PLASEP (Clopidogrel Tablets USP 75mg)

PLASEP (Clopidogrel Tablets USP 75mg)

PLASEP (Clopidogrel Tablets USP 75mg)

Pharmacotherapeutic group: platelet aggregation inhibitors excl. heparin, ATC Code: B01AC-04.

Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation.

Clopidogrel must be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversible binding, platelets exposed are affected for the remainder of their lifespan (approximately 7-10 days) and recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the 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 medicinal products, not all patients will have adequate platelet inhibition.

Therapeutic indications

Secondary prevention of atherothrombotic events

Clopidogrel is indicated in:

  • Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease.
  • Adult patients suffering from acute coronary syndrome:

Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA).

ST segment elevation acute myocardial infarction, in combination with ASA in medically treated patients eligible for thrombolytic therapy.

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation

In adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke.

Posology and method of administration

Posology:

Adults and elderly: Clopidogrel should be given as a single daily dose of 75mg. In patients suffering from acute coronary syndrome.

Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction): clopidogrel treatment should be initiated with a single 300-mg loading dose and then continued at 75 mg once a day (with acetylsalicylic acid (ASA) 75 mg-325 mg daily).

Since higher doses of ASA were associated with higher bleeding risk it is recommended that the dose of ASA should not be higher than 100 mg. The optimal duration of treatment has not been formally established. Clinical trial data support use up to 12 months, and the maximum benefit was seen at 3 months.

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ST segment elevation acute myocardial infarction: clopidogrel should be given as a single daily dose of 75 mg initiated with a 300-mg loading dose in combination with ASA and with or without thrombolytics. For patients over 75 years of age clopidogrel should be initiated without a loading dose. Combined therapy should be started as early as possible after symptoms start and continued for at least four weeks. The benefit of the combination of clopidogrel with ASA beyond four weeks has not been studied in this setting.

In patients with atrial fibrillation, clopidogrel should be given as a single daily dose of 75 mg. ASA (75-100 mg daily) should be initiated and continued in combination with clopidogrel.

If a dose is missed:

  • Within less than 12 hours after regular scheduled time: patients should take the dose immediately and then take the next dose at the regular scheduled time.
  • For more than 12 hours: patients should take the next dose at the regular scheduled time and should not double the dose.

Paediatric population: Clopidogrel should not be used in children because of efficacy concerns.

Renal impairment: Therapeutic experience is limited in patients with renal impairment.

Hepatic impairment: Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses.

Method of administration

For oral use. It may be given with or without food.

Contraindications

  • Hypersensitivity to the active substance or to any of the excipients
  • Severe hepatic impairment.
  • Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.

Special warnings and precautions for use

Bleeding and haematological disorders: Due to the risk of bleeding and haematological adverse reactions, blood cell count determinationand/or other appropriate testing should be promptly considered whenever clinical symptomssuggestive of bleeding arise during the course of treatment. As with otherantiplatelet agents, clopidogrel should be used with caution in patients who may be at risk ofincreased bleeding from trauma, surgery or other pathological conditions and in patients receivingtreatment with ASA, heparin, glycoprotein IIb/IIIa inhibitors or non-steroidal anti-inflammatorydrugs (NSAIDs) including Cox-2inhibitors. Patients should be followed carefully for any signs ofbleeding including occult bleeding, especially during the first weeks of treatment and/or afterinvasive cardiac procedures or surgery. The concomitant administration of clopidogrel with oralanticoagulants is not recommended since it may increase the intensity of bleedings.

Patients should be told that it might take longer than usual to stop bleeding when they take clopidogrel (alone or in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician.

Thrombotic Thrombocytopenic Purpura (TTP): Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use ofclopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia andmicroangiopathic haemolytic anaemia associated with either neurological findings, renaldysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment includingplasmapheresis.

Recent ischaemic stroke: In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acuteischaemic stroke.

Cytochrome P450 2C19 (CYP2C19): Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, clopidogrel at recommendeddoses forms less of the active metabolite of clopidogrel and has a smaller effect on plateletfunction. Tests are available to identify a patient’s CYP2C19 genotype.

Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged.

CYP2C8 substrates: Caution is required in patients treated concomitantly with clopidogrel and CYP2C8 substratemedicinal products.

Cross reactions among thienopyridines: Patients should be evaluated for history of hypersensitivity to thienopyridines (such asclopidogrel, ticlopidine, prasugrel) since cross reactivity among thienopyridines has been reported. Thienopyridines may cause mild to severe allergic reactions such as rash,angioedema, or haematological cross reactions such as thrombocytopenia and neutropenia.

Patients who had developed a previous allergic reaction and/or haematological reaction to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for signs of hypersensitivity in patients with a known allergy to thienopyridines is advised.

Renal impairment: Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore,clopidogrel should be used with caution in these patients.

Hepatic impairment: Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses.Clopidogrel should therefore be used with caution in this population.

Excipients: Clopidogrel contains lactose. Patients with rare hereditary problems of galactose intolerance, theLapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.This medicinal product contains hydrogenated castor oil which may cause stomach upset anddiarrhoea.

Interaction with other medicinal products and other forms of interaction

Medicinal products associated with bleeding risk: There is an increased risk of bleeding due to the potential additive effect. The concomitantadministration of medicinal products associated with bleeding risk should be undertakenwith caution.

Oral anticoagulants: The concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings. Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin or International Normalised Ratio (INR) in patients receiving long-term warfarin therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis.

Glycoprotein IIb/IIIa inhibitors: Clopidogrel should be used with caution in patients who receive concomitant glycoprotein IIb/IIIa inhibitors.

Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution. However, clopidogrel and ASA have been administered together for up to one year.

Heparin: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution.

Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are co-administered with ASA.

NSAIDs: in a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox-2 inhibitors and clopidogrel should be co-administered with caution.

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Other concomitant therapy: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged.

Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.

Fertility, pregnancy and lactation

Pregnancy: As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable not touse clopidogrel during pregnancy as a precautionary measure.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Breastfeeding: It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shownexcretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not becontinued during treatment with Clopidogrel.

Fertility: Clopidogrel was not shown to alter fertility in animal studies.

Effects on ability to drive and use machines

Clopidogrel has no or negligible influence on the ability to drive and use machines.

Overdose

Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. Appropriate therapy should be considered if bleedings are observed.

No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel.

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