Side Effects of Ticlid (ticlopidine)

Ticlid (ticlopidine) is a P2Y12 inhibitor that inhibits the ability of platelets to clump and form blood clots. Ticlid, a discontinued brand in the U.S., is a medication prescribed for preventing strokes or TIAs (mini-strokes), and for preventing blood clots in stents placed in the heart.

Off-label uses include prevention of heart attacks in individuals with unstable angina or who have experienced previous heart attacks, in combination with aspirin for preventing blood clots in stents, and for intermittent claudication.

It prevents blood clots by binding to the P2Y12 receptor on platelets, preventing adenosine diphosphate (ADP) from activating platelets. Blood clots that form within the arteries of the brain or pieces of blood clots that break off from clots in other parts of the body and lodge in blood vessels in the brain cause strokes. 

Similarly, heart attacks occur when blood clots block an artery in the heart. In both cases the blood supply to part of the brain or heart is blocked, and that part of the brain or heart is damaged or dies. Ticlid works by making the blood less likely to clot, reducing the likelihood of a stroke or heart attack. 

Common side effects of Ticlid include:

• diarrhea,
• nausea,
• rash,
• stomach upset, and
• vomiting.

Serious side effects of Ticlid include a severe reduction in white blood cell count. Ticlid also causes a serious condition called thrombotic thrombocytopenic purpura (TTP) in which blood clots form throughout the body. 

Drug interactions of Ticlid include other drugs such as the following that promote bleeding because this increases the risk of bleeding:

• aspirin,
• warfarin, and
• heparin. 

Ticlid may increase duloxetine levels by reducing the breakdown of duloxetine in the liver and thereby lead to side effects from duloxetine. 

The combination may also increase the risk of bleeding because duloxetine can interfere with platelet function. 

Ticlid may increase pimozide levels by reducing the breakdown of pimozide in the liver. Increased pimozide levels may cause abnormal heart rhythms. 

Ticlid has not been adequately studied in pregnant women. It is unknown if Ticlid is secreted in human breast milk. Consult your doctor before breastfeeding.

Common side effects of ticlopidine include:

• diarrhea,
• nausea,
• rash,
• stomach upset, and
• vomiting.

Ticlopidine has been associated with a severe reduction in white blood cell count. Ticlopidine also causes a condition called thrombotic thrombocytopenic purpura (TTP). TTP is a serious condition in which blood clots form throughout the body. Blood platelets, which participate in clotting, are consumed, and the result can be bleeding because enough platelets are no longer left to allow blood to clot normally.

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 (ticlopidine hcl) , 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 (ticlopidine hcl) are shown in the following table:

Percent of Patients With Adverse Events in Controlled Studies (TASS and CATS)

Incidence of discontinuation, regardless of relationship to therapy, is shown in parentheses.

Hematological: Neutropenia/thrombocytopenia, TTP, aplastic anemia, leukemia, agranulocytosis, eosinophilia, pancytopenia, thrombocytosis and bone-marrow depression have been reported.

Gastrointestinal: Ticlid (ticlopidine hcl) 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 (ticlopidine hcl) 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 (ticlopidine hcl) , 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 (ticlopidine hcl) 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.

Therapeutic doses of Ticlid (ticlopidine hcl) caused a 30% increase in the plasma half-life of antipyrine and may cause analogous effects on similarly metabolized drugs. Therefore, the dose of drugs metabolized by hepatic microsomal enzymes with low therapeutic ratios or being given to patients with hepatic impairment may require adjustment to maintain optimal therapeutic blood levels when starting or stopping concomitant therapy with ticlopidine. Studies of specific drug interactions yielded the following results:

Aspirin and Other NSAIDs: Ticlopidine potentiates the effect of aspirin or other NSAIDs on platelet aggregation. The safety of concomitant use of ticlopidine and NSAIDs has not been established. The safety of concomitantuse of ticlopidine and aspirin beyond 30 days has not been established. Aspirin did not modify the ticlopidine-mediated inhibition of ADP-induced platelet aggregation, but ticlopidine potentiated the effect of aspirin on collagen-induced platelet aggregation. Caution should be exercised in patients who have lesions with a propensity to bleed, such as ulcers. Long-term concomitant use of aspirin and ticlopidine is not recommended.

Antacids: Administration of Ticlid (ticlopidine hcl) after antacids resulted in an 18% decrease in plasma levels of ticlopidine.

Cimetidine: Chronic administration of cimetidine reduced the clearance of a single dose of Ticlid (ticlopidine hcl) by 50%.

Digoxin: Coadministration of Ticlid (ticlopidine hcl) with digoxin resulted in a slight decrease (approximately 15%) in digoxin plasma levels. Little or no change in therapeutic efficacy of digoxin would be expected.

Theophylline: In normal volunteers, concomitant administration of Ticlid (ticlopidine hcl) resulted in a significant increase in the theophylline elimination half-life from 8.6 to 12.2 hours and a comparable reduction in total plasma clearance of theophylline.

Phenobarbital: In 6 normal volunteers, the inhibitory effects of Ticlid (ticlopidine hcl) on platelet aggregation were not altered by chronic administration of phenobarbital.

Phenytoin: In vitro studies demonstrated that ticlopidine does not alter the plasma protein binding of phenytoin. However, the protein binding interactions of ticlopidine and its metabolites have not been studied in vivo. Several cases of elevated phenytoin plasma levels with associated somnolence and lethargy have been reported following coadministration with Ticlid (ticlopidine hcl) . Caution should be exercised in coadministering this drug with Ticlid (ticlopidine hcl) , and it may be useful to remeasure phenytoin blood concentrations.

Propranolol: In vitro studies demonstrated that ticlopidine does not alter the plasma protein binding of propranolol. However, the protein binding interactions of ticlopidine and its metabolites have not been studied in vivo. Caution should be exercised in coadministering this drug with Ticlid (ticlopidine hcl) .

Other Concomitant Therapy: Although specific interaction studies were not performed, in clinical studies Ticlid (ticlopidine hcl) was used concomitantly with beta blockers, calcium channel blockers and diuretics without evidence of clinically significant adverse interactions.

Food Interaction: The oral bioavailability of ticlopidine is increased by 20% when taken after a meal. Administration of Ticlid (ticlopidine hcl) with food is recommended to maximize gastrointestinal tolerance. In controlled trials in stroke patients, Ticlid (ticlopidine hcl) was taken with meals.