CoPlavix Drug Interactions

Oral Anticoagulants: The concomitant administration of CoPlavix with oral anticoagulants is not recommended since it may increase the intensity of bleeding (see Precautions).
Glycoprotein IIb/IIIa Inhibitors: As a pharmacodynamic interaction between clopidogrel and glycoprotein IIb/IIIa inhibitors is possible, CoPlavix should be used with caution.
Injectable Anticoagulants: 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. As a pharmacodynamic interaction between clopidogrel and heparin is possible, 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 MI. 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).
Nonsteroidal Anti-Inflammatory Drugs: 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).
Selective Serotonin Reuptake Inhibitors (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 drugs 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. Concomitant use of strong or moderate CYP2C19 inhibitors (eg, omeprazole) should be discouraged (see Pharmacology: Pharmacokinetics: Pharmacogenetics under Actions and Precautions). If a proton-pump inhibitor is to be used concomitantly with clopidogrel, consider using one with less CYP2C19 inhibitory activity eg, pantoprazole.
Proton Pump Inhibitors (PPI): In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 45% (day 1) and 40% (day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) with 5 mM ADP was diminished by 39% (24 hrs) and 21% (day 5) when clopidogrel and omeprazole were administered together.
In a 2nd interaction study with omeprazole 80 mg administered 12 hrs apart from the clopidogrel standard regimen, the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19.
In a 3rd interaction study with omeprazole 80 mg administered with a higher dose regimen of clopidogrel (600 mg loading dose followed by 150 mg/day), a degree of interaction was observed similar to that noted in the other omeprazole interaction studies. However, active metabolite formation and platelet aggregation were at the same level as clopidogrel administered alone at the standard dose regimen.
In a crossover clinical study, healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with pantoprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 20% (day 1) and 14% (day 5) when clopidogrel and pantoprazole were administered together. Mean inhibition of platelet aggregation was diminished by 15% (24 hrs) and 11% (day 5) when clopidogrel and pantoprazole were administered together. These results indicate that clopidogrel can be administered with pantoprazole.
The CURRENT trial compared 2 dosing regimens of clopidogrel (600 mg loading dose, then 150 mg/day for 6 days followed by 75 mg/day up to 30 days vs 300 mg loading dose followed by 75 mg/day up to 30 days). A subanalysis (n=18,432) correlated PPI use (mainly omeprazole and pantoprazole) at randomization and hospital discharge and demonstrated no interaction between clopidogrel and PPI use for the primary endpoint (CV death, MI or stroke) or any secondary endpoints, including stent thrombosis.
A number of other clinical studies have been conducted with clopidogrel and other concomitant medications to investigate the potential for pharmacodynamic and pharmacokinetic 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.
Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or 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. However, at high concentrations in vitro, clopidogrel inhibits CYP2C9. It is unlikely that clopidogrel may interfere with the metabolism of drugs eg, phenytoin and tolbutamide and the NSAIDs, which are metabolised by CYP450 2C9. Data from the CAPRIE study indicate that phenytoin and tolbutamide can be safely co-administered with clopidogrel.
Other Concomitant Therapy with Acetylsalicylic Acid: 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 >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.
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.
Other Interactions with Acetylsalicylic Acid: Interactions with the following medicinal products with higher (anti-inflammatory) doses of ASA have also been reported: Angiotensin converting enzyme inhibitors, acetazolamide, anticonvulsants (phenytoin and valproic acid), β-blockers, diuretics and oral hypoglycaemic agents.
Other Interactions with Clopidogrel and Acetylsalicylic Acid: In addition to the previously mentioned specific interaction studies, >30,000 patients entered into clinical trials with clopidogrel plus ASA at maintenance doses ≤325 mg and received a variety of concomitant medicinal products including diuretics, β-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.
Incompatibilities: Not applicable.