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Pronunciation:

(tye KLOE pi deen)

U.S. Brand Names:

Ticlid®

Synonyms:

Ticlopidine Hydrochloride

Generic Available:

Yes

Canadian Brand Names:

Alti-Ticlopidine; Apo-Ticlopidine®; Gen-Ticlopidine; Novo-Ticlopidine; Nu-Ticlopidine; PMS-Ticlopidine; Rhoxal-ticlopidine; Ticlid®

Use:

Platelet aggregation inhibitor that reduces the risk of thrombotic stroke in patients who have had a stroke or stroke precursors. Note: Due to its association with life-threatening hematologic disorders, ticlopidine should be reserved for patients who are intolerant to aspirin, or who have failed aspirin therapy. Adjunctive therapy (with aspirin) following successful coronary stent implantation to reduce the incidence of subacute stent thrombosis.

Use - Unlabeled/Investigational:

Protection of aortocoronary bypass grafts, diabetic microangiopathy, ischemic heart disease, prevention of postoperative DVT, reduction of graft loss following renal transplant

Pregnancy Risk Factor:

Lactation:

Excretion in breast milk unknown

Contraindications:

Hypersensitivity to ticlopidine or any component of the formulation; active pathological bleeding such as PUD or intracranial hemorrhage; severe liver dysfunction; hematopoietic disorders (neutropenia, thrombocytopenia, a past history of TTP)

Warnings/Precautions:

Use with caution in patients who may have an increased risk of bleeding (such as, ulcers). Consider discontinuing 10-14 days before elective surgery. Use caution in mixing with other antiplatelet drugs. Use with caution in patients with severe liver disease or severe renal impairment (experience is limited). May cause life-threatening hematologic reactions, including neutropenia, agranulocytosis, thrombotic thrombocytopenia purpura (TTP), and aplastic anemia. Routine monitoring is required (see Monitoring Parameters). Monitor for signs and symptoms of neutropenia including WBC count. Discontinue if the absolute neutrophil count falls to <1200/mm³ or if the platelet count falls to <80,000/mm³.

Adverse Reactions:

As with all drugs which may affect hemostasis, bleeding is associated with ticlopidine. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the use of multiple agents which alter hemostasis and patient susceptibility.

>10%:

Endocrine & metabolic: Increased total cholesterol (increases of ~8% to 10% within 1 month of therapy)

Gastrointestinal: Diarrhea (13%)

1% to 10%:

Central nervous system: Dizziness (1%)

Dermatologic: Rash (5%), purpura (2%), pruritus (1%)

Gastrointestinal: Nausea (7%), dyspepsia (7%), gastrointestinal pain (4%), vomiting (2%), flatulence (2%), anorexia (1%)

Hematologic: Neutropenia (2%)

Hepatic: Abnormal liver function test (1%)

<1% (Limited to important or life-threatening): Thrombotic thrombocytopenic purpura (TTP), thrombocytopenia (immune), agranulocytosis, eosinophilia, pancytopenia, thrombocytosis, anaphylaxis, bone marrow suppression, gastrointestinal bleeding, ecchymosis, epistaxis, hematuria, menorrhagia, conjunctival bleeding, intracranial bleeding (rare), urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, erythema multiforme, maculopapular rash, erythema nodosum, headache, weakness, pain, tinnitus, hemolytic anemia, aplastic anemia, hepatitis, jaundice, hepatic necrosis, peptic ulcer, renal failure, nephrotic syndrome, hyponatremia, vasculitis, sepsis, pneumonitis (allergic), angioedema, positive ANA, systemic lupus erythematosus, peripheral neuropathy, serum sickness, arthropathy, myositis

Postmarketing and/or case reports: Chronic diarrhea, increase in serum creatinine, bronchiolitis obliterans-organized pneumonia

Overdosage/Toxicology:

Symptoms of overdose include ataxia, seizures, vomiting, abdominal pain, and hematologic abnormalities. Specific treatments are lacking. Treatment is symptomatic and supportive.

Drug Interactions:

Substrate of CYP3A4 (major); Inhibits CYP1A2 (weak), 2C8/9 (weak), 2C19 (strong), 2D6 (moderate), 2E1 (weak), 3A4 (weak)

Antacids reduce absorption of ticlopidine (~18%).

Anticoagulants or other antiplatelet agents may increase the risk of bleeding; use with caution.

Carbamazepine blood levels may be increased by ticlopidine.

Cimetidine increases ticlopidine levels.

Cyclosporine blood levels may be reduced by ticlopidine.

CYP2C19 substrates: Ticlopidine may increase the levels/effects of CYP2C19 substrates. Example substrates include citalopram, diazepam, methsuximide, phenytoin, propranolol, and sertraline.

CYP2D6 substrates: Ticlopidine may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Ticlopidine may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of ticlopidine. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

Digoxin blood levels may be decreased by ticlopidine.

Phenytoin blood levels may be increased by ticlopidine (case reports).

Theophylline blood levels may be increased by ticlopidine.

Ethanol/Nutrition/Herb Interactions:

Food: Ticlopidine bioavailability may be increased (20%) if taken with food. High-fat meals increase absorption, antacids decrease absorption.

Herb/Nutraceutical: Avoid cat's claw, dong quai, evening primrose, feverfew, garlic, ginkgo, ginger, red clover, horse chestnut, green tea, ginseng (all have additional antiplatelet activity).

Mechanism of Action:

Ticlopidine is an inhibitor of platelet function with a mechanism which is different from other antiplatelet drugs. The drug significantly increases bleeding time. This effect may not be solely related to ticlopidine's effect on platelets. The prolongation of the bleeding time caused by ticlopidine is further increased by the addition of aspirin in ex vivo experiments. Although many metabolites of ticlopidine have been found, none have been shown to account for in vivo activity.

Pharmacodynamics/Kinetics:

Onset of action: ~6 hours

Peak effect: 3-5 days; serum levels do not correlate with clinical antiplatelet activity

Metabolism: Extensively hepatic; has at least one active metabolite

Half-life elimination: 24 hours

Dosage:

Oral: Adults:

Stroke prevention: 250 mg twice daily with food

Coronary artery stenting (initiate after successful implantation): 250 mg twice daily with food (in combination with antiplatelet doses of aspirin) for up to 30 days

Administration:

Oral: Administer with food.

Monitoring Parameters:

Signs of bleeding; CBC with differential every 2 weeks starting the second week through the third month of treatment; more frequent monitoring is recommended for patients whose absolute neutrophil counts have been consistently declining or are 30% less than baseline values. The peak incidence of TTP occurs between 3-4 weeks, the peak incidence of neutropenia occurs at approximately 4-6 weeks, and the incidence of aplastic anemia peaks after 4-8 weeks of therapy. Few cases have been reported after 3 months of treatment. Liver function tests (alkaline phosphatase and transaminases) should be performed in the first 4 months of therapy if liver dysfunction is suspected.

Test Interactions:

Increased cholesterol (S), increased alkaline phosphatase, increased transaminases (S)

Dietary Considerations:

Should be taken with food to reduce stomach upset.

Patient Education:

Take exact dosage prescribed, with food. Do not use aspirin or aspirin-containing medications and OTC medications without consulting prescriber. You may experience easy bleeding or bruising (use soft toothbrush or cotton swabs and frequent mouth care, use electric razor, avoid sharp knives or scissors). Report unusual bleeding or bruising, persistent fever, sore throat, weakness, paleness, changes in neurological status; blood in urine, stool, or vomitus; delayed healing of any wounds; skin rash; yellowing of skin or eyes; changes in color of urine or stool; pain or burning on urination; respiratory difficulty; or skin rash. Breast-feeding precaution: Consult prescriber if breast-feeding.

Nursing Implications:

Monitor bleeding times, platelets, CBC, hemoglobin and hematocrit

Anesthesia and Critical Care Concerns/Other Considerations:

The adverse effect profile including neutropenia and thrombotic thrombocytopenia purpura (TTP), along with twice-daily dosing and GI upset, makes ticlopidine a less attractive option than clopidogrel. Neutropenia usually resolves within 1-3 weeks of discontinuation of therapy. TTP, although rare, is life-threatening and requires immediate plasma exchange.

Cardiovascular Considerations:

May be used for secondary prevention with an efficacy at least similar to that of aspirin. Indicated in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI) who are unable to tolerate aspirin due to hypersensitivity or gastrointestinal disease. It takes time to achieve full antiplatelet effect. The adverse effect profile including neutropenia and thrombotic thrombocytopenia purpura (TTP), along with twice-daily dosing and GI upset, makes ticlopidine a less attractive option than clopidogrel. Neutropenia usually resolves within 1-3 weeks of discontinuation of therapy. TTP, although rare, is life-threatening and requires immediate plasma exchange.

Dental Health: Effects on Dental Treatment:

No significant effects or complications reported; if a patient is to undergo elective surgery and an antiplatelet effect is not desired, ticlopidine should be discontinued at least 7 days prior to surgery.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Mental Health: Effects on Mental Status:

None reported

Mental Health: Effects on Psychiatric Treatment:

May cause neutropenia; use caution with clozapine and carbamazepine

Dosage Forms:

Tablet, as hydrochloride: 250 mg

International Brand Names:

Aclotin® (PL); Agretik® (TR); Agulan® (ID); Alti-Ticlopidine (CA); Anagregal® (IT); Antigreg® (IT, SG); Antiplak® (DO); Aplaket® (IT, SG, TH); Aplatic® (HU); Apo-Clodin® (PL); Apo-Tic® (CZ); Apo-Ticlopidine® (CA); Ateroclar® (CL); Betlife® (PT); Cartrilet® (ID); Cloridrato de Ticlopidina® (BR); Clox® (IT); Desitic® (DE); Dosier® (AR); Fluilast® (IT); Flupid® (IT); Fluxidin® (IT); Gen-Ticlopidine (CA); Ifapidin® (PL); Ipaton® (CZ, HU, RO); Klodin® (IT); Klodipin® (PT); Lipozil® (DO); Movin® (PT); Novo-Ticlopidine (CA); Nufaclapide® (ID); Nu-Ticlopidine (CA); Opteron® (IT); Panaldine® (JP); Piclodin® (ID); Plaquetal® (PT); Plaquetil® (CL); PMS-Ticlopidine (CA); Rhoxal-ticlopidine (CA); Tacron® (SG); Tagren® (CZ, HR, PL, RU, SI); Thrombodine® (AT); Tiagren® (RO); Ticdine® (TH); Ticlid® (AR, AU, BE, BR, CA, CL, CO, CR, CZ, DO, EC, FR, GB, GT, HK, HN, HU, ID, LU, MX, NO, NZ, PA, PL, RO, RU, SE, SG, SV, TH, TR); Ticlidil® (IL); Ticlocard® (TR); Ticlodipine-Chinoin® (HU); Ticlodix® (PT, YU); Ticlodone® (AT, ES, IT); Ticlopidina Alter® (ES, PT); Ticlopidina Bayvit® (ES); Ticlopidina BIG® (IT); Ticlopidina Cinfa® (ES); Ticlopidina DOC® (IT); Ticlopidina Dorom® (IT); Ticlopidina Generis® (PT); Ticlopidina Hexan® (IT); Ticlopidina® (IT); Ticlopidina Lacer® (ES); Ticlopidin AL® (DE); Ticlopidina Merck® (ES, IT); Ticlopidina Normon® (ES); Ticlopidina Pliva® (IT); Ticlopidina Qualix® (ES); Ticlopidina Quesada® (AR); Ticlopidina Ratiopharm® (ES); Ticlopidina-ratiopharm® (IT); Ticlopidina RK® (IT); Ticlopidina Rubio® (ES); Ticlopidina Sanwin® (IT); Ticlopidina Teva® (IT); Ticlopidina Union Health® (IT); Ticlopidina Ur® (ES); Ticlopidin AZU® (DE); Ticlopidin beta® (DE); Ticlopidine Hexal® (AU); Ticlopidine Poli® (PL, RO); Ticlopidine Teva® (IL); Ticlopidin Heumann® (DE); Ticlopidin Hexal® (DE); Ticlopidin Neuraxpharm® (DE); Ticlopidin Puren® (DE); Ticlopidin Ratiopharm® (CZ, DE); Ticlopidin® (RU); Ticlopidin Sandoz® (DE); Ticlopidin Stada® (DE); ticlopidin von ct® (DE); Ticlop® (IN); Ticlo® (PL, TH); Ticloproge® (IT); Ticloratio® (PL); Ticlosyn® (CO); Ticuring® (ID); Tikleen® (IN); Tiklid® (AT, ES, IT); Tiklyd® (DE, PT); Tikol® (TH); Tilodene® (AU); Tilopin® (TH); Tipidine® (TH); Tipidin® (SG); Trombenal® (AR); Trombopat® (PT); Viladil® (TH)

References

Albiero R, Hall P, Itoh A, et al, "Results of a Consecutive Series of Patients Receiving Only Antiplatelet Therapy After Optimized Stent Implantation. Comparison of Aspirin Alone Versus Combined Ticlopidine and Aspirin Therapy,"Circulation, 1997, 95(5):1145-56.

Antman EM, Anbe SC, Alpert JS, et al, "ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction)," Circulation, 2004, 110:588-636. Available at: http://www.circulationaha.org/cgi/content/full/110/5/588. Last accessed October 26, 2004.

Balsano F, Rizzon P, Violi F, et al, "Antiplatelet Treatment With Ticlopidine in Unstable Angina. A Controlled Multicenter Clinical Trial. The Studio della Ticlopidina nell'Angina Instabile Group,"Circulation, 1990, 82(1):17-26.

Becquemin JP, "Effect of Ticlopidine on the Long-Term Patency of Saphenous-Vein Bypass Grafts in the Legs. Etude de la Ticlopidine apres Pontage Femoro-Poplite and the Association Universitaire de Recherche en Chirurgie,"N Engl J Med, 1997, 337(24):1726-31.

Berger PB, Bell MR, Hasdai D, et al, "Safety and Efficacy of Ticlopidine for Only 2 Weeks After Successful Intracoronary Stent Placement,"Circulation, 1999, 99(2):248-53.

Bertrand ME, Legrand V, Boland J, et al, "Randomized Multicenter Comparison of Conventional Anticoagulation Versus Antiplatelet Therapy in Unplanned and Elective Coronary Stenting. The Full Anticoagulation Versus Aspirin and Ticlopidine (Fantastic) Study,"Circulation, 1998, 98(16):1597-603.

Braunwald E, Antman EM, Beasley JW, et al, "ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction - Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina),"J Am Coll Cardiol, 2002, 40(7):1366-74. Available at: http://www.acc.org/clinical/guidelines/unstable/incorporated/index.htm. Accessed May 20, 2003.

Hass WK, Easton JD, Adams HP Jr, et al, "A Randomized Trial Comparing Ticlopidine Hydrochloride With Aspirin for the Prevention of Stroke in High-Risk Patients,"N Engl J Med, 1989, 321(8):501-7.

Kastrati A, Schuhlen H, Hausleiter J, et al, "Restenosis After Coronary Stent Placement and Randomization to a 4-Week Combined Antiplatelet or Anticoagulant Therapy: Six-Month Angiographic Follow-up of the Intracoronary Stenting and Antithrombotic Regimen (ISAR) Trial,"Circulation, 1997, 96(2):462-7.

Leon MB, Baim DS, Popma JJ, et al, "A Clinical Trial Comparing Three Antithrombotic-Drug Regimens After Coronary-Artery Stenting. Stent Anticoagulation Restenosis Study Investigators,"N Engl J Med, 1998, 339(23):1665-71.

Rupprecht HJ, Darius H, Borkowski U, et al, "Comparison of Antiplatelet Effects of Aspirin, Ticlopidine, or Their Combination After Stent Implantation,"Circulation, 1998, 97(11):1046-52.

Ryan TJ, Anderson JL, Antman EM, et al, "ACC/AHA Guidelines for the Management of Patients With Acute Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction),"J Am Coll Cardiol, 1996, 28(5):1328-428.

Schömig A, Neumann FJ, Kastrati A, et al, "A Randomized Comparison of Antiplatelet and Anticoagulant Therapy After the Placement of Coronary-Artery Stents,"N Engl J Med, 1996, 334(17):1084-9.

Steinhubl SR, Lauer MS, Mukherjee DP, et al, "The Duration of Pretreatment With Ticlopidine Prior to Stenting Is Associated With the Risk of Procedure-Related Non-Q-Wave Myocardial Infarctions,"J Am Coll Cardiol, 1998, 32(5):1366-70.

Urban P, Macaya C, Rupprecht HJ, et al, "Randomized Evaluation of Anticoagulation Versus Antiplatelet Therapy After Coronary Stent Implantation in High-Risk Patients: The Multicenter Aspirin and Ticlopidine Trial After Intracoronary Stenting (MATTIS),"Circulation, 1998, 98(2):2126-32.

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