Direct Oral Anticoagulant (DOAC) Interactions

1 North Central London Joint Formulary Committee Direct Oral Anticoagulant (DOAC) Interactions Disclaimer This guideline is registered at North Central London (NCL) Joint Formulary Committee (JFC) and is intended solely for use by healthcare professionals to aid the treatment of patients within NCL. However, clinical guidelines are for guidance only, their interpretation and application remain the responsibility of the individual clinician. If in doubt, contact a senior colleague or expert. Clinicians are advised to refer to the manufacturer's current prescribing information before treating individual patients. The authors and NCL JFC accept no liability for use of this information from this beyond its intended use.

2 While we have tried to compile accurate information in this guideline, and to keep it updated in a timely manner, we cannot guarantee that it is fully complete and correct at all times. If you identify information within this guideline that is inaccurate, please report this to the If a patient is harmed as a consequence of following this guideline, please complete a local incident report and inform This guideline should not be to used or reproduced for commercial or marketing purposes. NCL JFC is funded by and provides advice to Acute Trusts and Clinical Commissioning Groups in NCL. North Central London Joint Formulary Committee 1 of 9. DOAC Interactions Approval date: August 2018.

3 Version Expiry date: May 2019. Document control Date Version Amendments 17 May17 1 New Document 21 Aug18 Include Table of contents'. Document management Groups / Individuals who have overseen the C Gates, Thrombosis and Anticoagulation Pharmacist, development of this guidance: UCLH. J Minshull, JFC Support Pharmacist, NCL. Groups which were consulted and have given NCL Medicines Optimisation Committee approval: File name: DOAC Interactions Guide Version number: Available on: Disseminated to: NCL Heads of Medicines Management, NCL Trust Formulary Pharmacists, NCL DOAC Stakeholder Group Equality impact assessment: Low NCL Joint Formulary Committee Approval date: August 2018 (MOC Chair's Action).

4 Review date: May 2019. Contents Pharmacokinetic data (DOACs) .. 3. Drug Interactions with DOACs (therapeutic doses).. 4. Disclaimer .. 4. Interaction table .. 4. Clinical risk factors for bleeding .. 4. Antiarrhythmics .. 4. Antiarrhythmics contd.. 5. Antibiotics .. 5. Anticoagulants .. 5. Antidepressants .. 5. Anti-inflammatory 6. Antiplatelet agents .. 6. Antivirals .. 6. Azole antimycotics (systemic) .. 7. GI 7. Immunosuppressants .. 7. Others .. 8. Thrombolytic agents, GPIIb/IIIa receptor antagonists .. 8. References .. 8. North Central London Joint Formulary Committee 2 of 9. DOAC Interactions Approval date: August 2018. Version Expiry date: May 2019.

5 Pharmacokinetic data (DOACs). Apixaban Dabigatran etexilate Edoxaban Rivaroxaban Bioavailability approx. 50% Bioavailability approx. 7% Bioavailability approx. 62% Bioavailability approx. 66%. % of administered dose % of administered dose % of administered dose without fooda; >80% with renally eliminated: 27% renally eliminated: 85% renally eliminated: 35% fooda,b Tmax 3-4h Tmax Tmax 1-2h % of administered dose T 1/2 12h T 12-14h T 10-14h renally eliminated: 66%. (CrCL>80ml/min) (1/2 as unchanged active drug ie 33%). Tmax 2-4h T 5-9h young; 11-13h elderly Mainly metabolized by Not metabolised by the CYP3A4/5 weakly involved Metabolised via CYP3A4, CYP3A4/5 CYP450 system; not with metabolism (<10%) CYP2J2 and CYP- Substrate of efflux expected to induce/inhibit Substrate of the efflux independent mechanisms transport proteins P-gp it transport protein P-gp Substrate of efflux and breast cancer Dabigatran etexilate is a Dose adjustment not transport proteins P-gp resistance protein (BCRP) substrate of the efflux needed for strong CYP3A4 and breast cancer Not expected to inhibit / transport protein P-gp.

6 Inhibitors resistance protein (BCRP). induce major CYP isoforms Affected by strong P-gp Affected by strong P-gp Does not inhibit / induce ( CYP3A4). inhibitors or inducers inhibitors or inducers major CYP isoforms ( Not a significant inhibitor CYP3A4). of P-gp Affected by drugs that are Affected by drugs that are strong inhibitors/inducers strong inhibitors/inducers of both CYP3A4 and P-gp of both CYP3A4 and P-gp pathways pathways a b Abbreviations: P-gp, P-glycoprotein. Footnote: 20 mg dose; 15mg/20 mg doses. Reference: Summary Product Characteristics ; Heidbuchel et al. Updated EHRA practical guide on the use of non-VKA AC in NVAF: Executive summary Revision 1.

7 EHJ 2016 North Central London Joint Formulary Committee 3 of 9. DOAC Interactions Approval date: August 2018. Version Expiry date: May 2019. Drug Interactions with DOACs (therapeutic doses). Disclaimer Available data is limited and may change as DOACs become more widely prescribed. Absence of an individual drug/specific recommendation or information does not translate into safety for use. The suggested actions are a combination of SPC advice, EHRA practical guidance (see references) and local interpretation. Refer to the relevant SPC/BNF for the most-up-to date information when prescribing Where stated, AUC' relates to DOAC concentration Interaction table Clinical risk factors for bleeding Apixaban Dabigatran Edoxaban Rivaroxaban 80yrs > 75yrs Elderly Elderly 60kg < 50kg < 60kg < 50kg Additional risk factors that will or may Cr >133 mol/L, moderate renal imp moderate renal imp moderate renal imp increase the risk of bleeding, in addition to CrCL 30-50mL/min (CrCL 30-50mL/min) (CrCL 30-50 mL/min) (CrCL 30 - 50 ml/min).

8 Any of the potential drug Interactions listed below (NB: not exhaustive) gastritis, oesophagitis, gastritis, oesophagitis, gastritis, oesophagitis, GORD GORD GORD. History of GI bleeding; recent surgery on critical organ; thrombocytopenia; HASBLED > 3. Interacting drug Mechanism Apixaban Dabigatran Edoxaban Rivaroxaban factors Antiarrhythmics Amiodarone Moderate CYP3A4 AUC 60%. Caution and mild-mod and close clinical P-gp inhibitor Caution surveillance required AUC 40% Not listed in SPC. Note long half-life of specially in mild-mod Caution amiodarone; any drug renal imp or other interaction may persist yellow' risk factors - for some weeks after consider lower dose.

9 Stopping amiodarone (NB: different advice for orthopaedic VTE. prophylaxis: see SPC). Digoxin P-gp substrate No interaction No interaction Not clinically relevant Not clinically relevant Diltiazem Moderate CYP3A4 AUC fold Not listed in SPC; Not listed in SPC; Not listed in SPC;. and weak P-gp significant interaction significant interaction significant interaction inhibitor Caution not expected not expected not expected. Caution in renal impairment Antiarrhythmics continued overleaf Key Red box, white text Yellow box, black text Purple box, white text White box, black text Blue box, white text Contraindicated / avoid / Caution use / monitor Reduce dose as per SPC No or limited data / not No clinically meaningful not recommended closely (note: If >2 yellow (caution use / monitor listed in SPC / unable to interaction expected factors are present, closely if additional yellow advise (unless otherwise consider alternative drug / factors present; consider stated).))

10 Seek advice) alternative / seek advice). Renal impairment: SPCs for DOAC classify renal impairment (CrCL, Cockcroft Gault) as follows: Mild: 50-80mL/min; Mod: 30-50mL/min; Severe: <30mL/min (this may differ from the classification of renal impairment in the BNF). NOTE: Dabigatran is contraindicated with severe renal failure (CrCL <30mL/min); NCL advises against the use of apixaban/edoxaban/rivaroxaban with CrCL 15-30mL/min unless discussed with haematologist. North Central London Joint Formulary Committee 4 of 9. DOAC Interactions Approval date: August 2018. Version Expiry date: May 2019. Interacting drug Mechanism via Apixaban Dabigatran Edoxaban Rivaroxaban Antiarrhythmics contd.