Rhea Clopidogrel Bisulfate Drug Interactions

Thrombolytics: The safety of the concomitant administration of clopidogrel, thrombolytics and heparin was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytics and heparin are co-administered with acetylsalicylic acid.
Glycoprotein IIb/IIIa inhibitors: As a pharmacodynamic interaction between clopidogrel and glycoprotein IIb/IIIa inhibitors is possible, concomitant use should be undertaken 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.
Oral anticoagulants: Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel should be undertaken with caution.
Acetylsalicylic acid: Acetylsalicylic acid did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of acetylsalicylic acid twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. As a pharmacodynamic interaction between clopidogrel intake. As a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, concomitant use should be undertaken with caution. However clopidogrel and ASA (75-325 mg once daily) have been administered together for up to one year.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs, it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs and clopidogrel should be co-administered with caution.
Other concomitant therapy: 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 (e.g., omeprazole) should be discouraged (see Precautions). If a proton pump inhibitor is to be used concomitantly with clopidogrel, consider using one with less CYP2C19 inhibitory activity, such as 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 5μM ADP was diminished by 39% (24 hours) and 21% (Day 5) when clopidogrel and omeprazole were administered together.
In a second interaction study with omeprazole 80 mg administered 12 hours 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 third 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 hours) 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 concomitaot 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. coadministration 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 such as phenytoin and tolbutamide and the NSAIDs, which are metabolised by cytochrome P450 2C9 Data from the CAPRIE study indicate that phenvtoin and tolbutamide can be safely co-administered with clopidogrel.
In addition to the above specific interaction studies, patients entered into large clinical studies CAPRIE and CURE) received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, anti-diabetic agents (including insulin), anti-epileptic agents. GPIIb/IIIa antagonists and hormone replacement therapy, without evidence of clinically significant adverse interactions.