Ticlopidine

Ticlopidine is a P2Y12 ADP receptor antagonist on platelets belonging to Antiplatelet Agent.

Ticlopidine is a platelet aggregation inhibitor used in the prevention of conditions associated with thrombi, such as stroke and transient ischemic attacks (TIA).

Readily and almost completely absorbed from the gastrointestinal tract. Food may increase bioavailability by approximately 20%. The time to peak plasma concentration is about 2 hours. Plasma protein binding is around 98%, mainly to albumin and lipoproteins; ≤15%, to α₁-acid glycoprotein. It was extensively metabolized in the liver into at least 1 active metabolite. Ticlopidine is excreted via urine (approximately 60% as metabolites); feces (23%, with low amounts as unchanged drug). It has an elimination half-life of about 13 hours.

Ticlopidine shows common side effects like low blood cell counts, diarrhea, nausea, vomiting, upset stomach; rash, Tinnitus, Headache, and Abdominal and stomach pain.

Ticlopidine is available in Oral Tablets.

Ticlopidine is available in India, the UK, Russia, Japan, New Zealand, China, and Australia.

Ticlopidine belonging to the Antiplatelet Agent, acts as an P2Y12 ADP receptor antagonist.

The active metabolite of ticlopidine prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. It is proposed that the inhibition involves a defect in the mobilization from the storage sites of the platelet granules to the outer membrane. No direct interference occurs with the GPIIb / IIIa receptor. As the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation. By blocking the amplification of platelet activation by released ADP, platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of ticlopidine.

The Onset of action of Ticlopidine is not clinically established.

There is no well-established clinical data available regarding the duration of action of Ticlopidine.

The Tmax of Ticlopidine is approximately 2 hours.

Ticlopidine is available in the form of Oral Tablet.

Ticlopidine tablet is taken orally usually twice daily. Take with food, it can help Ticlopidine-induced stomach upset.

Ticlopidine is used to prevent clots in blood vessels and for the prevention and treatment of stroke in patients for whom the use of aspirin is not recommended. Ticlopidine can be taken in combination with other antiplatelet agents for better effectiveness. Ticlopidine is not recommended for use in patients with bleeding disorders. Close monitoring of platelet count is necessary during treatment with this medicine.

Ticlopidine is a P2Y12 ADP receptor antagonist on platelets belonging to Antiplatelet Agent.

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.

Ticlopidine is approved for use in the following clinical indications:

• Prophylaxis of thrombotic stroke

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, Ticlopidine should be reserved for patients who are intolerant or allergic to aspirin therapy or who have failed aspirin therapy.

• Prophylaxis of subacute stent occlusion after Intracoronary stenting

As adjunctive therapy with aspirin to reduce the incidence of subacute stent thrombosis in patients undergoing successful coronary stent implantation.

• Prophylaxis of thrombotic stroke

Oral: 250 mg twice daily.

• Prophylaxis of subacute stent occlusion after Intracoronary stenting

Oral: As an adjunct to aspirin: 250 mg twice daily, to be started before or on the

day of the stent placement and continued for 4-6 weeks.

Ticlopidine is available in various strengths as 250mg.

Ticlopidine is available in the form of an Oral Tablet.

Ticlopidine is contraindicated in patients with

● 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

• Hematologic toxicity:

May cause life-threatening hematologic reactions, including neutropenia, agranulocytosis, thrombotic thrombocytopenic 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. The use of ticlopidine is contraindicated in patients with hypersensitivity to ticlopidine.

• Bleeding disorders:

Use caution in patients with platelet disorders, bleeding disorders, 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.

• Anticoagulants and platelet aggregation inhibitors:

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

• Lower GI bleed patients:

An individualized and multidisciplinary approach should be utilized to determine therapy discontinuation and management in patients with acute lower GI bleed (LGIB) who are on antiplatelet medications; the risk of ongoing bleeding should be weighed with the risk of thromboembolic events. In patients receiving dual antiplatelet therapy (aspirin plus P2Y₁₂ receptor blocker [eg, clopidogrel, prasugrel, ticagrelor, ticlopidine]) or thienopyridine monotherapy, the thienopyridine should generally be resumed as soon as possible and at least within 7 days, taking into account control of bleeding and cardiovascular risk (aspirin should not be discontinued); however, dual antiplatelet therapy should not be discontinued in the 90 days post-acute coronary syndrome or 30 days post-coronary stenting

• 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, the 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.

• 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 the cardiologist.

Studies in rats have shown ticlopidine is excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ticlopidine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Teratology studies have been conducted in mice (doses up to 200 mg/kg/day), rats (doses up to 400 mg/kg/day), and rabbits (doses up to 200 mg/kg/day). Doses of 400 mg/kg in rats, 200 mg/kg/day in mice and 100 mg/kg in rabbits produced maternal toxicity, as well as fetal toxicity, but there was no evidence of the teratogenic potential of ticlopidine. There are, however, no adequate and well-controlled studies on pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

• Common Adverse effects

Diarrhea, Elevated alkaline phosphatase, Nausea, Dyspepsia, Rash, GI pain, Elevated AST/SGOT, Neutropenia, Purpura, Vomiting, Flatulence, Pruritus, Dizziness, Abnormal LFTs, Anorexia.

• Rare Adverse effects

Agranulocytosis, anaphylaxis, angioedema, aplastic anemia, arthropathy, bone marrow depression, bronchiolitis obliterans organizing pneumonia, conjunctival hemorrhage, ecchymosis, eosinophilia, epistaxis, erythema multiforme, erythema nodosum, exfoliative dermatitis, gastrointestinal hemorrhage, headache, hematuria, hemolytic anemia, hepatic necrosis, hepatitis, hypermenorrhea, hypersensitivity pneumonitis, hyponatremia, increased serum bilirubin, intracranial hemorrhage, immune thrombocytopenia, increased serum creatinine, jaundice, maculopapular rash, myositis, nephrotic syndrome, pain, pancytopenia, peptic ulcer, peripheral neuropathy, positive ANA titer, renal failure, sepsis, serum sickness, Stevens-Johnson syndrome, systemic lupus erythematosus, thrombocythemia, thrombotic thrombocytopenic purpura (TTP), tinnitus, urticaria, vasculitis, weakness.

Ticlopidine may interact with other drugs such as:

• 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. 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.

• 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

Co-administration of Ticlopidine(ticlopidine HCl) with digoxin resulted in a slight decrease (approximately 15%) in digoxin plasma levels. Little or no change in the therapeutic efficacy of digoxin would be expected.

• Theophylline

In normal volunteers, concomitant administration of Ticlopidine(ticlopidine hcl) 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 (ticlopidine hcl) on platelet aggregation were not altered by chronic administration of phenobarbital.

• Phenytoin

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

• Propranolol

In vitro 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 in vivo. Caution should be exercised in co-administering this drug with Ticlopidine (ticlopidine hcl).

• Other Concomitant Therapy

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

The common side effect of Ticlopidine include the following

• Common

Low blood cell counts, diarrhea, nausea, vomiting, upset stomach; or rash, Tinnitus, Headache, Abdominal and stomach pain.

• Rare

Any bleeding that will not stop, severe or ongoing diarrhea, pink or brown urine, low blood cell counts--fever, chills, flu-like symptoms, swollen gums, mouth sores, skin sores, rapid heart rate, pale skin, easy bruising, unusual bleeding, feeling light-headed, liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes), signs of stomach bleeding--bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds; or signs of a serious blood-clotting problem--pale skin, purple spots under your skin or on your mouth, problems with speech, weakness, seizures (convulsions), dark urine, jaundice.

• Pregnancy

Pregnancy Category B.

Teratology studies have been conducted in mice (doses up to 200 mg/kg/day), rats (doses up to 400 mg/kg/day), and rabbits (doses up to 200 mg/kg/day). Doses of 400 mg/kg in rats, 200 mg/kg/day in mice and 100 mg/kg in rabbits produced maternal and fetal toxicity. Still, there was no evidence of the teratogenic potential of ticlopidine. There are, however, no adequate and well-controlled studies on pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

• Nursing Mothers

Studies in rats have shown ticlopidine is excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ticlopidine, a decision should be made whether to discontinue nursing or to discontinue the drug, considering the importance of the drug to the mother.

• Pediatric Use

As per FDA, the safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

Clearance of ticlopidine is somewhat lower in elderly patients and trough levels are increased. The major clinical trials with Ticlopidine in stroke patients were conducted in an elderly population with an average age of 64 years. Of the total number of patients in the therapeutic trials, 45% of patients were over 65 years old, and 12% were over 75 years old. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

• One case of deliberate overdosage with Ticlopidine (ticlopidine hcl) has been reported by a foreign post-marketing surveillance program. A 38-year-old male took a 6000-mg dose of Ticlopidine (ticlopidine HCl) (equivalent to 24 standard 250-mg tablets). The only abnormalities reported were increased bleeding time and increased SGPT. No particular 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 bleeding, convulsions, hypothermia, dyspnea, loss of equilibrium, and abnormal gait.

Pharmacodynamic

Ticlopidine is a prodrug that is metabolized to a yet undetermined metabolite that acts as a platelet aggregation inhibitor. Inhibition of platelet aggregation causes a prolongation of bleeding time. In its prodrug form, ticlopidine has no significant in vitro activity at the concentrations attained in vivo.

Pharmacokinetics

Absorption

Readily and almost completely absorbed from the gastrointestinal tract. Food may increase bioavailability by approximately 20%. Time to peak plasma concentration: Approximately 2 hours.

• Distribution

Plasma protein binding: Approx 98%, mainly to albumin and lipoproteins; ≤15%, to α₁-acid glycoprotein.

• Metabolism

Extensively metabolized in the liver into at least 1 active metabolite.

• Excretion

Ticlopidine is excreted via urine (approximately 60% as metabolites); feces (23%, with low amounts as unchanged drug). It has an elimination half-life of approximately 13 hours.

• https://www.uptodate.com/contents/ticlopidine-united-states-not-available-drug-information#F227732
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