Ticlopidine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]
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Black Box Warning
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Warning
See full prescribing information for complete Boxed Warning.
Ticlopidine can cause life-threatening hematological adverse reactions, including neutropenia/agranulocytosis, thrombotic thrombocytopenic purpura (TTP) and aplastic anemia.
Neutropenia/Agranulocytosis: Among 2048 patients in clinical trials in stroke patients, 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 thrombotic thrombocytopenic purpura was reported during clinical trials in stroke patients. 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 one 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 one case in every 4000 to 8000 patients exposed. Monitoring of Clinical and Hematologic Status: Severe hematological 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 therapy. Hematological adverse reactions cannot be reliably predicted by any identified demographic or clinical characteristics. During the first 3 months of treatment, patients receiving ticlopidine must, therefore, be hematologically and clinically monitored for evidence of neutropenia or TTP. If any such evidence is seen, ticlopidine should be immediately discontinued. |
Overview
Ticlopidine is a platelet aggregation inhibitor that is FDA approved for the prophylaxis of thromboembolic stroke, and subacute stent thrombosis in patients undergoing successful coronary stent implantation.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, abdominal pain, diarrhea, indigestion, loss of appetite, nausea, hemorrhage, leukopenia, dizziness.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Stroke
- Dosing Information
- Recommended dose: 250 mg bid taken with food.
Coronary Artery Stenting
- Dosing Information
- Recommended dose: 250 mg bid taken with food together with antiplatelet doses of aspirin for up to 30 days of therapy following successful stent implantation.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ticlopidine in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ticlopidine in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ticlopidine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ticlopidine in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ticlopidine in pediatric patients.
Contraindications
- 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
Warnings
|
Warning
See full prescribing information for complete Boxed Warning.
Ticlopidine can cause life-threatening hematological adverse reactions, including neutropenia/agranulocytosis, thrombotic thrombocytopenic purpura (TTP) and aplastic anemia.
Neutropenia/Agranulocytosis: Among 2048 patients in clinical trials in stroke patients, 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 thrombotic thrombocytopenic purpura was reported during clinical trials in stroke patients. 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 one 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 one case in every 4000 to 8000 patients exposed. Monitoring of Clinical and Hematologic Status: Severe hematological 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 therapy. Hematological adverse reactions cannot be reliably predicted by any identified demographic or clinical characteristics. During the first 3 months of treatment, patients receiving ticlopidine must, therefore, be hematologically and clinically monitored for evidence of neutropenia or TTP. If any such evidence is seen, ticlopidine should be immediately discontinued. |
General
- Ticlopidine should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or pathological conditions.
- If it is desired to eliminate the antiplatelet effects of ticlopidine prior to elective surgery, the drug should be discontinued 10 to 14 days prior to surgery.
- Several controlled clinical studies have found increased surgical blood loss in patients undergoing surgery during treatment with ticlopidine.
- In TASS and CATS it was recommended that patients have ticlopidine discontinued prior to elective surgery.
- Several hundred patients underwent surgery during the trials, and no excessive surgical bleeding was reported.
- Prolonged bleeding time is normalized within 2 hours after administration of 20 mg methylprednisolone IV.
- Platelet transfusions may also be used to reverse the effect of ticlopidine on bleeding.
- Because platelet transfusions may accelerate thrombosis in patients with TTP on ticlopidine, they should, if possible, be avoided.
GI Bleeding
- Ticlopidine prolongs template bleeding time.
- The drug should be used with caution in patients who have lesions with a propensity to bleed (such as ulcers).
- Drugs that might induce such lesions should be used with caution in patients on ticlopidine
Cholesterol Elevation
- Ticlopidine therapy causes increased serum cholesterol and triglycerides.
- Serum total cholesterol levels are increased 8% to 10% within 1 month of therapy and persist at that level.
- The ratios of the lipoprotein subfractions are unchanged.
Anticoagulant Drugs
- The tolerance and long-term safety of coadministration of ticlopidine with heparin, oral anticoagulants or fibrinolytic agents have not been established.
- In trials for cardiac stenting, patients received heparin and ticlopidine concomitantly for approximately 12 hours.
- If a patient is switched from an anticoagulant or fibrinolytic drug to ticlopidine, the former drug should be discontinued prior to ticlopidine administration.
Adverse Reactions
Clinical Trials Experience
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:
Hematological
Neutropenia
Neutropenia may occur suddenly. Bone-marrow examination typically shows a reduction in white blood cell precursors. After withdrawal of ticlopidine, the neutrophil count usually rises to >1200/mm3 within 1 to 3 weeks.
Thrombocytopenia
Rarely, thrombocytopenia may occur in isolation or together with neutropenia.
Thrombotic Thrombocytopenic Purpura (TTP)
TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever. The signs and symptoms can occur in any order, in particular, clinical symptoms may precede laboratory findings by hours or days. With prompt treatment (often including plasmapheresis), 70% to 80% of patients will survive with minimal or no sequelae. Because platelet transfusions may accelerate thrombosis in patients with TTP on ticlopidine, they should, if possible, be avoided.
Aplastic Anemia
Aplastic anemia is characterized by anemia, thrombocytopenia and neutropenia together with a bone marrow examination that shows decreases in the precursor cells for red blood cells, white blood cells, and platelets. Patients may present with signs or symptoms suggestive of infection, in association with low white blood cell and platelet counts. Prompt treatment, which may include the use of drugs to stimulate the bone marrow, can minimize the mortality associated with aplastic anemia.
Other Hematological Effects
Rare cases of agranulocytosis, pancytopenia, or leukemia have been reported in postmarketing experience, some of which have been fatal. All forms of hematological adverse reactions are potentially fatal.
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
Postmarketing Experience
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
- 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 CLINICAL TRIALS: Stent Patients). 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 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
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. Caution should be exercised in coadministering this drug with ticlopidine, 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 coadministering this drug with ticlopidine.
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.
Food Interaction
The oral bioavailability of ticlopidine is increased by 20% when taken after a meal. Administration of ticlopidine with food is recommended to maximize gastrointestinal tolerance. In controlled trials in stroke patients, ticlopidine was taken with meals.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
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Pregnancy Category (AUS):
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Labor and Delivery
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Nursing Mothers
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Pediatric Use
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Geriatic Use
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Gender
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Race
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Renal Impairment
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Hepatic Impairment
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Females of Reproductive Potential and Males
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Immunocompromised Patients
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Others
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Administration and Monitoring
Administration
(Oral/Intravenous/etc)
Monitoring
Starting just before initiating treatment and continuing through the third month of therapy, patients receiving ticlopidine must be monitored every 2 weeks. Because of ticlopidine’s long plasma half-life, patients who discontinue ticlopidine during this 3-month period should continue to be monitored for 2 weeks after discontinuation. More frequent monitoring, and monitoring after the first 3 months of therapy, is necessary only in patients with clinical signs (eg, signs or symptoms suggestive of infection) or laboratory signs (eg, neutrophil count less than 70% of the baseline count, decrease in hematocrit or platelet count) that suggest incipient hematological adverse reactions.
Clinically, fever might suggest neutropenia, TTP, or aplastic anemia; TTP might also be suggested by weakness, pallor, petechiae or purpura, dark urine (due to blood, bile pigments, or hemoglobin) or jaundice, or neurological changes. Patients should be told to discontinue ticlopidine and to contact the physician immediately upon the occurrence of any of these findings.
Laboratory monitoring should include a complete blood count, with special attention to the absolute neutrophil count (WBC x % neutrophils), platelet count, and the appearance of the peripheral smear. Ticlopidine is occasionally associated with thrombocytopenia unrelated to TTP or aplastic anemia. Any acute, unexplained reduction in hemoglobin or platelet count should prompt further investigation for a diagnosis of TTP, and the appearance of schistocytes (fragmented RBCs) on the smear should be treated as presumptive evidence of TTP. A simultaneous decrease in platelet count and WBC count should prompt further investigation for a diagnosis of aplastic anemia. If there are laboratory signs of TTP or aplastic anemia, or if the neutrophil count is confirmed to be <1200/mm3, then ticlopidine should be discontinued immediately.
IV Compatibility
There is limited information regarding the compatibility of Ticlopidine and IV administrations.
Overdosage
There is limited information regarding Ticlopidine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
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Ticlopidine
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Mechanism of Action
(Description)
Structure
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Pharmacodynamics
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Pharmacokinetics
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Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year oral carcinogenicity study in rats, ticlopidine at daily doses of up to 100 mg/kg (610 mg/m2) was not tumorigenic. For a 70-kg person (1.73 m2 body surface area) the dose represents 14 times the recommended clinical dose on a mg/kg basis and two times the clinical dose on body surface area basis. In a 78-week oral carcinogenicity study in mice, ticlopidine at daily doses up to 275 mg/kg (1180 mg/m2) was not tumorigenic. The dose represents 40 times the recommended clinical dose on a mg/kg basis and four times the clinical dose on body surface area basis.
Ticlopidine was not mutagenic in vitro in the Ames test, the rat hepatocyte DNA-repair assay, or the Chinese-hamster fibroblast chromosomal aberration test; or in vivo in the mouse spermatozoid morphology test, the Chinese-hamster micronucleus test, or the Chinese-hamster bone-marrow-cell sister-chromatid exchange test. Ticlopidine was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg/day.
Clinical Studies
Condition 1
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Condition 2
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Condition 3
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How Supplied
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Storage
There is limited information regarding Ticlopidine Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
(Patient Counseling Information)
Precautions with Alcohol
Alcohol-Ticlopidine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
Ticlid
Look-Alike Drug Names
- Ticlid - Tequin
Drug Shortage Status
Drug Shortage
Price
References
The contents of this FDA label are provided by the National Library of Medicine.