ADVERSE REACTIONS
Adverse reactions 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, Gl 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 hydrochloride, 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 hydrochloride are shown in the following table:
| Incidence of discontinuation, regardless of relationship to therapy, is shown in parentheses. |
| Percent of Patients with Adverse Events in Controlled Studies (TASS and CATS) |
| Event | Ticlopidine hydrochloride (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) |
| Gl 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) |
Hematological
Neutropenia/thrombocytopenia, TTP, aplastic anemia (see BOXED WARNING and WARNINGS), leukemia, agranulocytosis, eosinophilia, pancytopenia, thrombocytosis, and bone marrow depression have been reported.
Gastrointestinal
Ticlopidine hydrochloride 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 hydrochloride has been associated with increased bleeding, spontaneous post-traumatic 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 with ticlopidine hydrochloride, 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 patients in the controlled trials include:
• Digestive System: Gl fullness
• Body as a Whole: asthenia, pain
• Skin and Appendages: urticaria
• Hemostatic System: epistaxis
• Nervous System: headache
• Special Senses: tinnitus
In addition, rarer, relatively serious and potentially fatal events associated with the use of ticlopidine hydrochloride 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.
OVERDOSAGE
One case of deliberate overdosage with ticlopidine hydrochloride has been reported by a foreign postmarketing surveillance program. A 38 year old male took a single 6000 mg dose of ticlopidine hydrochloride (equivalent to 24 standard 250 mg tablets). The only abnormalities reported were increased bleeding time and increased SGPT. No special therapy was instituted and the patient recovered without sequelae.
Single oral doses of ticlopidine at 1600 mg/kg and 500 mg/kg were lethal to rats and mice, respectively. Symptoms of acute toxicity were Gl hemorrhage, convulsions, hypothermia, dyspnea, loss of equilibrium and abnormal gait.
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