Rekloventa (Tablets) Instructions for Use

Marketing Authorization Holder

Elius, LLC (Russia)

Manufactured By

Vertex, JSC (Russia)

ATC Code

B01AC24 (Ticagrelor)

Active Substance

Ticagrelor (Rec.INN registered by WHO)

Dosage Forms

	Rekloventa	Film-coated tablets 60 mg
		Film-coated tablets 90 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

14 pcs. – blister packs (12 pcs.) – cardboard packs (168 pcs.) – By prescription
14 pcs. – blister packs (4 pcs.) – cardboard packs (56 pcs.) – By prescription
15 pcs. – blister packs (12 pcs.) – cardboard packs (180 pcs.) – By prescription
15 pcs. – blister packs (4 pcs.) – cardboard packs (60 pcs.) – By prescription
20 pcs. – blister packs (3 pcs.) – cardboard packs (60 pcs.) – By prescription
20 pcs. – blister packs (9 pcs.) – cardboard packs (180 pcs.) – By prescription

Film-coated tablets

14 pcs. – blister packs (12 pcs.) – cardboard packs (168 pcs.) – By prescription
14 pcs. – blister packs (4 pcs.) – cardboard packs (56 pcs.) – By prescription
15 pcs. – blister packs (12 pcs.) – cardboard packs (180 pcs.) – By prescription
15 pcs. – blister packs (4 pcs.) – cardboard packs (60 pcs.) – By prescription
20 pcs. – blister packs (3 pcs.) – cardboard packs (60 pcs.) – By prescription
20 pcs. – blister packs (9 pcs.) – cardboard packs (180 pcs.) – By prescription

Clinical-Pharmacological Group

Antiplatelet agent

Pharmacotherapeutic Group

Antithrombotic agents; antiplatelet agents, other than heparin

Pharmacological Action

An antiplatelet agent, a representative of the chemical class of cyclopentyltriazolopyrimidines. It is a selective and reversible antagonist of the P2Y₁₂ receptor for adenosine diphosphate (ADP), capable of preventing ADP-mediated P2Y₁₂-dependent activation and aggregation of platelets. Ticagrelor is active when taken orally and reversibly interacts with the P2Y₁₂ ADP receptor of platelets. It does not interact with the ADP binding site itself, but its interaction with the P2Y₁₂ ADP receptor of platelets prevents signal transduction.

Ticagrelor has an additional mechanism of action, increasing local concentrations of endogenous adenosine by inhibiting the endogenous equilibrative nucleoside transporter type 1 (ENT-1). Inhibition of ENT-1 by ticagrelor prolongs the T_1/2 of adenosine and thereby increases its local extracellular concentration, enhancing the local adenosine response. Ticagrelor has no clinically significant direct effect on adenosine receptors (A₁, A_2A, A_2B, A₃) and is not metabolized to adenosine.

In patients with stable coronary artery disease on acetylsalicylic acid, Ticagrelor begins to act rapidly, as confirmed by the results of determining the mean value of platelet aggregation inhibition (PAI): 0.5 hours after taking a loading dose of 180 mg of ticagrelor, the mean PAI value is approximately 41%, the maximum PAI value of 89% is reached 2-4 hours after administration and is maintained for 2-8 hours. In 90% of patients, a final PAI value of more than 70% is achieved 2 hours after administration.

Pharmacokinetics

Ticagrelor is characterized by linear pharmacokinetics; the exposure of ticagrelor and the active metabolite (AR-C124910XX) is approximately proportional to the dose up to 1260 mg.

After oral administration, Ticagrelor is rapidly absorbed with a mean T_max of approximately 1.5 hours. The formation of the main circulating metabolite AR-C124910XX (also active) from ticagrelor occurs rapidly with a mean T_max of approximately 2.5 hours. After administration of a 90 mg dose of ticagrelor on an empty stomach, C_max is 529 ng/ml, AUC is 3451 ng×h/ml. The ratio of C_max and AUC of the metabolite to ticagrelor is 0.28 and 0.42, respectively. The mean absolute bioavailability of ticagrelor is 36%. Intake of fatty food does not affect the C_max of ticagrelor or the AUC of the active metabolite, but leads to a 21% increase in the AUC of ticagrelor and a 22% decrease in the C_max of the active metabolite. These small changes have minimal clinical significance; therefore, Ticagrelor can be administered regardless of food intake.

The plasma protein binding of ticagrelor and its active metabolite is high (>99%). The V_d of ticagrelor at steady state is 87.5 L.

CYP3A4 is the main isoenzyme responsible for the metabolism of ticagrelor and the formation of the active metabolite, and their interaction with other CYP3A substrates varies from activation to inhibition. Ticagrelor and the active metabolite are weak inhibitors of P-glycoprotein.

The main metabolite of ticagrelor is AR-C124910XX, which is also active, as confirmed by the results of in vitro assessment of binding to the P2Y₁₂ ADP receptor of platelets. The systemic exposure of the active metabolite is approximately 30-40% of the exposure of ticagrelor.

The main route of elimination of ticagrelor is hepatic metabolism. After administration of radiolabeled ticagrelor, on average approximately 57.8% of the radioactivity is excreted in the feces, 26.5% in the urine. The excretion of ticagrelor and the active metabolite in the urine is less than 1% of the dose. The active metabolite is mainly excreted in the bile. The mean T_1/2 of ticagrelor and the active metabolite was 7 and 8.5 hours, respectively.

In elderly patients (aged 75 years and older) with acute coronary syndrome, higher exposure of ticagrelor (C_max and AUC approximately 25% higher) and the active metabolite was observed compared to young patients.

The mean bioavailability of the drug in Asian patients is 39% higher than in Caucasians. The bioavailability of ticagrelor is 18% lower in patients of Black race compared to Caucasian patients.

The exposure of ticagrelor and the active metabolite is approximately 20% lower, and its active metabolite is approximately 17% higher in patients with severe renal impairment (CrCl <30 ml/min) compared to patients with normal renal function.

C_max and AUC of ticagrelor were 12% and 23% higher in patients with mild hepatic impairment compared to healthy volunteers.

Indications

In combination with acetylsalicylic acid: for the prevention of atherothrombotic complications in patients with acute coronary syndrome (unstable angina, myocardial infarction without ST-segment elevation or myocardial infarction with ST-segment elevation), including patients receiving drug therapy and patients undergoing percutaneous coronary intervention or coronary artery bypass grafting; for the prevention of atherothrombotic complications in adult patients with a history of myocardial infarction (myocardial infarction occurred 1 year or more ago) and at high risk of atherothrombotic complications; for the prevention of atherothrombotic complications in patients aged 50 years and older with coronary artery disease and type 2 diabetes mellitus, without a history of myocardial infarction and/or stroke, who have undergone percutaneous coronary intervention.

ICD codes

Dosage Regimen

Administer orally with or without food.

For Acute Coronary Syndrome, initiate with a 180 mg loading dose (two 90 mg tablets or three 60 mg tablets).

Follow with a maintenance dose of 90 mg twice daily.

Continue treatment for up to 12 months unless contraindicated.

For long-term secondary prevention post- Myocardial Infarction (occurring one year or more prior), use a 60 mg twice daily maintenance dose.

For patients with coronary artery disease and type 2 diabetes (aged 50 years and older) without prior MI/stroke, use a 60 mg twice daily maintenance dose.

Co-administer with acetylsalicylic acid unless specifically contraindicated. The recommended acetylsalicylic acid maintenance dose is 75-150 mg once daily.

Do not use acetylsalicylic acid maintenance doses exceeding 100 mg.

For patients undergoing Percutaneous Coronary Intervention, initiate therapy with a loading dose prior to the procedure.

For patients undergoing Coronary Artery Bypass Grafting, discontinue ticagrelor at least 5 days before surgery if antiplatelet effect is not desired.

In patients with moderate hepatic impairment, use with caution; it is contraindicated in severe hepatic impairment.

No dose adjustment is required for patients with renal impairment or for elderly patients.

If a dose is missed, take the next dose at the scheduled time; do not double the dose.

Do not discontinue therapy prematurely due to increased risk of cardiovascular events.

Adverse Reactions

Immune system disorders uncommon – hypersensitivity reactions, including angioedema.

Metabolism and nutrition disorders very common – hyperuricemia; common – gout, gouty arthritis.

Psychiatric disorders uncommon – confusion.

Nervous system disorders common – headache, dizziness, syncope; uncommon – intracranial hemorrhage.

Eye disorders uncommon – eye hemorrhage.

Ear and labyrinth disorders common – vertigo; uncommon – ear bleeding.

Cardiac disorders common – arterial hypotension.

Respiratory, thoracic and mediastinal disorders very common – dyspnea; common – respiratory tract bleeding.

Gastrointestinal disorders common – gastrointestinal bleeding, diarrhea, nausea, dyspepsia, constipation; uncommon – retroperitoneal bleeding.

Skin and subcutaneous tissue disorders common – subcutaneous or skin bleeding, skin itching, rash.

Musculoskeletal and connective tissue disorders uncommon – muscle hemorrhage.

Renal and urinary disorders uncommon – genital bleeding.

Reproductive system and breast disorders uncommon – genital bleeding.

Investigations common – increased blood creatinine concentration.

General disorders and administration site conditions very common – bleeding related to blood disorders (e.g., increased tendency to bruise, spontaneous hematoma, hemorrhagic diathesis); common – post-procedural bleeding, traumatic bleeding; uncommon – tumor bleeding (e.g., bladder tumor bleeding, gastric tumor bleeding, colon tumor bleeding); frequency unknown – thrombotic thrombocytopenic purpura.

Contraindications

Active pathological bleeding; history of intracranial hemorrhage; severe hepatic impairment; concomitant use of ticagrelor with potent inhibitors of CYP3A4 (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir); age under 18 years; pregnancy, breastfeeding period; hypersensitivity to ticagrelor.

Use in Pregnancy and Lactation

The use of ticagrelor is contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment.

Should be used with caution in patients with moderate hepatic impairment.

Use in Renal Impairment

Should be used with caution in patients with moderate or severe renal impairment.

Pediatric Use

Contraindicated in patients under 18 years of age.

Special Precautions

Ticagrelor should be used with caution in patients predisposed to bleeding (e.g., due to recent trauma, recent surgery, coagulation disorders, moderate hepatic impairment, active or recent gastrointestinal bleeding) or at increased risk of injury; in patients with concomitant therapy with drugs that increase the risk of bleeding (i.e., NSAIDs, oral anticoagulants and/or fibrinolytics) within 24 hours before taking ticagrelor; in patients with a previous ischemic stroke when therapy duration is more than 1 year (for patients with a history of myocardial infarction); in patients with moderate hepatic impairment; in patients with an increased risk of bradycardia (e.g., patients with sick sinus syndrome without a pacemaker, with second- or third-degree AV block; syncope associated with bradycardia); concomitantly with drugs that cause bradycardia; in patients with a history of bronchial asthma and/or COPD; in patients aged 75 years and older; in patients with moderate or severe renal impairment; in patients receiving therapy with angiotensin II receptor antagonists; in patients with hyperuricemia or gouty arthritis; with concomitant therapy with digoxin, potent inhibitors of P-glycoprotein and moderate inhibitors of the CYP3A4 isoenzyme (e.g., verapamil and quinidine), selective serotonin reuptake inhibitors (e.g., paroxetine, sertraline and citalopram).

Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or therapy with recombinant factor VIIa may enhance hemostasis. After the cause of bleeding has been established and it has been stopped, ticagrelor therapy can be resumed.

If a patient is scheduled for surgery and the antithrombotic effect is not desired, ticagrelor therapy should be discontinued 5 days before surgery.

Patients with acute coronary syndrome with a previous ischemic stroke can take Ticagrelor for up to 12 months.

In the absence of data, therapy lasting more than 1 year should be carried out with caution (for patients with a history of myocardial infarction).

During the use of ticagrelor, an increase in serum creatinine content is possible, therefore, it is necessary to assess renal function in accordance with routine clinical practice, paying special attention to patients aged 75 years and older, patients with moderate and severe renal impairment, patients receiving therapy with angiotensin II receptor antagonists.

Caution is required when using ticagrelor in patients with a history of hyperuricemia or gouty arthritis. As a preventive measure, the use of ticagrelor should be avoided in patients with hyperuricemic nephropathy.

Thrombotic thrombocytopenic purpura has been very rarely reported during the use of ticagrelor, which is a serious condition and requires immediate treatment.

False-negative results of platelet function analysis in the diagnosis of heparin-induced thrombocytopenia were obtained in patients taking Ticagrelor. This is due to the inhibition of P2Y₁₂ receptors of healthy donor platelets by ticagrelor when the test is performed in the patient’s serum/plasma. Information about concomitant therapy with ticagrelor should be taken into account when interpreting the results of platelet function analysis in the diagnosis of heparin-induced thrombocytopenia. Before considering the possibility of discontinuing ticagrelor, the benefits and risks of continuing therapy should be assessed, taking into account both the prothrombotic state due to heparin-induced thrombocytopenia and the increased risk of bleeding with the concomitant use of an anticoagulant and ticagrelor.

Concomitant use of ticagrelor and acetylsalicylic acid in a high maintenance dose (more than 300 mg) is not recommended.

Early discontinuation of any antiplatelet therapy, including Ticagrelor, may increase the risk of cardiovascular death, myocardial infarction, or stroke due to the underlying disease. Premature discontinuation of the drug should be avoided.

Effect on ability to drive vehicles and operate machinery

Dizziness and confusion have been reported during therapy with ticagrelor. If these phenomena occur, patients should exercise caution when driving vehicles and operating other machinery.

Drug Interactions

Concomitant use of ticagrelor with potent inhibitors of CYP3A4 (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir) is contraindicated, as it may lead to a significant increase in ticagrelor exposure.

Concomitant use of ticagrelor with potent inducers of CYP3A4 (e.g., rifampicin, phenytoin, carbamazepine and phenobarbital) is not recommended, as their concomitant use may reduce the exposure and effectiveness of ticagrelor.

Moderate inhibitors of CYP3A4: concomitant use of diltiazem with ticagrelor increases the C_max of ticagrelor by 69% and AUC by 2.7 times, while reducing the C_max of the active metabolite by 38% and AUC does not change. Ticagrelor does not affect the plasma concentrations of diltiazem. Other moderate inhibitors of CYP3A4 (e.g., amprenavir, aprepitant, erythromycin, fluconazole) can be prescribed simultaneously with ticagrelor.

According to the results of pharmacological interaction studies, concomitant use of ticagrelor with heparin, enoxaparin and acetylsalicylic acid or desmopressin does not affect the pharmacokinetics of ticagrelor, its active metabolite and ADP-dependent platelet aggregation. If there are clinical indications for the prescription of drugs affecting hemostasis, they should be used with caution in combination with ticagrelor.

There are no data on the concomitant use of ticagrelor with potent inhibitors of P-glycoprotein (e.g., verapamil, quinidine and cyclosporine), which can increase the exposure of ticagrelor. If concomitant use cannot be avoided, then combination therapy should be carried out with caution.

A slowdown and decrease in the exposure of oral P2Y₁₂ inhibitors, including Ticagrelor and its active metabolite, was noted in patients receiving morphine therapy (reduction in ticagrelor exposure by approximately 35%). This interaction may be associated with a decrease in gastrointestinal motility and therefore applicable to other opioids. The clinical significance is unknown, but the data indicate a possible decrease in the effectiveness of ticagrelor in patients simultaneously receiving Ticagrelor and morphine. In patients with acute coronary syndrome in whom the use of morphine cannot be delayed and rapid P2Y₁₂ inhibition is considered critical, the use of a parenteral P2Y₁₂ inhibitor may be considered.

Concomitant use of simvastatin at a dose of more than 40 mg/day with ticagrelor may lead to the development of side effects of simvastatin. Therefore, if this combination is necessary, the ratio of potential risk and benefit of therapy should be assessed. Concomitant use of ticagrelor with simvastatin and lovastatin at a dose of more than 40 mg is not recommended. Concomitant use of atorvastatin and ticagrelor increases the C_max and AUC of atorvastatin acid metabolites by 23% and 36%, respectively. A similar increase in C_max and AUC values is observed for all atorvastatin acid metabolites. These changes are considered clinically insignificant. Similar effects with statins metabolized by CYP3A4 cannot be excluded.

Ticagrelor is a weak inhibitor of CYP3A4. Concomitant use with CYP3A4 substrates with a narrow therapeutic index (for example, cisapride or ergot alkaloids) is not recommended, as Ticagrelor may increase the exposure of these drugs.

When digoxin was co-administered with ticagrelor, the mean C_min of digoxin increased by approximately 30%, and in some individual cases, doubled. The C_max and AUC of ticagrelor and its active metabolite were not changed with digoxin use. Therefore, appropriate clinical and/or laboratory monitoring (heart rate, and if clinically indicated, also ECG and blood digoxin concentrations) is recommended during the concomitant use of ticagrelor and P-gp-dependent drugs with a narrow therapeutic index, such as digoxin.

Concomitant use of ticagrelor, levonorgestrel, and ethinylestradiol increases the exposure of ethinylestradiol by approximately 20%, but does not affect the pharmacokinetics of levonorgestrel. A clinically significant effect on contraceptive efficacy is not expected with the concomitant use of levonorgestrel, ethinylestradiol, and ticagrelor.

Due to the identification of mostly asymptomatic ventricular pauses and bradycardia, Ticagrelor should be used with caution in combination with medicinal products that can cause bradycardia.

Concomitant use of ticagrelor with heparin, enoxaparin, or desmopressin did not affect aPTT, activated clotting time, and anti-Factor Xa assay; however, due to a potential pharmacodynamic interaction, caution is required when co-administering with drugs affecting hemostasis.

Due to reports of subcutaneous hemorrhages with selective serotonin reuptake inhibitors (for example, paroxetine, sertraline, and citalopram), caution is advised when they are co-administered with ticagrelor.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.