 78 79 80

Before implantation of a DES, carefully assess patients for likelihood of compliance with prolonged dual-drug antiplatelet therapy.70 81 Consider avoiding use of a DES in patients who are not expected to comply.70 81 (See Advice to Patients.) In patients who are likely to require invasive or surgical procedures ≤12 months after DES implantation, consider implantation of a bare-metal stent or use of balloon angioplasty with provisional stent implantation instead.70

Clinicians performing invasive procedures must understand the consequences of premature discontinuance of thienopyridine derivative therapy in patients with DES.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 Defer elective procedures with substantial bleeding risk until completion of dual-drug antiplatelet therapy.70 For non-elective procedures that mandate discontinuance of thienopyridine-derivative therapy, continue aspirin therapy if at all possible.70 Restart thienopyridine therapy as soon as possible after the procedure.70

General Precautions

Trauma, Surgery, or Other Pathologic Conditions

Use with caution in patients at risk for increased bleeding from trauma, surgery, or other pathologic conditions.1 71 Discontinue therapy 10–14 days prior to elective surgery to minimize excessive surgical bleeding.1 28 33 71 Administer IV methylprednisolone (20 mg) to normalize prolonged bleeding time1 10 28 71 or platelet transfusions to reverse effect on bleeding.1 33 71 Avoid administering platelets in patients who have had TTP secondary to ticlopidine therapy; such transfusions may accelerate thrombosis.1 33 71

Conditions Predisposing to Bleeding

Possible prolonged template bleeding time; use with caution in patients who have lesions (e.g., peptic ulcers) with a propensity to bleed.1 71 Also, use with caution in patients receiving drugs that may predispose to development of such lesions.1 71

Hepatic Effects

Possible elevations in liver function test results1 3 11 71 (e.g., serum alkaline phosphatase,1 11 18 71 transaminases, and, rarely, bilirubin concentrations);1 11 71 monitoring of hepatic function (e.g., ALT, AST, γ-glutamyltransferase concentrations) recommended when hepatic dysfunction is suspected, especially during the first 4 months of therapy.1 71

Conditions Altering Ticlopidine Metabolism

Use with caution in patients with any systemic disease or condition that may alter metabolism of the drug.1 11 71

Specific Populations

Pregnancy

Category B.1 71

Lactation

Not known whether ticlopidine is distributed into milk;1 71 distributed into milk in rats.1 11 71 Discontinue nursing or the drug.1 9 11 71

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 11 71

Geriatric Use

Safety and efficacy appear to be similar to that in younger adults in clinical trials;1 2 71 however, increased sensitivity to ticlopidine cannot be ruled out.1 71 Decreased clearance and increased trough plasma concentrations; also, possible increased frequency of adverse GI effects.1 11 71

Hepatic Impairment

Possible increased plasma ticlopidine concentrations.1 71 Possible risk for bleeding diathesis.1 6 9 11 71 Use contraindicated in patients with severe hepatic impairment.1 71 (See Contraindications under Cautions and see Special Populations under Pharmacokinetics.)

Renal Impairment

Possible decreased plasma clearance, increased AUC values, and prolonged bleeding times; use with caution in patients with moderate to severe renal impairment.1 71 Reduce dosage or discontinue therapy if hemorrhagic or hematopoietic complications occur.1 71 Unexpected adverse effects not observed in patients with mild renal impairment; no experience in patients with more severe degrees of impairment.1 71

Common Adverse Effects

Diarrhea,1 4 11 71 nausea,1 4 11 71 dyspepsia,1 4 11 71 rash,1 4 11 71 GI pain,1 4 11 71 neutropenia,1 71 purpura,1 71 vomiting,1 71 flatulence,1 71 pruritus,1 dizziness,1 anorexia,1 71 abnormal liver function test.1 71

Interactions for Ticlid

Drugs Metabolized by Hepatic Microsomal Enzymes

Possible increased plasma half-life of concomitantly administered drugs metabolized by hepatic microsomal enzymes; dosage adjustments may be required when initiating or discontinuing ticlopidine therapy.1 71

Specific Drugs

Drug

Interaction

Comments

Antacids

Decreased plasma ticlopidine concentrations1 71

Anticoagulants

Additive effects1 71

Manufacturer recommends discontinuing anticoagulant therapy prior to initiating ticlopidine1 71

Aspirin, other NSAIAs

Additive effect on platelet aggregation1 71

Use with caution in patients who have lesions with a propensity to bleed (e.g., peptic ulcers)1 71 (see Conditions Predisposing to Bleeding under Cautions)

Safety of concomitant use of ticlopidine and aspirin beyond 30 days not established;1 46 71 long-term concomitant use not recommended1

Digoxin

Slight decrease in plasma digoxin concentrations1 71

Little or no change in digoxin efficacy expected1 71

Phenobarbital

No inhibition of platelet aggregation effects of ticlopidine1 71

Phenytoin

Increased plasma phenytoin concentrations with associated somnolence and lethargy reported1 71

Cautious use recommended; monitor plasma phenytoin concentrations1 71

Propranolol

Potential for altered protein binding of propranolol1 71

Cautious use recommended1 71

Theophylline

Decreased elimination half-life and total plasma clearance of theophylline1 71

Thrombolytic agents

Additive effects1 71

Manufacturer recommends discontinuing of thrombolytic agents prior to initiating ticlopidine1 71

Ticlid Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed (>80%) following oral administration.1 Peak plasma concentrations at 2 hours.1 71

Food

Increases bioavailability by 20%.1 71

Distribution

Plasma Protein Binding

Binds reversibly (98%), mainly to serum albumin and lipoproteins.1 71

Elimination

Metabolism

Extensively metabolized by the liver.1 71

Elimination Route

Excreted in urine (60%) and feces (23%).1 71

Special Populations

Increased plasma concentrations in patients with advanced cirrhosis.1 71 Decreased plasma clearance in patients with mild to moderate renal impairment.1 71

Stability

Storage

Oral

Tablets

15–30°C1 or 20–25°C.71

Actions

  • Structurally and pharmacologically related to clopidogrel.1 2 52 71

  • Time- and dose-dependent inhibition of platelet aggregation and release of platelet granule constituents; also prolongs bleeding time.1 71

  • Inhibits ADP-induced platelet-fibrinogen binding and subsequent platelet-platelet interactions.1 71

  • Platelet effects irreversible for the life of the platelet.1 71

Advice to Patients

  • Importance of routine laboratory monitoring (e.g., CBCs, leukocyte differential, platelet counts).1 3 9 11 33 71

  • Importance of informing patients of potential adverse effects and toxicities.1 71 Importance of immediately informing clinician of signs or symptoms of these adverse effects.1 8 9 11 71

  • Importance of immediately discontinuing therapy and contacting 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

  • Before implantation of drug-eluting stent (DES), determine likelihood of patient compliance with ≥12 months of aspirin–ticlopidine combination therapy.70

  • Importance of informing patients prior to hospital discharge about risks associated with premature discontinuance of such combination therapy.70 Importance of informing patient not to discontinue therapy without consulting their prescribing clinician, even if instructed to do so by another health-care professional (e.g., dentist).70

  • Importance of patients informing clinicians and dentists that they are receiving ticlopidine prior to scheduling of any surgery or prescription of any new drug.1 9 11 71

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 71

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 71

  • Importance of informing patients of other important precautionary information. (See Cautions.)1 3 9 11 33 71

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ticlopidine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

250 mg*

Ticlopidine Hydrochloride Tablets

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Ticlopidine HCl 250MG Tablets (TEVA PHARMACEUTICALS USA): 100/$197.09 or 300/$558.40

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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