HSA would like to highlight the recent findings of significant drug interactions which healthcare professionals need to be aware of. Specifically this relates to the interaction between clopidogrel and proton pump inhibitors (PPI), as well as the interaction between colchicine, P-glycoprotein (P-gp) and strong CYP3A4 inhibitors. Healthcare professionals are reminded to report adverse events suspected to be related to the above interactions to the Vigilance Branch of HSA.
A) Interaction between clopidogrel and proton pump Inhibitors (PPI)
Clopidogrel is an antiplatelet prodrug used for the prevention of atherothrombotic events. One of the pathways for forming the active metabolite involves the CYP2C19 isoenzyme. Several studies, including large clinical outcome studies, have shown that the effectiveness of clopidogrel is diminished in patients with a polymorphism of the CYP2C19 allele that results in reduced activity of this enzyme.
Some reports suggest that use of certain PPI may make clopidogrel less effective by inhibiting the enzyme that converts clopidogrel to the active form of the drug while others do not suggest this effect. PPI decrease stomach acid and are used to treat frequent heartburn and stomach ulcers. Clopidogrel can irritate the stomach so PPI are commonly used with clopidogrel to help reduce this irritation. 1,2
Clopidogrel is available in Singapore as Plavix®, Plagril®, Clopidogrel Winthrop®, Apo-clopidogrel® and in combination with aspirin as Co-Plavix®. There are several PPI available in Singapore, namely, omeprazole, pantoprazole, esomeprazole, rabeprazole and lansoprazole.
Recent published report in JAMA
In March 2009, the results of a retrospective cohort study that investigated the risk of all-cause mortality or re-hospitalisation associated with use of clopidogrel with or without PPI following acute coronary syndrome (ACS) were published in JAMA.
Of 8,205 patients taking clopidogrel after discharge, 63.9% (n=5,244) were prescribed PPI at discharge, during follow-up, or both while 36.1% (n=2,961) were not prescribed PPI. Death or re-hospitalisation for ACS occurred more frequently in patients taking clopidogrel plus PPI (29.8%; n=1,561) than in patients taking clopidogrel without PPI (20.8%; n=615). In multivariable analyses, use of clopidogrel plus PPI was associated with an increased risk of death or re-hospitalisation for ACS compared with use of clopidogrel without PPI (adjusted odds ratio [AOR], 1.25; 95% confidence interval [CI], 1.11-1.41). Among patients taking clopidogrel after hospital discharge and prescribed PPI at any point during follow-up (n=5,244), periods of use of clopidogrel plus PPI (compared with periods of use of clopidogrel without PPI) were associated with a higher risk of death or re-hospitalisation for ACS (adjusted hazard ratio, 1.27; 95% CI, 1.10-1.46). 3
The results of this study support the findings from prior platelet studies demonstrating that PPI reduce the anti-platelet effects of clopidogrel, possibly by sharing common metabolic pathways mediated by cytochrome P450 isoenzymes (i.e. CYP2C19).
To date, HSA has not received local adverse reaction reports of drug interactions with PPI or a reduction in efficacy associated with Plavix®.
The local package insert of Plavix® has recently been updated to inform of the lower systemic exposure to the active metabolite of clopidogrel and diminished antiplatelet responses, as well as the exhibition of higher cardiovascular event rates following myocardial infarction, in patients with genetically reduced CYP2C19 function than do patients with normal CYP2C19 function. Hence, concomitant use of clopidogrel with drugs that inhibit CYP2C19 is discouraged. In addition, although the evidence of CYP2C19 inhibition varies within the class of PPI, clinical studies suggest an interaction between clopidogrel and possibly all members of this class of drugs. Therefore, it is recommended that the concomitant use of PPI with clopidogrel be avoided unless absolutely necessary.
B) Interaction between colchicine and P-glycoprotein (P-gp) or strong CYP3A4 inhibitors
Colchicine had been registered in Singapore for the treatment and prophylaxis of acute gout attacks. There are currently three generic colchicine products available locally namely, Colchicine Tablet® 500 mcg, Colchicine Tablets BP® 500 mcg and Colcitex Tablet® 0.6 mg.
Safety data from US Food and Drug Administration (FDA)
An analysis of safety data for colchicine from spontaneous reports to FDA, the literature and company sponsored clinical studies revealed 169 deaths associated with the use of oral colchicine. Of these, 117 cases occurred within the standard therapeutic doses of colchicine (≤2mg/ day). Sixty out of these 117 cases had clarithromycin, a CYP3A4 inhibitor, as a concomitant medication. The findings from this analysis suggested that drug interactions affecting gastrointestinal absorption and/or hepatic metabolism of colchicine play a central role in the development of colchicine toxicity.
The absorption of colchicine from the gastrointestinal tract is limited by the multidrug resistance efflux transporter P-glycoprotein (P-gp), while the metabolism of colchicine to inactive metabolites is catalysed by intestinal and hepatic cytochrome P450 CYP3A4. Colchicine is primarily eliminated by hepatobiliary excretion through the stool. Renal excretion accounts for 10% to 20% of colchicine elimination in patients with normal renal function. The theoretical risk of colchicine toxicity through the modulation of P-gp and CYP3A4 activity is further supported by the presence of fatal and non-fatal cases of colchicine toxicity reported in literature with concomitant use of other CYP3A4 and P-gp inhibitors such as cyclosporine, erythromycin and calcium channel blockers e.g. verapamil and diltiazem. Other examples of P-gp and strong CYP3A4 inhibitors include telithromycin, ketoconazole, itraconazole, HIV protease inhibitors, and nefazodone.4
Regulatory actions Taken in the US
Based on this information, FDA concluded that there is a risk for severe drug interactions in certain patients treated with colchicine and concomitant P-gp or strong CYP3A4 inhibitors. In view of this, FDA recommended that P-gp or strong CYP3A4 inhibitors not be used in patients with renal or hepatic impairment who are currently taking colchicine. Furthermore, FDA also recommended that healthcare professionals consider a dose reduction or interruption of colchicine in patients with normal renal and hepatic function if treatment with a P-gp or strong CYP3A4 inhibitor is required. 4
To date, HSA has not received any local adverse drug reaction reports of colchicine toxicity associated with concomitant use of P-gp and strong CYP3A4 inhibitors. Healthcare professionals are advised to take into consideration the above safety information when prescribing colchicine with a P-gp or strong CYP3A4 inhibitor.
- JAMA. 2009;301(9):937-944. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome