Dabigatran: interactions to think about
A regular patient telephones your pharmacy and asks you to collect a prescription for dabigatran (220mg od) from her GP. She has been discharged from hospital following a total hip replacement and advised to continue to take dabigatran for a month, but was only given a seven-day supply to take home. She also asks whether it is OK for her to take St John’s wort because a friend has recommended this might help — she has been feeling “a little down” since her surgery.
Dabigatran is a substrate of the P-glycoprotein efflux pump (see PJ 2011;286:595). Direct evidence of an interaction with St John’s wort is lacking; however, this supplement is known to be a P-glycoprotein inducer. Data with rifampicin, also a P-glycoprotein inducer, demonstrates an interaction leading to a reduction in the exposure to single-dose dabigatran. It is reasonable, therefore, to assume that St John’s wort might also affect the exposure to dabigatran, reducing its efficacy. So it would seem prudent to advise the patient to avoid the use of St John’s wort and dabigatran together. You could reassure the patient that mood changes can occur after surgery, and advise her to contact her GP if she feels she needs further support or treatment. Alternatively, she might consider taking St John’s wort once she has completed the course of dabigatran.
Could there be an interaction?
When you contact the patient’s surgery, the GP asks to speak to you. The hospital has sent a discharge letter requesting him to prescribe dabigatran and codeine, as well as the atorvastatin, diclofenac (which the patient had been taking for lower back pain and joint pain), enalapril, glibenclamide and pantoprazole, which the patient had been taking before her surgery. She had also been taking low-dose aspirin before her operation.
Is there any interaction between dabigatran and these drugs? Should the GP continue to prescribe the patient her regular aspirin 75mg od, or restart it after the course of dabigatran?
Clinical studies have shown that both atorvastatin and diclofenac have no clinically relevant pharmacokinetic interaction with dabigatran.
However, there might be an increased risk of bleeding on the concurrent use of dabigatran and a non-steroidal anti-inflammatory drug or aspirin, and therefore diclofenac and aspirin should be given with dabigatran with caution. The GP could restart the aspirin but advise the patient to report any signs of bleeding or bruising.
Generally, codeine is the preferred analgesic for any post-operative pain the patient might be experiencing. Diclofenac can be used as an add-on, but only if necessary. However, if the diclofenac is still considered necessary for this patient, advise her to report any unexplained signs of bleeding or bruising; in the event of severe bleeding, dabigatran should be discontinued.
It has been suggested that the absorption of dabigatran might be affected by the reduced gastric acidity caused by pantoprazole. In a drug interaction study, however, pantoprazole only reduced the bioavailability of dabigatran by up to 24 per cent, and this was insufficient to alter the anticoagulant response to dabigatran. Therefore no dabigatran dose adjustment is required on concurrent use.
There is no known interaction between dabigatran and glibenclamide or enalapril.
A week later, the patient telephones you again. She has been prescribed clarithromycin by an out-of-hours service for a chest infection. She has read the dabigatran patient information leaflet, which advises patients to consult their doctor or pharmacist before taking clarithromycin.
Should she continue taking the antibiotic?
Clarithromycin is a P-glycoprotein inhibitor and might, therefore, be expected to increase dabigatran exposure and also increase its adverse effects. However, a study in healthy subjects found that clarithromycin only increases dabigatran exposure by 19 per cent, which would not be expected to be clinically relevant.
Nevertheless, because experience of the use of clarithromycin with dabigatran is generally lacking, it would be prudent to reinforce the advice given previously and remind the patient to report any unexplained bleeding or bruising.
In terms of her other medicines, clarithromycin increases atorvastatin exposure, and cases of rhabdomyolysis have been reported on the concurrent use of atorvastatin and a macrolide. It is advisable to withhold atorvastatin temporarily while taking a macrolide. If this is not possible, the patient should take the lowest appropriate dose of the atorvastatin (no more than 20mg od) and be instructed to report any unexplained muscle pain or weakness. It would be advisable to contact the patient’s GP to determine which of these options he would prefer, and ensure the patient is aware of the duration of any changes that need to be made to her statin regimen.
The newer anticoagulants, such as dabigatran, appear to have similar efficacy to warfarin in the prevention of venous thromboembolism, without the need for regular international normalised ratio monitoring (see PJ, 2013;290:197). It is likely that community pharmacists will increasingly encounter these anticoagulants. This case illustrates some of the interactions that should be considered when dabigatran is prescribed or dispensed, and highlights that not all potential drug interactions will be clinically relevant.
- Dabigatran is a P-glycoprotein substrate: inhibitors of this efflux pump (eg, clarithromycin) can increase its exposure, while inducers (eg, St John’s wort) can decrease its exposure.
- Concurrent use of dabigatran and a non-steroidal anti-inflammatory drug might increase the risk of bleeding.
- Pantoprazole might affect dabigatran bioavailability, but this does not appear to be clinically important.
This theoretical case has been produced by Nilufer Karim, Karen Baxter and Claire L. Preston on behalf of the ‘Stockley’s drug interactions’ editorial team.
“Stockley’s drug interactions” is available in print through Pharmaceutical Press (www.pharmpress.com) or electronically with quarterly updates through MedicinesComplete (available at www.medicinescomplete.com).
Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2013.11131454
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