Clopidogrel 75 Mg Film-Coated Tablets

CLOPIDOGREL AUSTELL is indicated for the following:

• reduction of atherosclerotic events (myocardial infarction, stroke, death due to vascular causes) in patients with a history of symptomatic atherosclerotic disease defined by ischaemic stroke (from 7 days until less than 6 months), myocardial infarction (from a few days until less than 35 days) or established peripheral arterial disease.
• for patient with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave myocardial infarction [MI]) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG (coronary artery bypass graft), CLOPIDOGREL AUSTELL in combination with ASA has been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined end point of cardiovascular death, MI, stroke, or refractory ischaemia.
• for patients with ST-segment elevation acute myocardial infarction, CLOPIDOGREL AUSTELL in combination with ASA has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction or stroke.

Adults:

Recent Myocardial Infarction (MI), Recent stroke, or Established Peripheral Arterial Disease: CLOPIDOGREL AUSTELL should be given as a single daily dose of 75 mg.

Acute Coronary Syndrome: For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI), CLOPIDOGREL AUSTELL should be initiated with a single 300 mg loading dose and then continued at 75 mg daily. Aspirin (75 mg - 325 mg once daily) should be initiated and continued in combination with CLOPIDOGREL AUSTELL.

For patients with ST-segment elevation acute myocardial infarction, the recommended dose at CLOPIDOGREL AUSTELL is one tablet, once daily administered in combination with aspirin, with or without thrombolytics. CLOPIDOGREL AUSTELL may be initiated with or without a loading dose.

Special populations:

Elderly: No dosage adjustment is necessary for elderly patients.

Renal disease: No dosage adjustment is necessary for patients with renal disease.

Pharmacogenetics: CYP2C19 poor metaboliser status is associated with diminished antiplatelet response to clopidogrel. An appropriate dose regimen for this patient population has not been established in clinical outcome trials.

Paediatric population: CLOPIDOGREL AUSTELL should not be used in children below the age of 18 years because of efficacy concerns.

Method of administration: CLOPIDOGREL AUSTELL is for oral use, with or without food.

• hypersensitivity to the clopidogrel or to any of the excipients listed in section 6.1
• active bleeding such as peptic ulcer and intracranial haemorrhage
• safety and efficacy in patients below the age of 18 have not been established
• pregnancy and lactation
• severe liver impairment
• thrombocytopenia
• platelet dysfunction
• haemophilia, congenital or acquired, or history of acquired haemophilia related to clopidogrel.

Bleeding and haematological disorders: Due to the risk of bleeding and haematological adverse reactions, blood cell count determination and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise during the course of treatment (see section 4.8). As with other antiplatelet CLOPIDOGREL AUSTELL should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions and in patients receiving treatment with ASA, heparin, glycoprotein IIb/IIIa inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2 inhibitors, or selective serotonin reuptake inhibitors (SSRIs), or CYP2C19 strong inducers or other medicines associated with bleeding risk such as pentoxifylline (see section 4.5).

THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) HAS BEEN REPORTED TO OCCUR WITH CLOPIDOGREL AUSTELL DURING POST-MARKETING EXPERIENCE. MOST CASES WERE REPORTED IN THE FIRST TWO WEEKS OF TREATMENT. PRESCRIBERS SHOULD ALSO WARN PATIENTS ABOUT THE SIGNS AND SYMPTOMS OF THROMBOTIC THROMBOCYTOPENIC PURPURA.

Patients should be followed carefully for any signs of bleeding including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or surgery. If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 7 days prior to surgery. Patients should inform medical practitioners and dentists that they are taking CLOPIDOGREL AUSTELL before any surgery is scheduled and before any new medicines are taken. CLOPIDOGREL AUSTELL prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intra-ocular). Patients should be told that it might take longer than usual to stop bleeding when they take CLOPIDOGREL AUSTELL (alone or in combination with ASA), and that they should report any unusual bleeding (site or duration) to their medical practitioner.

The use of CLOPIDOGREL AUSTELL 600 mg loading dose is not recommended in patients with non-ST segment elevation acute coronary syndrome and u2265 75 years of age due to increased bleeding risk in this population.

Thrombotic Thrombocytopenic Purpura (TTP): Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of CLOPIDOGREL AUSTELL, sometimes after a short exposure. It is characterised by thrombocytopenia, and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. In the event of TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.

Acquired haemophilia: Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired haemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by specialists, and clopidogrel should be discontinued.

Recent ischemic stroke:

• Initiation of therapy: In acute minor IS or moderate to high-risk TIA patients, dual antiplatelet therapy (clopidogrel and ASA) should be started no later than 24 hours after the event onset.
• There is no data regarding the benefit-risk of short term dual antiplatelet therapy in acute minor IS or moderate to high-risk TIA patients, with a history of (non-traumatic) intracranial haemorrhage.
• In non-minor IS patients, clopidogrel monotherapy should be started only after first 7 days of the event.
• Non-minor IS patients (NIHSS> 4): In view of the lack of data, use of dual antiplatelet therapy is not recommended (see section 4.1).
• Recent minor IS or moderate to high-risk TIA in patients for whom intervention is indicated or planned: There is no data to support the use of dual antiplatelet therapy in patients for whom treatment with carotid endarterectomy or intravascular thrombectomy is indicated, or in patients planned for thrombolysis or anticoagulant therapy. Dual antiplatelet therapy is not recommended in these situations.

Cytochrome P450 2C19 (CYP2C19): Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, CLOPIDOGREL AUSTELL at recommended doses forms less of the active metabolite of CLOPIDOGREL AUSTELL and has a smaller effect on platelet function. Tests are available to identify a patientu2019s CYP2C19 genotype. Since CLOPIDOGREL AUSTELL is metabolised to its active metabolite partly by CYP2C19, use of medicines that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of CLOPIDOGREL AUSTELL. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see section 4.5 for a list of CYP2C19 inhibitors, see also section 5.2). Use of medicine that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of CLOPIDOGREL AUSTELL and might potentiate the bleeding risk. As a precaution concomitant use of strong CYP2C19 inducers should be discouraged (see section 4.5).

CYP2C8 substrates: Caution is required in patients treated concomitantly with CLOPIDOGREL AUSTELL and CYP2C8 substrate medicines (see section 4.5).

Cross-reactions among thienopyridines: Patients should be evaluated for history of hypersensitivity to thienopyridines (such as clopidogrel, ticlopidine and prasugrel) since cross-reactivity among thienopyridines has been reported (see section 4.8). 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 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 AUSTELL should be used with caution in these patients (see section 4.2).

Hepatic impairment: Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. CLOPIDOGREL AUSTELL should be used with caution in this population (see section 4.2).

Excipient lactose: CLOPIDOGREL AUSTELL tablets contain lactose. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency or glucose-galactose malabsorption should not take CLOPIDOGREL AUSTELL.

Medicines associated with bleeding risk: There is an increased risk of bleeding due to the potential additive effect. The concomitant administration of medicines associated with bleeding risk should be undertaken with caution (see section 4.4).

Oral anticoagulants: The concomitant administration of CLOPIDOGREL AUSTELL with oral anticoagulants is not recommended since it may increase the intensity of bleedings (see section 4.4). Although the administration of CLOPIDOGREL AUSTELL/day did not modify the pharmacokinetics of S-warfarin or International Normalised Ratio (INR) in patients receiving long-term warfarin therapy, coadministration of CLOPIDOGREL AUSTELL with warfarin increases the risk of bleeding because of independent effects on hemostasis.

NSAIDs: In a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to lack of interaction studies with other NSAIDs it is presently unclear whether there is an increased risk of gastro-intestinal bleeding with all NSAIDs. Consequently, NSAIDs including cox-2 inhibitors and clopidogrel should be co-administered with caution (see section 4).

Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, 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 (see section 4.4).

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 usage should be undertaken with caution (see section 4.4).

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 (see section 4.8).

Glycoprotein IIb/IIIa inhibitors: Caution is advised when clopidogrel is used in patients who receive concomitant glycoprotein IIb/IIIa inhibitors (see section 4.4).

Selective serotonin reuptake inhibitors (SSRIs): Concomitant administration of SSRIs with clopidogrel should be undertaken with caution as SSRIs affect platelet activation and increase the risk of bleeding.

Proton Pump Inhibitors (PPIs): Omeprazole 80 mg once daily administered either concurrently with clopidogrel or with 12 hours between the administrations of the two medicines, decreased the exposure of the active metabolite by 45% (loading dose) and 40% (maintenance dose). The decrease was associated with a 39% (loading dose) and 21% (maintenance dose) reduction of inhibition of platelet aggregation. Esomeprazole is expected to give a similar interaction with clopidogrel. Inconsistent data on the clinical implications of this pharmacokinetic (PK)/ pharmacodynamic (PD) interaction in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution, concomitant use of omeprazole or esomeprazole should be discouraged (see section 4.4). Less pronounced reductions of metabolite exposure have been observed with pantoprazole or lansoprazole. The plasma concentration of the active metabolite was 20% reduced (loading dose) and 14% reduced (maintenance dose) during concomitant treatment with pantoprazole 80 mg once daily. This was associated with a reduction of the mean inhibition of platelet aggregation by 15% and 11%, respectively. These results indicate that clopidogrel can be administered with pantoprazole. There is no evidence that other medicines that reduce stomach acid such as H2 blockers or antacids interfere with the antiplatelet activity of clopidogrel.

Boosted anti-retroviral therapy (ART): HIV patients treated with boosted anti-retroviral therapies (ART) are at high risk of vascular events. A significantly reduced platelet inhibition has been shown in HIV patients treated with ritonavir- or-cobicistat-boosted ART. Although the clinical relevance of these findings is uncertain, there have been spontaneous reports of HIV-infected patients treated with ritonavir boosted ART, who have experienced re-occlusive events after de-obstruction or have suffered thrombotic events under a clopidogrel loading treatment schedule. Average platelet inhibition can be decreased with concomitant use of clopidogrel and ritonavir. Therefore, concomitant use of clopidogrel with ART boosted therapies should be discouraged.

Other concomitant therapy: Inducers of CYP2C19: Clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicines that induce the activity of this enzyme would be expected to result in increased drug levels of the active metabolite of clopidogrel. Rifampicin strongly induces CYP2C19, resulting in both an increased level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, concomitant use of strong CYP2C19 inducers should be discouraged (see section 4.4). Inhibitors of CYP2C19: Clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicines that inhibit the activity of this enzyme would be expected to result in reduced drug levels of 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 (see section 4.4 and 5.2). Medicines that are strong or moderate CYP2C19 inhibitors include, for example, omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine and efavirenz.

Other medicines: Co-administration of clopidogrel with atenolol, nifedipine, or both atenolol and nifedipine showed no clinically significant pharmacodynamic interactions. Co-administration of clopidogrel with phenobarbitone, or oestrogen did not significantly influence the pharmacodynamic activity of clopidogrel. The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption. Data from the CAPRIE study indicate that phenytoin, and tolbutamide which are metabolised by CYP2C9 can be safely co-administered with clopidogrel. CYP2C8 substrate medicines: Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to risk of increased plasma concentrations, concomitant administration of clopidogrel and medicines primarily cleared by CYP2C8 metabolism (e.g. repaglinide, paclitaxel) should be undertaken with caution (see section 4.4). Apart from the specific medicines interaction information described above, interaction studies with clopidogrel and some medicines commonly administered in patients with atherothrombotic disease have not been performed. However, patients received concomitant medicines including diuretics, beta-blocking medicines, angiotensin converting enzyme inhibitors (ACEI), calcium antagonists, cholesterol lowering medicines, coronary vasodilators, anti-diabetic medicines (including insulin), anti-epileptic medicines and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions.

As with other oral P2Y12 inhibitors, co-administration of opioid agonists has the potential to delay and reduce the absorption of clopidogrel presumably because of slowed gastric emptying. The clinical relevance is unknown. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

Rosuvastatin: Clopidogrel has been shown to increase rosuvastatin exposure in patients by 2-fold (AUC) and 1.3-fold (Cmax) after administration of a 300 mg clopidogrel dose, and by 1.4-fold (AUC) without effect on Cmax after repeated administration of a 75 mg clopidogrel dose.

Pregnancy: The use of CLOPIDOGREL AUSTELL during pregnancy and lactation is not recommended as safety and efficacy have not been established (see section 4.3).

Breastfeeding: It is not known whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion of clopidogrel in breast milk. CLOPIDOGREL AUSTELL is contraindicated in breastfeeding. Breastfeeding should not be continued during treatment with CLOPIDOGREL AUSTELL.

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

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

a) Summary of the safety profile: The clinically relevant adverse reactions observed in the studies are discussed below. In addition to clinical studies experience, adverse reactions have been spontaneously reported. Bleeding is the most common reaction reported both in clinical studies as well as in post-marketing experience where it was mostly reported during the first month of treatment.

b) Tabulated list of adverse reactions: The table below shows all adverse drug reactions (ADRs) observed during clinical trials and postmarket spontaneous reports with clopidogrel bisulphate.

System Organ Class Frequency Frequent Less Frequent Not known

Blood and the lymphatic system disorders: Thrombocytopenia, leucopenia, eosinophilia, neutropenia (including severe neutropenia), thrombotic thrombocytopenic purpura (TTP) (see section 4.4), aplastic anaemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired haemophilia A, granulocytopenia, anaemia.

Immune system disorders: Serum sickness, anaphylactoid reactions, cross-reactive drug hypersensitivity among thienopyridines (such as ticlopidine, prasugrel) (see section 4.4), insulin autoimmuno syndrome, which can lead to severe hypoglycemia, particularly in patients with HLA DRA4 subtype (more frequent in the Japanese population).

Psychiatric disorders: Hallucinations, confusion.

Nervous system disorders: Intracranial bleeding (some cases were reported with fatal outcome), headache, paraesthesia, dizziness, taste disturbances, ageusia.

Eye disorders: Eye bleeding (conjunctival, ocular, retinal).

Ear and labyrinth disorders: Vertigo.

Cardiac disorders: Kounis syndrome (vasospastic allergic angina / allergic myocardial infarction) in the context of a hypersensitivity reaction due to clopidogrel.

Vascular disorders: Haematoma, serious haemorrhage, haemorrhage of operative wound, vasculitis, hypotension.

Respiratory, thoracic and mediastinal disorders: Epistaxis, respiratory tract bleeding (haemoptysis, pulmonary hemorrhage).

Gastrointestinal disorders: Gastrointestinal haemorrhage, diarrhoea, abdominal pain, dyspepsia, gastric ulcer and duodenal ulcer, gastric, vomiting, nausea, constipation, flatulence, retroperitoneal haemorrhage, gastrointestinal and retroperitoneal haemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis.

Hepato-biliary disorders: Acute liver failure, hepatitis, abnormal liver function test.

Skin and subcutaneous tissue disorders: Bruising, rash, pruritus, skin bleeding (purpura), bullous dermatitis (toxic epidermal necrolysis, Stevens Johnson Syndrome, erythema multiforme, acute generalised exanthematous pustulosis (AGEP)), angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), rash (erythematous or exfoliative), urticaria, eczema, lichen planus.

Musculoskeletal and connective tissue disorders: Musculo-skeletal bleeding (haemarthrosis), arthritis, arthralgia, myalgia.

Renal and urinary disorders: Haematuria, glomerulonephritis, blood creatinine increased.

Reproductive system and breast disorders: Gynaecomastia.

General disorders and administration site conditions: Bleeding at puncture site, fever.

Investigations: Bleeding time prolonged, neutrophil count decreased, platelet count decreased.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Suspected adverse reactions can also be reported directly to the HCR via [email protected].

Signs and symptoms: Overdose following CLOPIDOGREL AUSTELL administration may lead to prolonged bleeding time and subsequent bleeding complications.

Management: No antidote to the pharmacological activity of CLOPIDOGREL AUSTELL has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the effects of CLOPIDOGREL AUSTELL. Treatment is symptomatic and supportive.