Managing interactions with direct oral anticoagulants (DOACs)

Increased risk of bleeding

Amiodarone may increase the blood levels of DOACs, increasing their anticoagulant effect.

Management options

Use concomitantly with caution. Monitor for anaemia and signs of bleeding.

Further information

Amiodarone moderately inhibits P-gp.

No interaction

No interactions are expected between digoxin and DOACs.

Theoretical increased risk of bleeding

Diltiazem may increase the blood levels of DOACs, increasing their anticoagulant effect.

Management options

Monitor for anaemia and signs of bleeding.

Further information

Diltiazem moderately inhibits CYP3A4 and weakly inhibits P-gp.

Increased risk of bleeding

Dronedarone may increase the blood levels of DOACs and therefore increase their anticoagulant effect.

Management options

Monitor for anaemia and signs of bleeding.

For dabigatran and rivaroxaban

Avoid concomitant use.

For edoxaban

Reduce the dose of edoxaban to 30mg once daily.

Further information

Dronedarone moderately inhibits CYP3A4 and strongly inhibits P-gp.

Increased risk of bleeding

Verapamil may increase the blood levels of DOACs, increasing their anticoagulant effect. This is unlikely to be clinically relevant interaction for rivaroxaban and apixaban.

Management options

Monitor for anaemia and signs of bleeding.

For dabigatran

Reduce the dose of dabigatran to 110mg twice daily for the:

• prevention of stroke and systemic embolism in people with non-valvular atrial fibrillation
• prevention and treatment of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE)

Further information

Verapamil weakly inhibits CYP3A4 and inhibits P-gp.

Increased risk of bleeding

Macrolides such as clarithromycin and erythromycin (systemic) may increase the blood levels of DOACs and increase their anticoagulant effect.

Management options

Use concomitantly with caution.

Monitor for anaemia and signs of bleeding, particularly in the elderly or in people with renal impairment.

For edoxaban

Reduce the edoxaban dose to 30mg daily if administering concomitantly with erythromycin (systemic).

Further information

Macrolides inhibit CYP3A4 and P-gp.

Risk of thrombosis

Rifampicin decreases the blood levels of DOACs and reduces their anticoagulant effect.

Management options

Prescribe a different anticoagulant for which monitoring is available e.g. warfarin or consider an alternative medicine to be used with the DOAC.

Apixaban

If concomitant use cannot be avoided, use apixaban with caution for the following indications:

• prevention of stroke and systemic embolism in people with non-valvular atrial fibrillation
• prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE)

Dabigatran

Avoid concomitant use.

Edoxaban and rivaroxaban

If concomitant use cannot be avoided, monitor for signs of thrombosis.

Further information

Rifampicin strongly induces CYP3A4 and P-gp.

Increased risk of bleeding

Concomitant use of DOACs with other DOACs, heparin or warfarin may increase bleeding risk.

Management options

Avoid concomitant use unless switching to or from warfarin treatment or under specialist supervision.

Increased risk of bleeding

Selective serotonin re-uptake inhibitors (SSRIs) and serotonin and noradrenaline re-uptake inhibitors (SNRIs) may increase the bleeding risk associated with DOACs.

Management options

Use concomitantly with caution or avoid.

If concomitant use is indicated, consider appropriate gastroprotection if the individual also has other risk factors for bleeding.

Monitor for anaemia and bleeding.

Dabigatran

For dabigatran, consider a dose reduction (as per the Summary of Product Characteristics) if the individual also has other risk factors for bleeding.

Further information

Antiplatelet medicines can affect haemostasis.

Theoretical increased risk of bleeding

Fluconazole may increase the blood levels of apixaban, dabigatran and rivaroxaban and increase their anticoagulant effect. This is not considered to be clinically relevant for rivaroxaban.

No interaction is expected with edoxaban.

Management options

Monitor for anaemia and signs of bleeding, particularly in renal impairment.

Further information

Fluconazole moderately inhibits CYP3A4.

Increased risk of bleeding

Itraconazole and ketoconazole are:

• contraindicated with dabigatran
• not recommended with apixaban or rivaroxaban

They may increase the blood levels of DOACs, increasing their anticoagulant effect.

Management options

If concomitant use with apixaban, edoxaban and rivaroxaban cannot be avoided, monitor for anaemia and signs of bleeding.

For edoxaban

Reduce the edoxaban dose to 30mg daily if administering concomitantly with ketoconazole.

Further information

Itraconazole and ketoconazole strongly inhibit CYP3A4 and P-gp.

Increased risk of bleeding

Antiplatelet medicines such as aspirin, clopidogrel and ticagrelor may increase the bleeding risk associated with DOACs. Ticagrelor has also been shown to increase the blood levels of dabigatran.

Management options

Avoid concomitant use unless advised by a specialist.

If concomitant use is indicated, consider appropriate gastroprotection.

Monitor for anaemia and bleeding.

Further information

Antiplatelet medicines can affect haemostasis. Ticagrelor also inhibits P-gp.

Risk of thrombosis

Carbamazepine, phenytoin and phenobarbital may decrease the blood levels of DOACs, reducing their anticoagulant effect.

Dabigatran

Although the Summary of Product Characteristics (SmPC) for dabigatran does not document an interaction between phenobarbital and dabigatran, it is still predicted.

Management options

Prescribe a different anticoagulant for which monitoring is available e.g. warfarin or consider an alternative medicine to be used with the DOAC.

Apixaban

If concomitant use cannot be avoided, use apixaban with caution for the following indications:

• prevention of stroke and systemic embolism in people with non-valvular atrial fibrillation
• prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE)

Dabigatran

Avoid concomitant use.

Edoxaban and rivaroxaban

If concomitant use cannot be avoided, monitor for signs of thrombosis.

Further information

Carbamazepine, phenytoin and phenobarbital are strong inducers of CYP3A4 and P-gp.

Dabigatran is not affected by CYP450 enzymes.

Theoretical risk of thrombosis

Levetiracetam and valproate-containing medicines may decrease the blood levels of DOACs, reducing their anticoagulant effect. Although, evidence is lacking and the mechanism of this interaction is unknown.

Management options

Use concomitantly with caution and be aware of the interaction in the case of an unexpected response to treatment.

Increased risk of bleeding

Ciclosporin is contraindicated with dabigatran. It may increase the blood levels of the other DOACs, increasing their anticoagulant effect.

Management options

Consult with the specialist and use apixaban, edoxaban or rivaroxaban cautiously with ciclosporin. Monitor for anaemia and signs of bleeding.

Edoxaban

Reduce the edoxaban dose to 30mg daily with ciclosporin.

Further information

Ciclosporin moderately inhibits CYP3A4 and strongly inhibits P-gp.

Increased risk of bleeding

Tacrolimus may increase the blood levels of dabigatran, increasing its anticoagulant effect. An interaction to a lesser extent is expected with the other DOACs.

Management options

Avoid concomitant use of dabigatran with tacrolimus.

Consult with specialist and use apixaban, edoxaban or rivaroxaban cautiously with tacrolimus.

Monitor for anaemia and signs of bleeding, particularly in those who are elderly or have renal impairment.

Further information

Tacrolimus mildly inhibits CYP3A4 and a strongly inhibits P-gp.

Increased risk of bleeding

NSAIDs such as ibuprofen and naproxen may increase the bleeding risk associated with DOACs.

Management options

Use concomitantly with caution or avoid if possible.

Review the need for the NSAID and avoid chronic use. If an alternative analgesic cannot be used and an NSAID is indicated, prescribe the lowest effective dose for the shortest possible duration.

If concomitant use is indicated, consider appropriate gastroprotection. The NICE CKS on NSAIDs prescribing issues  provides additional guidance on managing gastrointestinal adverse effects with NSAIDs.

Monitor for anaemia and bleeding.