What Are the Risks of Using Antidepressants Together with Noacs and How Should These Risks

Q&A 225.1

What are the risks of using antidepressants together with NOACs and how should these risks be managed?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals

Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp

Date prepared: 24th November 2015

Background

The non-vitamin K antagonist (non-VKA) oral anticoagulant (NOAC) drugs [also referred to as novel oral anticoagulants] allow for fixed daily dosing without the need for routine coagulation monitoring. These drugs include the direct thrombin inhibitor dabigatran and the direct activated factor X (Xa) inhibitors rivaroxaban, apixaban and edoxaban. These agents appear to have fewer clinically significant drug interactions than warfarin but concomitant use with strong/moderate inhibitors/inducers of CYP3A4 or P-glycoprotein (e.g. amiodarone and verapamil) can result in clinically significant interactions. Lack of familiarity with these agents may result in potential drug interactions being overlooked which can lead to patient harm because patients are not routinely monitored for changes in anticoagulation.

This review highlights potential drug interactions between the NOACs and antidepressant agents that are known inhibitors/inducers of CYP3A4 or P-glycoprotein and also those that affect haemostasis. The review focuses on these agents since no interactions were found with other categories of antidepressants

Answer

Dabigatran

Dabigatran etexilate is a prodrug which after oral administration is hydrolysed to its active metabolite dabigatran and is primarily renally excreted[1]. Dabigatran etexilate is not an inducer or inhibitor of CYP450 isoenzymes, so a pharmacokinetic interaction is unlikely with drugs affecting, or metabolised by hepatic microsomal enzymes[2].

The prodrug dabigatran etexilate is a substrate for the efflux transporter P-glycoprotein (P-gp)1. Therefore pharmacokinetic interactions may occur with drugs that effect P-gp transport2.

St John’s Wort

St John’s Wort (SJW) is a potent inducer of CYP3A4 and P-gp[3]. The manufacturers of dabigatran advise that concomitant administration with St John’s wort (Hypericum perforatum) is expected to result in reduced dabigatran plasma concentrations increasing the risk of thrombosis and should be avoided1.

Serotonin Re-uptake Inhibitors

Serotonin is released from platelets in response to vascular injury and promotes vasoconstriction and morphological changes in platelets that lead to aggregation. Serotonin alone is a relatively weak platelet aggregator. Selective serotonin re-uptake inhibitors (SSRIs) inhibit the serotonin transporter responsible for the uptake of serotonin into platelets. Thus, SSRIs might deplete platelet serotonin, leading to a reduced ability to form clots and a subsequent increase in the risk of bleeding3.

The manufacturers of dabigatran state that the bleeding risk may be increased in patients concomitantly treated with SSRIs or selective serotonin norepinephrine re-uptake inhibitors (SNRIs). Treatment with dabigatran in these groups requires a careful risk-benefit assessment1.

The phase III RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) study compared dabigatran exelate 110mg or 150mg twice daily with warfarin for the prevention of stroke and systemic embolism in 18,113 patients with non-valvular atrial fibrillation (AF)[4],[5],[6]. In the RE-LY study, co-administration with SSRIs or SNRIs increased the risk of bleeding in all RE-LY treatment groups1. The dabigatran Canadian monograph states that SSRI use increased the risk of bleeding in AF patients treated with 110mg and 150mg dabigatran twice daily and warfarin by about 50 – 100%. SNRI use increased the risk of bleeding in AF patients treated with 110mg and 150mg dabigatran twice daily by about 100%[7].

The manufacturers of dabigatran do not make any specific dose recommendations for patients receiving concomitant SSRIs or SNRIs. A dose reduction to 110mg twice a day can be considered, at the discretion of the treating physician following assessment of the potential risk and benefit to an individual patient1.

Combination use may increase the risk of bleeding and the patient should be closely monitored for signs of bleeding or anaemia, or changes in renal function throughout the treatment period (1) [8],[9]. Due to the increased risk of bleeding dabigatran should be used with caution, if at all, with SSRIs/SNRIs[10].

Rivaroxaban

Following administration, one-third of the rivaroxaban dose is eliminated unchanged via the kidneys and the remaining two-thirds as inactive metabolites after metabolic degradation[11]. Rivaroxaban is metabolised via the cytochrome P-450 CYP3A4 and CYP2J2 isoenzymes. Due to the involvement of CYP3A4, inhibitors or inducers of this isoenzyme may potentially alter rivaroxaban exposure2,11.

Rivaroxaban is also a substrate of the transporter protein P-gp. Therefore inhibitors or inducers of P-gp may alter rivaroxaban plasma concentrations11.

St John’s Wort

Although formal drug interaction studies have not been performed with SJW, concomitant use of rifampicin (also a combined P-gp and strong CYP3A4 inducer) led to a decrease in the area under the curve (AUC) and maximum concentration (Cmax) of rivaroxaban by about 50% and 22% respectively with an associated reduction in its anticoagulant effects. The manufacturer predicts that SJW would behave similarly9.

Co-administration of rivaroxaban with SJW may lead to reduced rivaroxaban plasma concentrations and therefore decrease its anticoagulant effect. The manufacturers of rivaroxaban advise that the combination should be avoided unless the patient is closely observed for the signs and symptoms of thrombosis11. Given the likely clinical risk of reduced rivaroxaban efficacy with concurrent use it would seem prudent to use an alternative drug with rivaroxaban.

Serotonin Re-uptake Inhibitors

Caution is needed if rivaroxaban is given with other drugs that affect bleeding10. The release of serotonin by platelets is important for maintaining haemostasis. SSRIs and SNRIs may increase bleeding risk. The concomitant use of SSRIs with anticoagulants may increase the risk of bleeding and the combination should be used with caution[12] .

The manufacturers of SSRIs also advise caution when SSRIs are used concomitantly with anticoagulants due to the increased risk of bleeding (refer to individual SPCs), although they do not distinguish between anticoagulants[13],[14],[15],[16],[17],[18],[19]. However the manufacturers of rivaroxaban do not include a specific caution with the concomitant use of SSRIs11.

Apixaban

Apixaban has multiple routes of elimination[20]. Similar to rivaroxaban, apixaban is metabolised via CYP3A4 and is a substrate of the transporter protein P-gp2,20. It is therefore susceptible to drug interactions, particularly with drugs affecting both pathways.

St John’s Wort

The concomitant use of apixaban with the strong CYP3A4 and P-gp inducer SJW may lead to reduced apixaban plasma concentrations. The manufacturer advises that dosage adjustment for apixaban is not required during concomitant therapy; however apixaban should be used with caution when given for the prevention of venous thromboembolism (VTE) in elective hip or knee replacement surgery, for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and for the prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE)20. Although given the likely clinical risk of reduced apixaban efficacy (e.g. increased risk of stroke) on concurrent use it would seem prudent to use an alternative drug with apixaban. However if this is not possible consideration should be given to monitoring the prothrombin time to ensure the anticoagulant effect of apixaban is maintained9.

The manufacturer advises the combination should be avoided when given for the treatment of DVT and PE in patients receiving SJW due to the risk of loss of efficacy20.

Although formal drug interaction studies have not been performed with SJW, a preliminary study of concomitant use of rifampicin (also a combined P-gp and strong CYP3A4 inducer) led to a decrease in the AUC and maximum concentration (Cmax) of oral apixaban by 54% and 42% respectively9,20. Other inducers of CYP3A4 and P-gp, such as SJW are predicted to interact similarly9.

Serotonin Re-uptake Inhibitors

There is a theoretical interaction between apixaban and SSRI/SNRIs due to additive effects on haemostasis resulting in an increased risk of bleeding with the combination. Co-administration of apixaban and drugs that affect haemostasis, such as SSRI therapy, increases the risk of bleeding. If concomitant apixaban and SSRI therapy is necessary, use caution and monitor the patient closely. Discontinue apixaban if active pathological bleeding occurs12.

The manufacturers for SSRIs also advise caution when SSRIs are used concomitantly with anticoagulants due to an increased risk of bleeding13,14,15,16,17,18,19. However the SPC statements do not distinguish between anticoagulants. The manufacturers of apixaban do not specify caution with the concomitant use of SSRIs20.

Edoxaban

Edoxaban is a substrate for the efflux transporter P-gp and concurrent use with selected P-gp inducers may result in decreased edoxaban efficacy12,[21].

St John’s Wort

Co-administration of edoxaban with the P-gp inducer rifampicin led to a decrease in mean edoxaban AUC and a shortened half-life, with possible decreases in its efficacy. The concomitant use of edoxaban with other P-gp inducers such as St John's Wort may lead to reduced edoxaban plasma concentrations. The UK manufacturer advises that edoxaban should be used with caution when co-administered with P-gp inducers21.

A USA resource recommends that co-administration of edoxaban with a P-gp inducer should be avoided due to the risk of a potential loss of efficacy12.

Serotonin Re-uptake Inhibitors

The manufacturers for SSRIs (SPCs) advise caution when SSRIs are used concomitantly with anticoagulants due to an increased risk of bleeding13,14,15,16,17,18,19. However the SPC statements do not distinguish between anticoagulants. The manufacturers of edoxaban do not specify caution with the concomitant use of SSRIs21.

Summary

¨  NOACs appear to have fewer clinically significant drug interactions than warfarin but concomitant use with strong/moderate inhibitors/inducers of CYP3A4 or P-glycoprotein can result in clinically significant interactions.

¨  Concomitant administration of non-vitamin K antagonist oral anticoagulants (NOACs) with St John’s Wort is not recommended. St John’s Wort is a potent inducer of CYP3A4 isoenzymes and intestinal P-glycoprotein (P-gp) transporter. Concomitant administration may lead to reduced NOAC plasma concentrations with possible reduction in anticoagulant effect.

o  Dabigatran is primarily renally excreted but is a substrate for P-gp. The manufacturer advises that co-administration with P-gp inducers such as St John’s Wort should be avoided.

o  Rivaroxaban is metabolised via the CYP3A4 isoenzymes and is also a substrate for P-gp. The manufacturer advises that co-administration with SJW should be avoided unless the patient is closely observed for the signs and symptoms of thrombosis.

o  Apixaban, like rivaroxaban, is metabolised via the CYP isoenzymes and is a substrate for P-gp. Concomitant use with SJW may lead to reduced apixaban levels. The manufacturer advises that dosage adjustment for apixaban is not required during concomitant therapy; however apixaban should be used with caution when given for the prevention of venous thromboembolism (VTE) in elective hip or knee replacement surgery, for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and for the prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE). The combination should be avoided when given for the treatment of DVT and PE in patients receiving SJW due to the risk of loss of efficacy.

o  Edoxaban is a substrate for P-gp. Concomitant administration with P-gp inducers such as SJW may lead to reduced edoxaban plasma concentrations and the manufacturer advises caution.

¨  The release of serotonin by platelets is important for maintaining haemostasis thus selective serotonin re-uptake inhibitors (SSRIs) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs) may increase the risk of bleeding. Co-administration of NOACs with drugs that affect haemostasis, such as SSRI therapy increases the risk of bleeding. The manufacturers of SSRIs advise caution when SSRIs are used concomitantly with anticoagulants due to the increased risk of bleeding (refer to individual SPCs), although they do not distinguish between anticoagulants.

¨  The manufacturers of dabigatran state that the bleeding risk may be increased in patients concomitantly treated with SSRIs or selective SNRIs. In the RE-LY study, co-administration with SSRIs or SNRIs increased the risk of bleeding in all RE-LY treatment groups. The manufacturers of dabigatran do not make any specific dose recommendations for patients receiving concomitant SSRIs or SNRIs. A dose reduction to 110mg twice a day can be considered, at the discretion of the treating physician following assessment of the potential risk and benefit to an individual patient. Close clinical surveillance (looking for signs of bleeding or anaemia, or changes in renal function) is recommended throughout the treatment period. The manufacturers of rivaroxaban, apixaban and edoxaban make no specific recommendations regarding concomitant use with SSRIs.

Limitations

This Q&A is based on theoretical considerations, no case reports of interactions were found.

References

1

Available through NICE Evidence Search at www.evidence.nhs.uk

[1] Summary of Product Characteristics: Pradaxa 110mg hard capsules, Boehringer Ingelheim Ltd. Last updated on the eMC 30/1/2015. Accessed online via http://www.medicines.org.uk/emc/ on 10/2/2015.

[2] McEvoy G (Ed in Chief), American Society of Health-System Pharmacists. AHFS Drug Information. [online] London: Pharmaceutical Press http://www.medicinescomplete.com/ (accessed on 13/10/15)

[3] Taylor D, Paton C, Kapur S. The Maudsley Prescribing Guidelines 12th Edition. Wiley-Blackwell UK. (2015).

[4] Connolly SJ et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Eng J Med 2009;361:1139-1151. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa0905561

[5] Connolly SJ et al. Newly identified events in the RE-LY trial. N Eng J Med 2010;363:1875-1876. Available at: http://www.nejm.org/doi/full/10.1056/NEJMc1007378

Includes supplementary appendix available at: http://www.nejm.org/doi/suppl/10.1056/NEJMc1007378/suppl_file/nejmc1007378_appendix.pdf

[6] Connolly SJ et al. Additional events in the RE-LY trial. N ENG J Med 2014;371:1464-1465. Available at: http://www.nejm.org/doi/full/10.1056/NEJMc1407908

[7] Pradaxa Product Monograph. Available at: http://www.boehringer-ingelheim.ca/content/dam/internet/opu/ca_EN/documents/humanhealth/product_monograph/PradaxaPMEN.pdf

[8] Medscape Reference Drug Interaction Checker. Accessed online via: http://reference.medscape.com/drug-interactionchecker on 9/3/2015

[9] Preston CL (ed), Stockley's Drug Interactions. [online] London: Pharmaceutical Press http://www.medicinescomplete.com/ (accessed on 3/3/2015)

[10] Brayfield A (ed), Martindale: The Complete Drug Reference. [online] London: Pharmaceutical Press http://www.medicinescomplete.com/ (accessed on 3/3/2015)

[11] Summary of Product Characteristics: Xarelto 20mg film-coated tablets, Bayer. Last Updated on eMC 29/1/2015. Accessed online via http://www.medicines.org/emc/ on 10/2/2015

[12] Micromedex Solutions. DRUGDEX Drug Evaluations: Rivaroxaban. Accessed online via http://www.micromedexsolutions.com/home/dispatch on 3/3/2015