This is the retyped text of a letter from Roche. Contact the company for a copy of any referenced enclosures.

Dear Doctor:

We are notifying you today about important changes to labeling of TICLID (ticlopidine). These changes will more prominently describe an adverse reaction to TICLID, thrombotic thrombocytopenic purpura (TTP), a condition that is potentially life-threatening, and give information about its diagnosis and treatment. TICLID is indicated to reduce the risk of thrombotic stroke in patients who have experienced stroke precursors, or who have had a completed stroke, and who are intolerant or allergic to aspirin or have failed aspirin therapy. The revised labeling moves the warning about TTP into the boxed warning, previously included as a bolded warning. This change has been made to provide additional information regarding the diagnosis and management of TTP. Awareness of this disorder is critical because intervention is important in its management, because it can present in a variety of ways, and because it is important to distinguish TTP from uncomplicated thrombocytopenia.

As described in the TICLID package insert, monitoring of the CBC (including platelet count) should be performed every two weeks, from just before treatment is initiated to the end of the third month of therapy. Physicians should also focus on the platelet count, hemoglobin change, if any, and description of the peripheral smear. In addition, patients should be instructed to report promptly any changes in their status to their physician. Potential early symptoms of TTP include fever, weakness, aphasia, convulsions, jaundice, hematuria or dark urine, pallor, and petechiae.

• For your convenience, the revised boxed warning of the package insert is printed below:

• The WARNINGS section has been revised as follows:

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.

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 either neutropenia or TTP; 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. 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. If there are laboratory signs of TTP, or if the neutrophil count is confirmed to be <1200/mm3, then the drug should be discontinued.

• Related changes have also been made to the PRECAUTIONS and ADVERSE REACTIONS, Information for Patients and CONTRAINDICATIONS sections of the package insert. Please refer to the enclosed copy of the revised package insert for full prescribing information.

Health care professionals are encouraged to report any unexpected events suggestive of TTP or other serious adverse events associated with the use of ticlopidine directly to Roche Laboratories at 1-800-526-6367 or to the FDA MedWatch program by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178 or by mail (MEDWATCH, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20857).

Sincerely,

Russell H. Ellison, MD
Vice President, Medical Affairs

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