Apolets Drug Interactions

Drug Interactions: Studies of specific drug interactions yielded the following results: Aspirin: Aspirin did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of aspirin on collagen-induced platelet aggregation. Concomitant administration of 500 mg of aspirin twice a day for 1 day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. A pharmacodynamic interaction between clopidogrel and ASA is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution. Clopidogrel and aspirin have been administered together for up to one year.
Heparin: In a clinical study in healthy volunteers, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Coadministration of heparin had no effect on inhibition of platelet aggregation induced by clopidogrel.
A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore concomitant use should be undertaken with caution.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): In healthy volunteers receiving naproxen, concomitant administration of clopidogrel was associated with increased occult gastrointestinal blood loss. NSAIDs including COX-2 inhibitors and clopidogrel should be coadministered with caution.
Warfarin: Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel is not recommended since it may increase the intensity of bleeding (See General under PRECAUTIONS).
Glycoprotein IIb/IIIa Inhibitors: Clopidogrel should be used with caution in patients who receive concomitant glycoprotein IIb/IIIa inhibitors.
Proton Pump Inhibitors (PPIs): 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.
Other Concomitant Therapy: No clinically significant pharmacodynamic interactions were observed when clopidogrel was coadministered with atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of clopidogrel was also not significantly influenced by the coadministration of phenobarbital, cimetidine or estrogen. The pharmacokinetics of digoxin or theophylline was not modified by the coadministration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.
Medicines metabolized by CYP₄₅₀ 2C9: At high concentrations in vitro, clopidogrel inhibits CYP₄₅₀(2C9). Accordingly, clopidogrel may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, torsemide, fluvastatin, and many non-steroidal anti-inflammatory agents, but there are no data with which to predict the magnitude of these interactions. Caution should be used when any of these drugs is coadministered with clopidogrel. However, data from the CAPRIE study indicates that phenytoin and tolbutamide which are metabolized by CYP2C9 can be safely coadministered with cloipidogrel.
Since clopidogrel is metabolized 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 and a reduction in clinical efficacy. Concomitant use of drugs that strongly or moderately inhibit CYP2C19 (e.g., omeprazole, esomeprazole should be avoided).
In addition to the previously mentioned specific interaction studies, patients entered into clinical trials with clopidogrel received a variety of concomitant medications including diuretics, beta-blocking agents, ACE inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (Hypoglycemic Agents including insulin), antiepileptic agents, hormone replacement therapy, heparins (unfractionated and LMWH) and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions. The use of oral anticoagulants, non-study antiplatelet drug and chronic NSAIDs was not allowed in CURE and there are no data on their concomitant use with clopidogrel.
Drug/Laboratory Test Interactions: No data.