Ipaton® [Ticlopidine]

Pharmacological properties

Ticlopidine ([5- (2- [chlorophenyl) -4,5,6,7, -tetrahydro-thieno [3,2-c] pyridine hydrochloride) is an antiplatelet agent with a unique pharmacological profile (mechanism of action). ticlopidine exhibits an antagonistic effect on adf, inhibits platelet aggregation and adhesion caused by adf, also by other factors (arachidonic acid, collagen, thrombin, platelet activation factor), causes increased platelet disaggregation.

The effect of inhibition of platelet aggregation can be observed already 2 days after taking the drug at a dose of 250 mg 2 times a day. The maximum antiplatelet effect is noted on the 5-8th day of treatment.

Ticlopidine reduces fibrinogen levels and blood viscosity in patients with chronic obliterating diseases of the lower limb arteries; normalizes platelet adhesion, erythrocyte elasticity and beta-thromboglobulin release in patients with diabetes mellitus. After discontinuation of the drug, its therapeutic effect remains for at least 1 week. The mechanism of action is not completely defined. It is believed that the drug interacts with glycoprotein IIb / IIIa by inhibiting the binding of fibrinogen to activated platelets. The drug does not affect the metabolism of prostanoids.

After a single oral administration in a therapeutic dose, ticlopidine is rapidly and almost completely absorbed. The maximum concentration in blood plasma is reached after 2 hours. The maximum bioavailability of the drug is observed when it is taken after a meal. Equilibrium plasma concentration is reached after 7-10 days of daily intake at a dose of 250 mg 2 times a day. The effect of inhibition of platelet aggregation does not depend on the level of the drug in blood plasma. About 98% of ticlopidine reversibly binds to plasma proteins. Ticlopidine is rapidly metabolized in the body to form one active metabolite. It is excreted mainly with urine (50-60%) and bile (23-30%). The elimination half-life is 30-50 hours.

Indications

Prevention of cerebrovascular and cardiovascular acute ischemic complications in patients with impaired cerebral and peripheral arterial circulation.

Prevention and correction of platelet dysfunction due to cardiopulmonary bypass during surgery and hemodialysis.

Prevention of occlusion after implantation of a coronary stent.

Application of Ipatonaccording to the indicated indications, it is recommended first of all to patients with intolerance or allergy to acetylsalicylic acid or in case of the ineffectiveness of her treatment.

Application

The usual dose for adults is 1 tablet 2 times a day with meals. for elderly patients, the usual dose for adults. tablets do not chew, drink plenty of fluids (water, juice). the duration of treatment is set individually.

In order to prevent occlusion after implantation of a coronary stent, it is recommended to begin treatment immediately before or immediately after implantation of the stent, 1 tablet of Ipaton 2 times a day in combination with 100–325 mg of acetylsalicylic acid per day. The duration of the combined treatment is at least 1 month.

Contraindications

Hypersensitivity to ticlopidine and / or other ingredients of the drug; hemorrhagic diathesis; blood diseases accompanied by an increase in bleeding time; organic lesions with a tendency to bleeding (exacerbation of peptic ulcer of the stomach and duodenum, hemorrhagic stroke in the acute and subacute periods); leukopenia, thrombocytopenia and agranulocytosis (including a history); high dose heparin treatment; liver disease with clinical manifestations of hepatitis or jaundice; During pregnancy and breastfeeding; children and adolescents under the age of 14 years.

In no case should the drug be used as a means of preventing thromboembolism in healthy patients.

Side effects

Hyperemia and nosebleeds are the most common hemorrhagic complications. in isolated cases, intra- and postoperative bleeding occurred.

From the hematopoietic system

Neutropenia, severe neutropenia (450 / mm³ neutrophilic white blood cells), agranulocytosis (in the first 3 months of treatment). Occasionally, bone marrow aplasia, pancytopenia, thrombocytopenia (80,000 / mm³) In some cases, thrombotic thrombocytopenic purpura (TTP, Moshkovich syndrome), as well as hemolytic anemia, can occur.

From the gastrointestinal tract

Most often, nausea and diarrhea. Diarrhea is usually mild, short-lived and occurs most often in the first 3 months of treatment. As a rule, this side effect disappears within 1-2 weeks, while there is no need to stop treatment with Ipaton. Diarrheal colitis (including lymphocytic colitis) can very rarely develop. Treatment should be discontinued if the disease is severe or prolonged.

Skin reactions

During the first 3 months of therapy, skin rashes (maculopapular or urticaria, often accompanied by itching). More often, changes in the skin disappear in the first few days after discontinuation of treatment, but in rare cases can spread. Very rarely, erythema multiforme and Stevens-Johnson syndrome can develop.

From the liver

Rarely - hepatitis and cholestatic jaundice, more often in the 1st month of treatment. After discontinuation of Ipaton therapy, liver function is restored.

Immunological reactions

Rarely, allergic reactions, anaphylaxis, Quinckes edema, arthralgia, vasculitis, lupus syndrome, nephropathy, allergic interstitial pneumonia.

Other side effects

Very rarely dizziness, headache, peripheral neuropathy, weakness, loss of appetite occur. Occasionally - lethargy, decreased concentration, tinnitus, tachycardia, nervousness.

special instructions

The drug can cause severe and sometimes fatal hematological reactions (neutropenia / agranulocytosis, thrombotic thrombocytopenic purpura), as well as hemorrhage, only in cases:

inappropriate clinical and hematological monitoring;

late diagnosis and inadequate monitoring of the patients condition with the appearance and development of side effects;

the simultaneous use of NSAIDs that inhibit the aggregation of platelets, salicylates and anticoagulants. However, when implanting a coronary stent, Ipaton should be used in combination with acetylsalicylic acid (100–325 mg / day) for at least 1 month after surgery.

At the beginning of therapy, as well as every 2 weeks during the first 3 months of treatment, hematological monitoring is necessary (general blood test with the determination of the leukocyte formula, determination of the level of platelets, bleeding time).

In the case of a reasonable cessation of treatment with Ipaton in the first 3 months of therapy, a repeated hematological examination should be carried out within 15 days after the cessation of drug treatment. Isolated cases of severe side effects from the hematopoietic organs were noted after the 3rd month of treatment with ticlopidine.

With neutropenia (neutrophilic granulocyte level of 1500 / mm³), thrombocytopenia (platelet count 100,000 / mm³) should immediately stop treatment and conduct hematological monitoring of the patients condition until normalization.

The decision to resume treatment with Ipaton should be based on an assessment of clinical signs and laboratory findings.

In the case of a complication such as thrombotic thrombocytopenic purpura (TTP, Moshkovich syndrome), thrombocytopenia, hemolytic anemia, neurological symptoms, impaired renal function and fever are noted. TTP develops suddenly and most often in the first 8 weeks of treatment. Since this complication can be fatal, a hematologist should be consulted for timely diagnosis of this complication if it is suspected. Plasmapheresis improves the prognosis of the outcome of this complication.

The drug should be used with extreme caution under medical supervision of patients with a tendency to hemorrhage / bleeding.

With planned surgical interventions (except in cases of the absolute need for antiplatelet therapy), due to the risk of excessive bleeding, it is necessary to stop using the drug at least 10 days before the planned operation.

In case of emergency surgery, the risk of an increase in bleeding time can be reduced by applying 0.5–1.0 mg / kg iv body weight of iv (if necessary repeatedly) and / or 0.2–0.4 μg / kg desmopressin and / or platelet-rich blood plasma.

Since ticlopidine is extensively metabolized by the liver, the treatment of patients with liver pathology requires special care, as well as in certain cases of dose reduction. Therapy should be discontinued if hepatitis or jaundice develops. The use of the drug is contraindicated in severe liver failure.

Ticlopidine is well tolerated by patients with mild to moderate renal failure. In severe renal failure, the excretion of ticlopidine decreases, and the concentration in the blood serum increases. Therefore, it may be necessary to reduce the dose of ticlopidine, and with the development of hematological side effects, discontinuation of treatment.

Therapy should be discontinued if prolonged and / or excessive diarrhea and nausea occur.

Patients should be warned about the need to inform the doctor about taking Ipaton before any surgical intervention or surgical dental manipulation. Patients should be warned about the need to immediately seek medical advice in case of any allergic skin reactions, bleeding, hematoma, fever, pharyngitis, wounds on the oral mucosa, sore throat, long-term persistent diarrhea, jaundice. Treatment should be discontinued if any of these side effects occur.

A blood test should be performed immediately if there is a fever, pharyngitis or wounds on the mucous membrane of the oral cavity. The decision to discontinue or continue treatment is based on an assessment of the results of hemogram indicators.

Sometimes taking the drug can cause dizziness, weakness, lethargy, tinnitus, and also reduce the ability to concentrate.

The restriction or prohibition of driving vehicles and performing work requiring increased attention should be determined individually.

Interactions

Special care should be taken when using ticlopidine in combination with such drugs:

theophylline (increases theophylline level in blood plasma). If necessary, combined use should monitor theophylline level in blood plasma;

digoxin (the level of digoxin in blood plasma is reduced by approximately 15%);

phenytoin (the level of phenytoin in blood plasma rises). It is recommended to monitor the concentration of phenytoin in blood plasma;

cyclosporine (simultaneous administration can lead to a decrease in the concentration of cyclosporine in blood plasma, which requires careful monitoring).

Due to the increased risk of hemorrhage with the combined use of Ipaton and the following drugs, special care and constant laboratory monitoring are necessary: ​​NSAIDs; oral anticoagulants (should be checked more often INR - international normalized ratio); heparin preparations (in the case of unfractionated heparin, regular monitoring of the formation time and thromboplastin activity is necessary); antiplatelet preparations, for example, salicylic acid derivatives.

In healthy patients, prolonged use of phenobarbital does not affect the antiplatelet effect of ticlopidine.

Clinically significant drug interactions with the simultaneous administration of ticlopidine with β-adrenergic blockers, calcium channel blockers and diuretics were not observed.

Overdose

Symptoms: overdose cases not described. any additional manifestations, except for the known effect of the drug on the blood coagulation system, with an overdose of ticlopidine is not expected.

Treatment: remove from the body the remains of the drug, which has not yet been absorbed, induce vomiting, and rinse the stomach.

Patients need careful monitoring.

When bleeding occurs, in order to inhibit the effect of ticlopidine, desmopressin or platelet transfusion is prescribed.

Storage conditions

At temperatures up to 25 ° C.