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 Adverse Reactions). As a dual antiplatelet agent, CoPlavix 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 Cox-2 inhibitors, heparin, glycoprotein IIb/IIIa inhibitors, selective serotonin reuptake inhibitors (SSRIs), thrombolytics or other medicinal products associated with bleeding risk such as pentoxifylline (see Interactions). 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 CoPlavix with oral anticoagulants is not recommended since it may increase the intensity of bleeding (see Interactions).
Patients should inform physicians and dentists that they are taking CoPlavix 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, CoPlavix should be discontinued 7 days prior to surgery.
CoPlavix 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 CoPlavix, 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.
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 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 Interactions for a list of CYP2C19 inhibitors, see also Pharmacology: Pharmacokinetics under Actions).
CYP2C8 substrates: Caution is required in patients treated concomitantly with clopidogrel and CYP2C8 substrate medicinal products (see Interactions).
Cross-reactions among thienopyridines: Patients should be evaluated for history of hypersensitivity to thienopyridines (such as clopidogrel, ticlopidine, prasugrel) since cross-reactivity among thienopyridines has been reported (see Adverse Reactions). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological cross-reactions such as thrombocytopaenia and neutropaenia. 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.
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.
This medicinal product must be administered under close medical supervision in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to risk of hemolysis (see Adverse Reactions).
Alcohol may increase the risk of gastrointestinal injury when taken with ASA. Patients should be counseled about the risks of gastrointestinal injury and bleeding while taking clopidogrel plus ASA with alcohol, especially if alcohol consumption is chronic or heavy. (See Interactions.)
Gastrointestinal (GI) risk: CoPlavix 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. Minor GI symptoms, such as dyspepsia, are common and can occur anytime during therapy. Physicians should remain alert for signs of GI 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. (See Adverse Reactions.)
In patients concomitantly receiving nicorandil and NSAIDs including ASA and LAS, there is an increased risk for severe complications such as gastrointestinal ulceration, perforation and haemorrhage (see Interactions).
NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events.
Renal effects: Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Advanced renal disease: No information is available from controlled clinical studies regarding the use of CoPlavix in patients with advanced renal disease. Therefore, treatment with CoPlavix is not recommended in these patients with advanced renal disease. If therapy must be initiated, close monitoring of the patient's renal function is advisable.
Excipients: CoPlavix contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
This medicinal product also contains hydrogenated castor oil which may cause stomach upset and diarrhoea.
Effects on ability to drive and use machines: CoPlavix has no or negligible influence on the ability to drive and use machines.