Published: 10 June 2015

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New Oral Anticoagulants — Interactions Still Important

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Prescriber Update 36(2): 28
June 2015

With three new oral anticoagulants available in New Zealand, prescribers are reminded of the importance of interactions and the clinical significance of these risks.

The three new oral anticoagulant medicines available in New Zealand are: dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto) and apixaban (Eliquis)^1,2,3. Dabigatran is a coagulation factor IIa inhibitor. Rivaroxaban and apixaban are factor Xa inhibitors.

Pharmacodynamic

The risk of bleeding with anticoagulants is increased with concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), and anti-platelet agents such as aspirin.

In addition, pharmacokinetic interactions can increase the risk of bleeding as well as reducing therapeutic effect.

Cytochrome P450 3A4

Rivaroxaban and apixaban are metabolised by cytochrome P450 3A4 (CYP3A4). Inter-individual variability in CYP3A4 activity is high⁴. Therefore, the concomitant administration of factor Xa inhibitors with CYP3A4 inhibitors or inducers will have important effects in some patients.

Factor Xa inhibitors are contraindicated for patients receiving HIV protease inhibitors (such as ritonavir) which are strong inhibitors of CYP3A4 enzymes^2,3.

Co-administration with inducers of CYP3A4 enzymes such as phenytoin may lead to a reduced rivaroxaban or apixaban plasma concentration and inadequate therapeutic effect^2,3.

Further information about CYP3A4 and medicines that inhibit or induce CYP3A4 can be found in the Prescriber Update article 'Drug Metabolism — the importance of cytochrome P450 3A4'⁴.

P-glycoprotein

Patients taking dabigatran, rivaroxaban or apixaban, have an increased risk of bleeding if they also take P-glycoprotein inhibitors. This is especially relevant because verapamil or amiodarone may be prescribed for atrial fibrillation⁵.

More examples of medicines that inhibit P-glycoprotein can be found in the Prescriber Update article 'Medicines interactions: the role of P-glycoprotein'⁶.

Many drugs that have an effect on P-glycoprotein also have an effect on CYP3A4. For example, carbamazepine and St. John's Wort which reduce absorption of oral anticoagulants through inducing P-glycoprotein activity also induce CYP3A4 metabolism of rivaroxaban and apixaban.

P-glycoprotein functions as a biological barrier by extruding toxins and xenobiotics out of intestinal cells back into the intestine. The contribution of intestinal P-glycoprotein to overall drug absorption is usually not large unless the oral drug dose is small, or the dissolution and diffusion rates of the drug are very slow. P-glycoprotein based interactions usually do not change plasma concentrations as much as CYP450 interactions⁶.

As with all medicines, healthcare professionals are encouraged to report any suspected adverse reactions to the Centre for Adverse Reactions Monitoring (CARM).

References

1. Boehringer Ingelheim (N.Z.) Limited. 2014. Pradaxa Data Sheet. 17 October 2014. URL: www.medsafe.govt.nz/profs/datasheet/p/pradaxacap.pdf (accessed 26 March 2015).
2. Bayer New Zealand Limited. 2014. Xarelto Data Sheet. 2 December 2014. URL: www.medsafe.govt.nz/profs/datasheet/x/xareltotab.pdf (accessed 26 March 2015).
3. Pfizer New Zealand Limited. 2014. Eliquis Data Sheet. 11 November 2014. URL: www.medsafe.govt.nz/profs/datasheet/e/eliquistab.pdf (accessed 26 March 2015).
4. Medsafe. 2014. Drug Metabolism — the importance of cytochrome P450 3A4. Prescriber Update 35(1): 4–6. URL: www.medsafe.govt.nz/profs/PUArticles/March2014DrugMetabolismCytochromeP4503A4.htm (accessed 19 May 2015).
5. McDonald CJ, Kalisch Ellett LM, Barratt JD, et al. 2015. An international comparison of spontaneous adverse event reports and potentially inappropriate medicine use associated with dabigatran. Pharmacoepidemiology and Drug Safety 24: 399–405.
6. Medsafe. 2011. Medicines interactions: the role of P-glycoprotein. Prescriber Update 32(3): 21–22. URL: www.medsafe.govt.nz/profs/PUArticles/P-glycoproteinSept2011.htm (accessed 19 May 2015).