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
|
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. |
Hematological Adverse Reactions
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.
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
Central Nervous System
- (list/description of adverse reactions)
Cardiovascular
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Respiratory
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Gastrointestinal
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Hypersensitive Reactions
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Miscellaneous
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Condition 2
Central Nervous System
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Cardiovascular
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Respiratory
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Gastrointestinal
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Hypersensitive Reactions
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Miscellaneous
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Postmarketing Experience
(Description)
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):
(Description)
Pregnancy Category (AUS):
(Description)
Labor and Delivery
(Description)
Nursing Mothers
(Description)
Pediatric Use
(Description)
Geriatic Use
(Description)
Gender
(Description)
Race
(Description)
Renal Impairment
(Description)
Hepatic Impairment
(Description)
Females of Reproductive Potential and Males
(Description)
Immunocompromised Patients
(Description)
Others
(Description)
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
Solution
Compatible
- Solution 1
- Solution 2
- Solution 3
Not Tested
- Solution 1
- Solution 2
- Solution 3
Variable
- Solution 1
- Solution 2
- Solution 3
Incompatible
- Solution 1
- Solution 2
- Solution 3
Y-Site
Compatible
- Solution 1
- Solution 2
- Solution 3
Not Tested
- Solution 1
- Solution 2
- Solution 3
Variable
- Solution 1
- Solution 2
- Solution 3
Incompatible
- Solution 1
- Solution 2
- Solution 3
Admixture
Compatible
- Solution 1
- Solution 2
- Solution 3
Not Tested
- Solution 1
- Solution 2
- Solution 3
Variable
- Solution 1
- Solution 2
- Solution 3
Incompatible
- Solution 1
- Solution 2
- Solution 3
Syringe
Compatible
- Solution 1
- Solution 2
- Solution 3
Not Tested
- Solution 1
- Solution 2
- Solution 3
Variable
- Solution 1
- Solution 2
- Solution 3
Incompatible
- Solution 1
- Solution 2
- Solution 3
TPN/TNA
Compatible
- Solution 1
- Solution 2
- Solution 3
Not Tested
- Solution 1
- Solution 2
- Solution 3
Variable
- Solution 1
- Solution 2
- Solution 3
Incompatible
- Solution 1
- Solution 2
- Solution 3
Overdosage
Acute Overdose
Signs and Symptoms
(Description)
Management
(Description)
Chronic Overdose
Signs and Symptoms
(Description)
Management
(Description)
Pharmacology
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Ticlopidine
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Mechanism of Action
(Description)
Structure
(Description with picture)
Pharmacodynamics
(Description)
Pharmacokinetics
(Description)
Nonclinical Toxicology
(Description)
Clinical Studies
Condition 1
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Condition 2
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Condition 3
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How Supplied
(Description)
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
There is limited information regarding Ticlopidine Brand Names in the drug label.
Look-Alike Drug Names
- (Paired Confused Name 1a) — (Paired Confused Name 1b)
- (Paired Confused Name 2a) — (Paired Confused Name 2b)
- (Paired Confused Name 3a) — (Paired Confused Name 3b)
Drug Shortage Status
Drug Shortage
Price
References
The contents of this FDA label are provided by the National Library of Medicine.