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Ticlopidine

Pronunciation

Pronunciation

(tye KLOE pi deen)

Index Terms

  • Ticlopidine HCl
  • Ticlopidine Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral, as hydrochloride:

Generic: 250 mg [DSC]

Pharmacologic Category

  • Antiplatelet Agent
  • Antiplatelet Agent, Thienopyridine

Pharmacology

Ticlopidine requires in vivo biotransformation to an unidentified active metabolite. This active metabolite irreversibly blocks the P2Y12 component of ADP receptors, which prevents activation of the GPIIb/IIIa receptor complex, thereby reducing platelet aggregation. Platelets blocked by ticlopidine are affected for the remainder of their lifespan.

Absorption

Well absorbed

Metabolism

Extensively hepatic; has at least 1 active metabolite

Excretion

Urine (60%); feces (23%)

Onset of Action

~6 hours; Peak effect: 3-5 days; serum levels do not correlate with clinical antiplatelet activity

Time to Peak

~2 hours

Half-Life Elimination

13 hours

Protein Binding

Parent drug: 98%; <15% bound to alpha1-acid glycoprotein

Special Populations: Hepatic Function Impairment

Average plasma concentration is slightly higher in cirrhosis.

Use: Labeled Indications

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.

Contraindications

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

Dosing: Adult

Note: Ticlopidine is no longer available in the US.

Stroke prevention: Oral: 250 mg twice daily

Coronary artery stenting (initiate after successful implantation): Oral: 250 mg twice daily (in combination with antiplatelet doses of aspirin). If initiated prior to percutaneous coronary intervention, a loading dose of 500 mg may be administered (Berger, 1999). May continue treatment for up to 30 days per the manufacturer; however, in general, duration of therapy may extend up to 12 months in patients with drug-eluting stents or those with stent implantation (bare metal or drug eluting) for acute coronary syndrome (Levine, 2011).

Note: Overall, the use of ticlopidine has largely been replaced by newer P2Y12 inhibitors (ie, clopidogrel, prasugrel, ticagrelor).

Dosing: Geriatric

250 mg twice daily with food; dosage in older patients has not been determined; however, in two large clinical trials, the average age of subjects was 63 and 66 years. A dosage decrease may be necessary if bleeding develops.

Dosing: Renal Impairment

No dosage adjustment provided in manufacturer’s labeling. While there were no statistically significant differences in ADP-induced platelet aggregation, AUC increases and clearance decreases were seen in patients with mild to moderate renal impairment. However, bleeding time may be prolonged in patients with moderate renal impairment

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling. Use with caution. Use is contraindicated in severe hepatic impairment.

Administration

Administer with food.

Dietary Considerations

Should be taken with food to reduce stomach upset.

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Apixaban: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

BuPROPion: CYP2B6 Inhibitors (Weak) may increase the serum concentration of BuPROPion. Monitor therapy

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Monitor therapy

Cilostazol: CYP2C19 Inhibitors may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification

Citalopram: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with a strong CYP2C19 inhibitor. Patients using this combination should be monitored closely for evidence of citalopram toxicity (e.g., serotonin syndrome, QT prolongation, etc.). Consider therapy modification

Clopidogrel: CYP2C19 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a strong CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

CYP2C19 Substrates: CYP2C19 Inhibitors (Strong) may decrease the metabolism of CYP2C19 Substrates. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Dabigatran Etexilate: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk of bleeding may be increased. Antiplatelet Agents (P2Y12 Inhibitors) may increase the serum concentration of Dabigatran Etexilate. Specifically, clopidogrel may increase dabigatran serum concentrations. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Edoxaban: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider the anticipated risks and benefits of this combination. If combined, increased monitoring for bleeding is recommended. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Flibanserin: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Flibanserin. Monitor therapy

Fosphenytoin: Ticlopidine may increase the serum concentration of Fosphenytoin. Monitor therapy

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification

Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Morphine (Liposomal): May diminish the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). Morphine (Liposomal) may decrease the serum concentration of Antiplatelet Agents (P2Y12 Inhibitors). Management: Consider alternative anti-ischemic/analgesic therapies (eg, beta-blockers, nitroglycerin) in patients with acute coronary syndromes treated with a P2Y12 inhibitor when possible. The risks associated with other opioids are unknown. Consider therapy modification

Morphine (Systemic): May diminish the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). Morphine (Systemic) may decrease the serum concentration of Antiplatelet Agents (P2Y12 Inhibitors). Management: Consider alternative anti-ischemic/analgesic therapies (eg, beta-blockers, nitroglycerin) in patients with acute coronary syndromes treated with a P2Y12 inhibitor when possible. The risks associated with other opioids are unknown. Consider therapy modification

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Perhexiline: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Perhexiline. Monitor therapy

Phenytoin: Ticlopidine may increase the serum concentration of Phenytoin. Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Rivaroxaban: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Theophylline Derivatives: Ticlopidine may decrease the metabolism of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

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: Total cholesterol increased (increases of ~8% to 10% within 1 month of therapy), triglycerides increased

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: Alkaline phosphatase increased (>2 x upper limit of normal; 8%), abnormal liver function test (1%)

<1% (Limited to important or life-threatening): Agranulocytosis, anaphylaxis, angioedema, aplastic anemia, arthropathy, bilirubin increased, bone marrow suppression, bronchiolitis obliterans-organized pneumonia, chronic diarrhea, conjunctival bleeding, eosinophilia, erythema multiforme, erythema nodosum, exfoliative dermatitis, gastrointestinal bleeding, hematuria, hemolytic anemia, hepatic necrosis, hepatitis, hyponatremia, intracranial bleeding (rare), jaundice, maculopapular rash, menorrhagia, myositis, nephrotic syndrome, pancytopenia, peptic ulcer, peripheral neuropathy, pneumonitis (allergic), positive ANA, renal failure, sepsis, serum creatinine increased, serum sickness, Stevens-Johnson syndrome, systemic lupus erythematosus, thrombocytopenia (immune), thrombocytosis, thrombotic thrombocytopenic purpura, urticaria, vasculitis

ALERT: U.S. Boxed Warning

Hematologic toxicity:

Ticlopidine HCl can cause life-threatening hematological adverse reactions, including neutropenia/agranulocytosis and thrombotic thrombocytopenic purpura (TTP) and aplastic anemia.

Neutropenia/agranulocytosis:

Among 2048 patients in clinical trials, there were 50 cases (2.4%) of neutropenia (less than 1200 neutrophils/mm3), and the neutrophil count was below 450/mm3 in 17 of these patients (0.8% of the total population).

TTP:

One case of TTP was reported during clinical trials. 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 1 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 1 case in every 4000 to 8000 patients exposed.

Monitoring of clinical and hematologic status:

Severe hematologic 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 treatment.

Hematological adverse reactions cannot be reliably predicted by any identified demographic or clinical characteristics. During the first 3 months of treatment, patients receiving ticlopidine HCl must, therefore, be hematologically and clinically monitored for evidence of neutropenia or TTP. If any such evidence is seen, ticlopidine HCl should be immediately discontinued.

Warnings/Precautions

Concerns related to adverse effects:

• Hematologic toxicity: [US Boxed Warning]: 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 <1,200/mm3 or if laboratory signs of TTP or aplastic anemia occur.

• Thienopyridine hypersensitivity: Because of structural similarities, cross-reactivity is possible among the thienopyridines (clopidogrel, prasugrel, and ticlopidine); use with caution or avoid in patients with previous thienopyridine hypersensitivity. Use of ticlopidine is contraindicated in patients with hypersensitivity to ticlopidine.

Disease-related concerns:

• Bleeding disorders: Use with caution in patients with platelet disorders, bleeding disorders and/or at increased risk for bleeding (eg, PUD, trauma, or surgery).

• Hepatic impairment: Use with caution in patients with mild-to-moderate hepatic impairment. Use is contraindicated with severe hepatic impairment.

• Renal impairment: Use with caution in patients with moderate-to-severe renal impairment (experience is limited); bleeding times may be significantly prolonged and the risk of hematologic adverse events (eg, neutropenia) may be increased.

Concurrent drug therapy issues:

• Anticoagulants and platelet aggregation inhibitors: Use with caution in patients receiving either anticoagulants (eg, heparin, warfarin) or other platelet aggregation inhibitors; bleeding risk is increased.

Other warnings/precautions:

• Coronary artery stents: In patients who have received bare-metal or drug-eluting stents (sirolimus or paclitaxel), premature interruption of antiplatelet therapy may result in stent thrombosis with subsequent fatal and nonfatal myocardial infarction. If ticlopidine is used, duration of therapy, in general, is determined by the type of stent placed (bare metal or drug eluting) and whether an ACS event was ongoing at the time of placement (Levine, 2011).

• Elective surgery: Consider discontinuing 10 to 14 days before elective surgery (except in patients with cardiac stents that have not completed their full course of dual antiplatelet therapy; patient-specific situations need to be discussed with cardiologist; AHA/ACC/SCAI/ACS/ADA Science Advisory provides recommendations).

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.

Pregnancy Risk Factor

B

Pregnancy Considerations

Teratogenic effects have not been observed in animal reproduction studies; a case report has demonstrated the safe use of ticlopidine in pregnant women (Ueno, 2001).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of infection, pinpoint red spots on skin, severe headache, dark urine, jaundice, loss of strength and energy, pale skin, seizures, vision changes, urinary retention, change in amount of urine passed, severe diarrhea, severe abdominal pain, or bloody diarrhea (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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