Ticlopidine warnings and precautions

Ticlopidine
Ticlopidine® FDA Package Insert
Indications and Usage
Dosage and Administration
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Overdosage
Description
Clinical Pharmacology
Nonclinical Toxicology
Clinical Studies
How Supplied/Storage and Handling
Patient Counseling Information
Labels and Packages
Clinical Trials on Ticlopidine
ClinicalTrials.gov

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]

WARNINGS

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. Monitoring for Hematologic Adverse Reactions: 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.

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 Tablets with heparin, oral anticoagulants or fibrinolytic agents have not been established. In trials for cardiac stenting, patients received heparin and Ticlopidine Tablets concomitantly for approximately 12 hours. If a patient is switched from an anticoagulant or fibrinolytic drug to Ticlopidine Tablets, the former drug should be discontinued prior to Ticlopidine Tablet administration.

Precautions

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 Tablets (see CONTRAINDICATIONS).

Use in Hepatically Impaired Patients

Since ticlopidine is metabolized by the liver, dosing of ticlopidine or other drugs metabolized in the liver may require adjustment upon starting or stopping concomitant therapy. Because of limited experience in patients with severe hepatic disease, who may have bleeding diatheses, the use of ticlopidine is not recommended in this population (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).

Use in Renally Impaired Patients

There is limited experience in patients with renal impairment. Decreased plasma clearance, increased AUC values and prolonged bleeding times can occur in renally impaired patients. In controlled clinical trials no unexpected problems have been encountered in patients having mild renal impairment, and there is no experience with dosage adjustment in patients with greater degrees of renal impairment. Nevertheless, for renally impaired patients, it may be necessary to reduce the dosage of ticlopidine or discontinue it altogether if hemorrhagic or hematopoietic problems are encountered (see CLINICAL PHARMACOLOGY ).

References

Adapted from the FDA Package Insert.