FDA label ddb4f9b4-e86b-4ccd-bed4-7a1bc2b23ece

WARNING: TICLID 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/mm 3 ), and the neutrophil count was below 450/mm 3 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 TICLID must, therefore, be hematologically and clinically monitored for evidence of neutropenia or TTP. If any such evidence is seen, TICLID should be immediately discontinued. The detection and treatment of ticlopidine-associated hematological adverse reactions are further described under WARNINGS.

WARNINGS: 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/mm 3 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 TICLID 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 TICLID 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/mm 3 , then TICLID 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: TICLID 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 TICLID with heparin, oral anticoagulants or fibrinolytic agents have not been established. In trials for cardiac stenting, patients received heparin and TICLID concomitantly for approximately 12 hours. If a patient is switched from an anticoagulant or fibrinolytic drug to TICLID, the former drug should be discontinued prior to TICLID administration.

ADVERSE REACTIONS: 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 TICLID, 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 TICLID are shown in the following table: Percent of Patients With Adverse Events in Controlled Studies (TASS and CATS) Event TICLID (n = 2048) Incidence Aspirin (n = 1527) Incidence Placebo (n = 536) Incidence Any Events 60.0 (20.9) 53.2 (14.5) 34.3 (6.1) Diarrhea 12.5 (6.3) 5.2 (1.8) 4.5 (1.7) Nausea 7.0 (2.6) 6.2 (1.9) 1.7 (0.9) Dyspepsia 7.0 (1.1) 9.0 (2.0) 0.9 (0.2) Rash 5.1 (3.4) 1.5 (0.8) 0.6 (0.9) GI Pain 3.7 (1.9) 5.6 (2.7) 1.3 (0.4) Neutropenia 2.4 (1.3) 0.8 (0.1) 1.1 (0.4) Purpura 2.2 (0.2) 1.6 (0.1) 0.0 (0.0) Vomiting 1.9 (1.4) 1.4 (0.9) 0.9 (0.4) Flatulence 1.5 (0.1) 1.4 (0.3) 0.0 (0.0) Pruritus 1.3 (0.8) 0.3 (0.1) 0.0 (0.0) Dizziness 1.1 (0.4) 0.5 (0.4) 0.0 (0.0) Anorexia 1.0 (0.4) 0.5 (0.3) 0.0 (0.0) Abnormal Liver Function Test 1.0 (0.7) 0.3 (0.3) 0.0 (0.0) Incidence of discontinuation, regardless of relationship to therapy, is shown in parentheses. Hematological: Neutropenia/thrombocytopenia, TTP, aplastic anemia (see BOXED WARNING and WARNINGS ), leukemia, agranulocytosis, eosinophilia, pancytopenia, thrombocytosis and bone-marrow depression have been reported. Gastrointestinal: TICLID 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: TICLID 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 TICLID, 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 In addition, rarer, relatively serious and potentially fatal events associated with the use of TICLID 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 and myositis.

<table width="60%"> <caption>Percent of Patients With Adverse Events in Controlled Studies (TASS and CATS)</caption> <col align="left" width="25%"/> <col align="center" width="25%"/> <col align="center" width="25%"/> <col align="center" width="25%"/> <thead> <tr> <th styleCode="Lrule" valign="bottom">Event</th> <th styleCode="Lrule">TICLID (n = 2048) Incidence</th> <th styleCode="Lrule">Aspirin (n = 1527) Incidence</th> <th styleCode="Lrule Rrule">Placebo (n = 536) Incidence</th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Botrule"> <content styleCode="italics">Any Events</content> </td> <td styleCode="Lrule Botrule"> <content styleCode="italics">60.0 (20.9)</content> </td> <td styleCode="Lrule Botrule"> <content styleCode="italics">53.2 (14.5)</content> </td> <td styleCode="Lrule Botrule Rrule"> <content styleCode="italics">34.3 (6.1)</content> </td> </tr> <tr> <td styleCode="Lrule Botrule">Diarrhea</td> <td styleCode="Lrule Botrule">12.5 (6.3)</td> <td styleCode="Lrule Botrule">5.2 (1.8)</td> <td styleCode="Lrule Botrule Rrule">4.5 (1.7)</td> </tr> <tr> <td styleCode="Lrule Botrule">Nausea</td> <td styleCode="Lrule Botrule">7.0 (2.6)</td> <td styleCode="Lrule Botrule">6.2 (1.9)</td> <td styleCode="Lrule Botrule Rrule">1.7 (0.9)</td> </tr> <tr> <td styleCode="Lrule Botrule">Dyspepsia</td> <td styleCode="Lrule Botrule">7.0 (1.1)</td> <td styleCode="Lrule Botrule">9.0 (2.0)</td> <td styleCode="Lrule Botrule Rrule">0.9 (0.2)</td> </tr> <tr> <td styleCode="Lrule Botrule">Rash</td> <td styleCode="Lrule Botrule">5.1 (3.4)</td> <td styleCode="Lrule Botrule">1.5 (0.8)</td> <td styleCode="Lrule Botrule Rrule">0.6 (0.9)</td> </tr> <tr> <td styleCode="Lrule Botrule">GI Pain</td> <td styleCode="Lrule Botrule">3.7 (1.9)</td> <td styleCode="Lrule Botrule">5.6 (2.7)</td> <td styleCode="Lrule Botrule Rrule">1.3 (0.4)</td> </tr> <tr> <td styleCode="Lrule Botrule">Neutropenia</td> <td styleCode="Lrule Botrule">2.4 (1.3)</td> <td styleCode="Lrule Botrule">0.8 (0.1)</td> <td styleCode="Lrule Botrule Rrule">1.1 (0.4)</td> </tr> <tr> <td styleCode="Lrule Botrule">Purpura</td> <td styleCode="Lrule Botrule">2.2 (0.2)</td> <td styleCode="Lrule Botrule">1.6 (0.1)</td> <td styleCode="Lrule Botrule Rrule">0.0 (0.0)</td> </tr> <tr> <td styleCode="Lrule Botrule">Vomiting</td> <td styleCode="Lrule Botrule">1.9 (1.4)</td> <td styleCode="Lrule Botrule">1.4 (0.9)</td> <td styleCode="Lrule Botrule Rrule">0.9 (0.4)</td> </tr> <tr> <td styleCode="Lrule Botrule">Flatulence</td> <td styleCode="Lrule Botrule">1.5 (0.1)</td> <td styleCode="Lrule Botrule">1.4 (0.3)</td> <td styleCode="Lrule Botrule Rrule">0.0 (0.0)</td> </tr> <tr> <td styleCode="Lrule Botrule">Pruritus</td> <td styleCode="Lrule Botrule">1.3 (0.8)</td> <td styleCode="Lrule Botrule">0.3 (0.1)</td> <td styleCode="Lrule Botrule Rrule">0.0 (0.0)</td> </tr> <tr> <td styleCode="Lrule Botrule">Dizziness</td> <td styleCode="Lrule Botrule">1.1 (0.4)</td> <td styleCode="Lrule Botrule">0.5 (0.4)</td> <td styleCode="Lrule Botrule Rrule">0.0 (0.0)</td> </tr> <tr> <td styleCode="Lrule Botrule">Anorexia</td> <td styleCode="Lrule Botrule">1.0 (0.4)</td> <td styleCode="Lrule Botrule">0.5 (0.3)</td> <td styleCode="Lrule Botrule Rrule">0.0 (0.0)</td> </tr> <tr> <td styleCode="Lrule">Abnormal Liver Function Test</td> <td styleCode="Lrule">1.0 (0.7)</td> <td styleCode="Lrule">0.3 (0.3)</td> <td styleCode="Lrule Rrule">0.0 (0.0)</td> </tr> </tbody> </table>