Medicinal products associated with bleeding risk: There is an increased risk of bleeding due to the potential additive effect. The concomitant administration of medicinal products associated with bleeding risk should be undertaken with caution (see Precautions).
Oral anticoagulants: The concomitant administration of CoPlavix with oral anticoagulants is not recommended since it may increase the intensity of bleeding (see Precautions). 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, co-administration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis.
Glycoprotein IIb/IIIa inhibitors: CoPlavix should be used with caution in patients who receive concomitant glycoprotein IIb/IIIa inhibitors (see Precautions).
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 CoPlavix and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see Precautions).
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 Adverse Reactions). The safety of the concomitant administration of CoPlavix with other thrombolytic agents has not been formally established and should be undertaken with caution (see Precautions).
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 Cox-2 inhibitors is not recommended (see Precautions).
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 Pharmacology: Pharmacodynamics under Actions).
Metamizole: Metamizole may reduce the effect of ASA on platelet aggregation when taken concomitantly. Therefore, this combination should be used with caution in patients taking low dose ASA for cardioprotection.
SSRIs: Since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration of SSRIs with clopidogrel should be undertaken with caution.
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 Precautions and Pharmacology: Pharmacokinetics under Actions).
Medicinal products that are strong or moderate CYP2C19 inhibitors include, for example, omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, and efavirenz.
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 Precautions).
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 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 pharmacodynamic and pharmacokinetic (PK) interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the co-administration of phenobarbital or oestrogen.
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 medicinal products: 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 the risk of increased plasma concentrations, concomitant administration of clopidogrel and drugs primarily cleared by CYP2C8 metabolism (e.g., repaglinide, paclitaxel) should be undertaken with caution (see Precautions).
Other concomitant therapy with ASA: Interactions with the following medicinal products have been reported with ASA: Uricosurics (benzbromarone, probenecid, sulfinpyrazone): Caution is required because ASA may inhibit the effect of uricosuric agents through competitive elimination of uric acid.
Methotrexate: Due to the presence of ASA, methotrexate used at doses higher than 20 mg/week should be used with caution with CoPlavix as it can inhibit renal clearance of methotrexate, which may lead to bone marrow toxicity.
Tenofovir: Concomitant administration of tenofovir disoproxil fumarate and NSAIDs may increase the risk of renal failure.
Valproic acid: The concomitant administration of salicylates and valproic acid may result in decreased valproic acid protein binding and inhibition of valproic acid metabolism resulting in increased serum levels of total and free valproic acid.
Varicella vaccine: It is recommended that patients not be given salicylates for an interval of six weeks after receiving the varicella vaccine. Cases of Reye's syndrome have occurred following the use of salicylates during varicella infections (see Precautions).
Acetazolamide: Caution is recommended when co-administering salicylates with acetazolamide as there is an increased risk of metabolic acidosis.
Nicorandil: 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 Precautions).
Other interactions with ASA: Interactions with the following medicinal products with higher (anti-inflammatory) doses of ASA have also been reported: angiotensin converting enzyme (ACE) inhibitors, acetazolamide, anticonvulsants (phenytoin and valproic acid), beta blockers, diuretics, and oral hypoglycemic agents.
Alcohol: 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 Precautions.)
Other interactions with clopidogrel and ASA: More than 30,000 patients entered into clinical trials with clopidogrel plus ASA at maintenance doses lower than or equal to 325 mg, and received a variety of concomitant medicinal products including diuretics, beta blockers, ACE Inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions.
Apart from the specific medicinal product interaction information described previously, interaction studies with CoPlavix and some medicinal products commonly administered in patients with atherothrombotic disease have not been performed.