Ticlopidine Side Effects

Brand Names: Ticlid

Please note - some side effects for Ticlopidine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Ticlopidine - for the consumer

Ticlopidine

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Ticlopidine:

Diarrhea; indigestion; nausea; stomach pain; vomiting.

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blood in urine; chills; dark urine; difficulty speaking; fever; increased bleeding; light-colored stools; mouth sores; pale skin; pinpoint dots or rash on the skin; seizures; sore throat; unusual bruising or bleeding; weakness; yellowing of the skin or eyes.

For the professional

Ticlopidine

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:

Hematological

Neutropenia/thrombocytopenia, TTP, aplastic anemia, 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.

By body system

Hematologic side effects

Hematologic dyscrasias have been the most serious adverse effects associated with ticlopidine therapy. Reversible neutropenia (severe in 0.9%) occurred in 2.4% of patients. Thrombocytopenia, agranulocytosis, pancytopenia, hemolytic anemia with reticulocytosis, and aplastic anemia have been reported.

Thrombotic thrombocytopenic purpura (TTP), not noted during clinical trials, has occurred at an estimated incidence of 1 case per 2000 to 4000 exposures. Symptoms include thrombocytopenia, microangiopathic hemolytic anemia (fragmented RBCs on a peripheral smear), renal dysfunction, fever, and neurological changes.

The majority of cases of neutropenia, agranulocytosis, aplastic anemia, and thrombotic thrombocytopenic purpura occur during the first three months of treatment. US physicians reported 100 cases of TTP between 1992 and 1997. Delayed onset of neutropenia, after discontinuation of ticlopidine, has been reported. Hematologic parameters should be monitored every other week for the first three months of therapy and ticlopidine should be discontinued if laboratory values are altered or if symptoms of infection or bleeding are noted. Thereafter, the patient should be monitored for signs of infection. Patients should be counseled concerning signs and symptoms of TTP (weakness, pallor, petechiae, purpura, dark urine, jaundice or mental status changes) and instructed to discontinue ticlopidine and immediately report any of these findings. Platelet infusions may accelerate thrombosis and should be avoided if possible.

Ecchymosis, epistaxis, hematuria, conjunctival hemorrhage, and gastrointestinal bleeding have been associated with ticlopidine therapy. Intracerebral bleeding occurred in approximately 0.5% of patients in clinical trials.

Postsurgical bleeding may also occur. To minimize the effects of postsurgical bleeding, it is generally recommended that ticlopidine be discontinued 2 weeks before any surgical or dental interventions.

Gastrointestinal side effects

Gastrointestinal disturbances have been noted in up to 40% of patients. Dyspepsia, nausea, diarrhea, vomiting, flatulence, and gastric pain have occurred. Some gastrointestinal symptoms lessen with continued therapy and administration with food may decrease gastrointestinal intolerance. Cases of ticlopidine-induced chronic diarrhea have been reported.

Dermatologic side effects

Two case reports of patients developing maculopapular pruritic rashes following administration of clopidogrel have been reported. The rash recurred in both patients after switching to ticlopidine. In one patient, rechallenge resulted in recurrence of the rash. These two cases illustrate the possibility of cross-sensitivity between thienopyridines.

Dermatologic adverse effects have occurred frequently. Rash, generally maculopapular or urticarial, has been experienced in up to 15% of treated patients. At least one case of multiple fixed-drug eruptions, consisting of rash and generalized patches of hyperpigmentation, has been reported.

Hepatic side effects

Hepatic side effects typically have been mild and have included reversible elevations in liver function tests (up to 4%). The incidence of cholestatic jaundice has increased. Postmarketing side effects have included hepatitis and hepatic necrosis.

Cholestatic jaundice has developed within 1 to 4 months of initiating therapy. Resolution of jaundice and normalization of hepatic enzymes concentrations occurred upon discontinuation of therapy.

Numerous cases of ticlopidine-induced cholestatic hepatitis have been reported. Time to the onset of hepatotoxicity is variable and ranges from 1 week to 6 months after initiating ticlopidine, 2 to 12 weeks in most patients. In one patient, hepatotoxicity appeared 1 month after discontinuing ticlopidine because of rash. Symptoms and liver abnormalities resolved following discontinuation of ticlopidine, typically within 1 to 3 months; however, recovery time may be protracted (i.e. more than 12 months). Cases of irreversible hepatic damage have not been reported.

Metabolic side effects

Metabolic disturbances have included persistent elevation of total serum cholesterol.

Renal side effects

Reversible renal failure has been reported in patients receiving ticlopidine after stent implantation. Other postmarketing reports have included incidences of nephrotic syndrome.

General side effects

Side effects have occurred in up to 50% of patients. Generally, side effects have been mild and most frequently involved the gastrointestinal tract (30% to 40%). Diarrhea, rash, nausea, vomiting, gastric pain, and neutropenia were the primary cause of a 21% discontinuation rate. Asthenia and generalized pain have been reported.

Nervous system side effects

Nervous system side effects of dizziness, anorexia, and headache have been reported. Postmarketing reports of peripheral neuropathy have been noted.

Hypersensitivity side effects

Postmarketing hypersensitivity reactions have included allergic pneumonitis, angioedema, vasculitis, and serum sickness. Several cases of ticlopidine-induced systemic and cutaneous lupus erythematosus (positive ANA) have been reported. Clinical improvement occurred in all patients following withdrawal of ticlopidine.

Musculoskeletal side effects

Postmarketing musculoskeletal side effects have included arthropathy and myositis. At least one case of ticlopidine-associated arthritis has been reported.

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