Platelet aggregation inhibitor.
Aplagrel Plus is indicated for the prevention of atherothrombotic events in adult patients who are already taking clopidogrel and acetylsalicylic acid (ASS). Aplagrel Plus is a fixed-dose combination drug for continuation treatment in:
- Acute coronary syndrome without ST segment elevation (unstable angina or acute myocardial infarction without Q wave), including patients who have had a stent placed after percutaneous coronary intervention.
- Patients with acute myocardial infarction with ST-segment elevation, who are candidates for thrombolytic therapy.
- To prevent thromboembolic and atherothrombotic events including stroke in patients with atrial fibrillation who have at least one vascular risk factor.
Pharmacological characteristics / Properties
Clopidogrel is a prodrug, it must be metabolized through CYP450 to give rise to the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor P2Y12 and subsequent activation of the GPIIB-IIA complex mediated by ADP, thereby inhibiting platelet aggregation. Due to irreversible binding, exposed platelets are affected for the rest of their life (approximately 7-10 days), and recovery of normal platelet function occurs at a rate that depends on the degree of platelet turnover. Platelet aggregation induced by other agonists other than ADP is also inhibited by blocking amplification of platelet activation by released ADP. Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other medications, not all patients would have adequate platelet inhibition.
Repeated dose administration of clopidogrel 75 mg / day produces, from the first day, considerable inhibition of ADP-induced platelet aggregation; it progressively increases and reaches steady state between day 3 and day 7. In steady state, the mean level of inhibition observed at a dose of 75 mg / day is between 40% and 60%. In general, platelet aggregation and bleeding time gradually return to baseline within 5 days after stopping treatment.
Clopidogrel is rapidly absorbed after administration of single and repeated oral doses of 75 mg / day.
Average plasma peak levels after a single 75-mg oral dose appear approximately 45 minutes after the dose. Absorption is less than 50% calculated based on the urinary excretion of clopidogrel metabolites. Clopidogrel and the circulating (inactive) major metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively).
Clopidogrel is extensively metabolized in the liver. Approximately 50% is excreted in the urine and approximately 46% faecally within 120 hours of administration. After a single 75-mg oral dose, Clopidogrel has a half-life of approximately 6 hours. The elimination half-life of the major circulating (inactive) metabolite is 8 hours after administration of single and repeated doses.
Acetylsalicylic acid (AAS):
It inhibits platelet aggregation by irreversible inhibition of cyclooxygenase and also inhibits the generation of thromboxane A2, an inducer of platelet aggregation and vasoconstrictor. This effect remains throughout the life of platelets. Upon absorption, the ASA in Aplagrel Plus is hydrolyzed to salicylic acid with peak plasma levels at the time of dosing, such plasma levels of ASA are essentially undetectable after 1.5-3 hours after dosing. ASA binds weakly to plasma proteins and its apparent volume of distribution is low. Its metabolite, salicylic acid binds strongly to plasma proteins, but its binding is depending on the concentration (non-linear), 90% of salicylic acid binds to albumin. Salicylic acid is widely distributed throughout the body’s tissues and fluids, including the central nervous system, breast milk, and fetal tissue.
ASA is rapidly hydrolyzed in plasma to salicylic acid, with a half-life of 0.3 and 0.4 hours for ASA doses of 75 to 100 mg. Salicylic acid is primarily conjugated in the liver to the form of salicylic acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites. After therapeutic doses, approximately 10% is excreted in the urine as salicylic acid, 75% as salicylic acid, 10% phenolic, and 5% acyl glucuronides of salicylic acid.
Hypersensitivity to the active substances or to any of the excipients, severe liver failure, pathological active bleeding, hypersensitivity to non-steroidal anti-inflammatory drugs and in patients with asthma, rhinitis and nasal polyps, severe renal failure, third trimester of pregnancy.
The use of Aplagrel Plus is not recommended in children and adolescents under 18 years of age.
Aplagrel Plus should be administered with caution in patients who are at high risk of bleeding due to trauma, surgery or derived from other pathologies. In patients with recent transient ischemic attack or stroke at high risk of recurrent ischemic episodes, the combination of ASA and clopidogrel has shown an increase in major bleeding. It should be used with caution in patients with a history of peptic ulcer or gastroduodenal hemorrhage or minor symptoms of the upper GI tract.
Aplagrel Plus should be administered with caution with other thrombolytic agents.
Due to the possible increase in the intensity of bleeding, the concomitant administration of warfarin with clopidogrel and ASA is not recommended. Concomitant use with NSAIDs including COX-2 inhibitors is not recommended. The use of drugs that inhibit the activity of the CYP2C19 enzyme is expected to result in a reduction in the levels of the active metabolite of clopidogrel; its use with strong or moderate enzyme inhibitors should be avoided; if the use of a proton pump inhibitor is necessary, one with weak activity on the CYP2C19 enzyme, such as pantoprazole, should be used. Interactions reported with ASA: uricosurics, methotrexate.
Common: hematoma, gastrointestinal bleeding, diarrhea, abdominal pain, dyspepsia, bleeding; Uncommon: thrombocytopenia, leukopenia, eosinophilia, intracranial hemorrhage, ocular hemorrhage, gastric ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence, rash, pruritus, bleeding from the skin, hematuria, increased bleeding time, decreased blood count platelets.
Sale under prescription. Keep out of reach of children.
Each coated tablet contains:
Clopidogrel bisulfate equivalent to 75 mg Clopidogrel.
Acetylsalicylic acid (AAS): 81 mg.
Oral, with or without food. The coated tablet should be swallowed whole, not broken or chewed.
Adults and elderly patients:
Aplagrel Plus should be administered as a single 75 mg / 81 mg dose and is used after initiating treatment with clopidogrel and ASA separately.
In patients with ACS without ST segment elevation: the maximum duration of treatment has not been established. In patients with ST-segment elevation AMI, treatment should be started as soon as possible after the first symptoms begin and continued for at least four weeks.
If you miss a dose:
- When less than 12 hours have passed after the usual time: patients should take the dose immediately and take the next dose at the usual time.
- When more than 12 hours have passed: patients should take the next dose at the usual time and should not double the dose.
Box containing 1 blister with 10 coated tablets.
Box containing 3 blisters with 10 coated tablets each.
Keep in a place at a temperature below 30 ° C. Protect from light and moisture.