DuoPlavin 75 mg/75 mg filmcoated tablets

Each filmcoated tablet contains 75 mg of clopidogrel (as hydrogen sulphate) and 75 mg of acetylsalicylic acid (ASA).

Excipients:

Each filmcoated tablet contains 7 mg of lactose and 3.3 mg of hydrogenated castor oil.

For a full list of excipients, see section 6.1.

Filmcoated tablet (tablet).

Yellow, oval, slightly biconvex, engraved with «C75» on one side and «A75» on the other side.

DuoPlavin is indicated for the prevention of atherothrombotic events in adult patients already taking both clopidogrel and acetylsalicylic acid (ASA). DuoPlavin is a fixeddose combination medicinal product for continuation of therapy in:

• NonST segment elevation acute coronary syndrome (unstable angina or nonQwave myocardial infarction) including patients undergoing a stent placement following percutaneous coronary intervention

• ST segment elevation acute myocardial infarction in medically treated patients eligible for thrombolytic therapy

For further information please refer to section 5.1.

Posology

• Adults and elderly

DuoPlavin should be given as a single daily 75 mg/75 mg dose.

DuoPlavin is used following initiation of therapy with clopidogrel and ASA given separately.

−In patients with nonST segment elevation acute coronary syndrome (unstable angina or nonQwave myocardial infarction): 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(see section 5.1). If the use of DuoPlavin is discontinued, patients may benefit with continuation of one antiplatelet medicinal product.

−In patients with ST segment elevation acute myocardial infarction: 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 (see section 5.1). If the use of DuoPlavin is discontinued, patients may benefit with continuation of one antiplatelet medicinal product.

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

The safety and efficacy of DuoPlavin in children and adolescents under 18 years old have not been established. DuoPlavin is not recommended in this population.

• Renal impairment

DuoPlavin must not be used in patients with severe renal impairment (see section 4.3). Therapeutic experience is limited in patients with mild to moderate renal impairment (see section 4.4). Therefore DuoPlavin should be used with caution in these patients.

• Hepatic impairment

DuoPlavin must not be used in patients with severe hepatic impairment (see section 4.3). Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses (see section 4.4). Therefore DuoPlavin should be used with caution in these patients.

Method of administration

For oral use.

It may be given with or without food.

Due to the presence of both components of the medicinal product, DuoPlavin is contraindicated in case of:

• Hypersensitivity to the active substances or to any of the excipients.

• Severe hepatic impairment.

• Active pathological bleeding such as peptic ulceror intracranial haemorrhage.

In addition, due to the presence of ASA, its use is also contraindicated in:

• Hypersensitivity to nonsteroidal antiinflammatory drugs (NSAIDs) and syndrome of asthma, rhinitis, and nasal polyps.

• Severe renal impairment.

• Third trimester of pregnancy (see section 4.6).

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 a dual antiplatelet agent, DuoPlavin 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 other NSAIDs including Cox2 inhibitors, heparin, glycoprotein IIb/IIIa inhibitors or thrombolytics. 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. The concomitant administration of DuoPlavin with oral anticoagulants is not recommended since it may increase the intensity of bleeding (see section 4.5).

Patients should inform physicians and dentists that they are taking DuoPlavin before any surgery is scheduled and before any new medicinal product is taken. Where elective surgery is being considered, the need for dual antiplatelet therapy should be reviewed and consideration given to the use of a single antiplatelet agent. If patients must temporarily stop antiplatelet therapy, DuoPlavin should be discontinued 7 days prior to surgery.

DuoPlavin prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular).

Patients should also be told that it might take longer than usual to stop bleeding when they take DuoPlavin, 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 of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.

Recent transient ischaemic attack or stroke

In patients with recent transient ischaemic attack or stroke who are at high risk of recurrent ischaemic events, the combination of ASA and clopidogrel has been shown to increase major bleeding. Therefore, such addition should be undertaken with caution outside of clinical situations where the combination has proven to be beneficial.

Cytochrome P450 2C19 (CYP2C19)

Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. 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 (see section 4.5 for a list of CYP2C19 inhibitors, see also section 5.2).

Caution required due to ASA

• In patients with a history of asthma or allergic disorders since they are at increased risk of hypersensitivity reactions

• In patients with gout since low doses of ASA increase urate concentrations.

• In children under 18 years of age, there is a possible association between ASA and Reye's syndrome. Reye's syndrome is a very rare disease which can be fatal.

Gastrointestinal (GI)

DuoPlavin should be used with caution in patients with a history of peptic ulcer or gastroduodenal haemorrhage or minor upper GI symptoms as this may be due to gastric ulceration which may lead to gastric bleeding. GI undesirable effects including stomach pain, heartburn, nausea, vomiting, and GI bleeding may occur. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Patients should be told about the signs and symptoms of GI undesirable effects and what steps to take if they occur.

Excipients

DuoPlavin contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicinal product.

This medicinal product also contains hydrogenated castor oil which may cause stomach upset and diarrhoea.

Oral anticoagulants: the concomitant administration of DuoPlavin with oral anticoagulants is not recommended since it may increase the intensity of bleeding (see section 4.4). Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of Swarfarin or International Normalised Ratio (INR) in patients receiving longterm warfarin therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis.

Glycoprotein IIb/IIIa inhibitors: DuoPlavin should be used with caution in patients who receive concomitant glycoprotein IIb/IIIa inhibitors (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. Coadministration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction between DuoPlavin and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4).

Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or nonfibrin 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 coadministered with ASA (see section 4.8). The safety of the concomitant administration of DuoPlavin with other thrombolytic agents has not been formally established and should be undertaken with caution (see section 4.4).

NSAIDs: in a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. Consequently, the concomitant use of NSAIDs including Cox2 inhibitors is not recommended (see section 4.4).

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Other concomitant therapy with clopidogrel: 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 (see sections 4.4 and 5.2).

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

Proton Pump Inhibitors (PPI):

Omeprazole 80 mg once daily administered either at the same time as clopidogrel or with 12 hours between the administrations of the two drugs 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 has been observed with pantoprazole or lansoprazole.

The plasma concentrations 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 medicinal products that reduce stomach acid such as H2 blockers (except cimetidine which is a CYP2C19 inhibitor) or antacids interfere with antiplatelet activity of clopidogrel.

Other medicinal products: A number of other clinical studies have been conducted with clopidogrel and other concomitant medicinal products to investigate the potential for pharmac