Drug interactions of Dabigatran

Drug Interactions of Anticoagulants – Part 7(Drug Interactions of Dabigatran)

Dr. P.NAINA MOHAMED PhDPharmacologist

Introduction

Anticoagulants are the drugs used to prevent harmful blood clots which can cause serious conditions like Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), or a Stroke, by affecting blood coagulation factors.

Interaction between one or more coadministered medications leading to change in their effectiveness or toxicity, is termed as “Adverse drug interaction”.

Anticoagulants can interact with prescription drugs, Over-the-counter (OTC) medications, Herbal products, Dietary supplements, Vitamins, Foods, Diseases, and Genetics (family history).

Anticoagulants Coumarins (Oral) Warfarin, Acenocoumarol, Dicoumarol, Ethyl biscoumacetate, Phenprocoumon Indandiones (Oral) Phenindione, Fluindione Factor Xa inhibitors Fondaparinux sodium, Rivaroxaban (Oral) Heparin Low Molecular Weight Heparins (LMWH) Enoxaparin, Dalteparin, Tinzaparin, Bemiparin, Certoparin, Nadroparin, Parnoparin, Reviparin Heparinoids Danaparoid, Dermatan sulphate, Pentosan polysulfate, Suleparoid, Sulodexide Direct Thrombin inhibitors Hirudins - Bivalirudin, Desirudin, Lepirudin Synthetic Thrombin Inhibitors – Argatroban Dabigatran etexilate (Oral)

Dabigatran & Itraconazole or Ketoconazole

https://products.boehringer-ingelheim.com/pradaxa/using-pradaxa/contraindications

Dabigatran + Itraconazole or Ketoconazole

Inhibition of P-glycoprotein-mediated

efflux transport of Dabigatran





Defibrotide & Antithrombotics

Concomitant use of defibrotide and a systemic antithrombotic agent is contraindicated.

http://www.bloodjournal.org/content/120/21/3411?sso-checked=true

Antithrombotics +

Defibrotide

Additive antithromboti

c effects




Dabigatran & Ticagrelor

Concomitant use should be avoided in patients with severe renal impairment.http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/022512Orig1s023ltr.pdf

Dabigatran + Ticagrelor

Ticagrelor inhibits P-glycoprotein-mediated efflux

transport of Dabigatran

Increased dabigatran exposure

http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/022512Orig1s023ltr.pdf



Dabigatran & P-gp Inducers

Concomitant use of dabigatran and a P-gp inducer should be avoided.https://www.nps.org.au/australian-prescriber/articles/p-glycoprotein-and-its-role-in-drug-drug-interactions

Dabigatran + P-Glycoprotein Inducers

(Carbamazepine, Rifampin, St. John's

wort)

Induction of P-gp-mediated efflux

transport of dabigatran

https://www.nps.org.au/australian-prescriber/articles/p-glycoprotein-and-its-role-in-drug-drug-interactions




Dabigatran & P-gp Inhibitors

When dabigatran is used for reducing the risk of stroke and systemic embolism in non-valvular atrial fibrillation, avoid coadministration of a P-gp inhibitor in patients with severe renal impairment

http://spo.escardio.org/eslides/view.aspx?eevtid=48&fp=129

Dabigatran + P-gp inhibitors (Verapamil, Quinidine, Amiodarone,

Ketoconazole, Itraconazole, Ritonavir, Saquinavir, Nelfinavir, Tacrolimus,

Cyclosporine)

Inhibition of P-gp-mediated efflux transport of dabigatran

Increased dabigatran exposure Increased risk of bleeding




Dabigatran & Other

Anticoagulants

Use caution and monitor closely for bleeding when Dabigatran is used concomitantly with other Anticoagulants.

Dabigatran + Other Anticoagulants

(Heparin, Enoxaparin, Dalteparin, Tinzaparin, Bivalirudin, Lepirudin,

Fondaparinux, Phenindione, Danaparoid,

Rivaroxaban, Apixaban)

Additive anticoagulation

Increased risk of bleeding

Anticoagulants & Fibrinolytics

Observe patients for external bleeding and be alert for signs and symptoms of internal bleeding, if concomitant use of an anticoagulant and a fibrinolytic agent is required.

https://www.ncbi.nlm.nih.gov/pubmed/11085346

Anticoagulants + Fibrinolytics

(Alteplase, Retaplase, Tenecteplase, Streptokinase,

Urokinase)






Anticoagulants & Antiplatelet agents

Concomitant use warrants close monitoring.http://circ.ahajournals.org/content/116/3/305

Anticoagulants + Antiplatelet

agents (Aspirin, Clopidogrel,

Ticagrelor, etc)



http://circ.ahajournals.org/content/116/3/305



Anticoagulants & Fenofibrate

Reduce the dose of the anticoagulant by about one-third at the start of treatment, if concomitant use is required.

Then gradually adjust the dose based on the results of INR monitoring.https://www.ncbi.nlm.nih.gov/pubmed/12549950

Anticoagulants +

Fenofibrate

Additive effects on

anticoagulation



Anticoagulants & Orlistat

Caution should be exercised when Anticoagulants and Orlistat are used concurrently.


Anticoagulants + Orlistat

Orlistat may reduce the absorption of

fat-soluble vitamins, including

vitamin K





Anticoagulants & NSAIDs

If used concomitantly, monitor for signs of bleeding.http://www.aafp.org/afp/2009/1215/p1371.html

Anticoagulants + NSAIDs (Ibuprofen,

Diclofenac, Naproxen, etc)

NSAIDs possess antiplatelet effects


http://www.aafp.org/afp/2009/1215/p1371.html

http://www.aafp.org/afp/2009/1215/p1371.html

Anticoagulants & SSRIs

Serotonin is essential in initiating the hemostatic response of platelets to vascular injury. Monitor patient for signs of increased bleeding When SSRIs and an anticoagulant are

given concurrently. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728939/

Anticoagulants + Selective serotonin reuptake inhibitors

(SSRIs) (Fluvoxamine, Paroxetine,

Vortioxetine, Escitalopram, Sertraline, Nefazodone,

vilazodone)

SSRIs block the uptake of serotonin by platelets

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728939/



Anticoagulants & SNRIs

Serotonin is essential in initiating the hemostatic response of platelets to vascular injury. Monitor patient for signs of increased bleeding When SNRIs and an anticoagulant are

given concurrently. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728939/

Anticoagulants + Selective Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

(Venlafaxine, Desvenlafaxine, Duloxetine, Milnacipran,

Levomilnacipran, Sibutramine)

SNRIs block uptake of serotonin by platelets




Anticoagulants & St. John's Wort

Prothrombin time should be monitored closely. Patients should not discontinue St. John's Wort without notifying their

health care provider.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917631/

Anticoagulants + St.John's

Wort

St. John's Wort induce CYP3A4 and CYP1A2 mediated

metabolism of R-warfarin and CYP2C9 mediated S-warfarin

metabolism



Anticoagulants & Ginkgo

Extreme caution is advised, due to the severity of the bleeding cases reported.

http://onlinelibrary.wiley.com/doi/10.1002/mnfr.200700098/epdf

Anticoagulants + Ginkgo

Ginkgolide B of Ginkgo may inhibit Platelet

Activating Factor (PAF) induced platelet

aggregation



Anticoagulants & Garlic

Monitor bleeding time and signs and symptoms of excessive bleeding, if garlic is taken with an anticoagulant.


Anticoagulants + Garlic

Garlic has Anti-platelet,

Antithrombotic and Fibrinolytic activities




Anticoagulants + Papaya

The patient should be monitored closely for symptoms of bleeding and the INR should be closely monitored, if taken concomitantly.


Anticoagulants + Papaya

Papain of Papaya may damage the mucous membranes of the

gastrointestinal tract




Anticoagulants & Chamomile

Patients should be educated about the potential risk of using chamomile products, while being treated with warfarin.

Monitor the patient for signs and symptoms of excessive bleeding.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1435958/

Anticoagulants + Chamomile (Matricaria

chamomilla)

Coumarins present in chamomile may

potentiate the effect of anticoagulants



Anticoagulants & Coenzyme Q10

Caution is advised if coenzyme Q10 and Anticoagulants are taken together. Monitor the INR to determine continued therapeutic effect.https://www.ncbi.nlm.nih.gov/pubmed/9621803

Anticoagulants + Coenzyme

Q10

Coenzyme Q10 is chemically similar

to Vitamin K2



Anticoagulants & Ginger

Caution is advised if ginger and an anticoagulant are taken concomitantly.


Anticoagulants + Ginger

Ginger may inhibit thromboxane B2

formation & may increase prostacyclin levels




Anticoagulants & Fenugreek

Monitor bleeding time and signs and symptoms of excessive bleeding, if fenugreek and anticoagulants are used concomitantly.

http://onlinelibrary.wiley.com/doi/10.1592/phco.21.5.509.34492/epdf

Anticoagulants +

Fenugreek

Coumarin content of fenugreek may add to the effect of anticoagulants



Anticoagulants & Anise

Caution is advised if anise is taken with an anticoagulant. Monitor for signs and symptoms of increased excessive bleeding.

http://www.ajhp.org/content/57/13/1221.long

Anticoagulants + AniseCoumarin content of

Anise may add to the effect of

anticoagulants



Anticoagulants & Clove Oil

Monitor the patient closely for signs and symptoms of bleeding, if both are taken together.


Anticoagulants + Clove Oil

Eugenol and Acetyl eugenol in clove oil

inhibit platelet aggregation



Anticoagulants & Asafetida

Monitor the patient closely for signs and symptoms of bleeding.http://www.ajhp.org/content/57/13/1221.long

Anticoagulants + Asafetida

Asafetida contains free ferulic acid and coumarin

derivatives


Anticoagulants & Capsaicin

Signs and symptoms of excessive bleeding should be monitored closely if capsaicin (or large amounts of red pepper) and anticoagulants are taken concomitantly.

http://article.sciencepublishinggroup.com/pdf/10.11648.j.cmr.20140305.17.pdf

Anticoagulants + Capsaicin

Capsaicin may inhibit platelet aggregation

and enhance fibrinolytic activity



Anticoagulants & Evening primrose

oil

Monitor for signs and symptoms of excessive bleeding.https://www.ncbi.nlm.nih.gov/pubmed/19783511

Anticoagulants + Evening primrose oil

Gamma-linolenic acid from Evening primrose oil may inhibit thromboxane B2 production and increase prostacyclin production




Anticoagulants & Licorice

Monitor for signs and symptoms of excessive bleeding, if licorice is taken with an anticoagulant.


Anticoagulants + Licorice

Inhibition of thrombin and

platelet aggregation by licorice



Anticoagulants & Celery

Monitor the patient closely for signs and symptoms of bleeding, if both are taken together.

http://naturaldatabase.therapeuticresearch.com/nd/PrintVersion.aspx?id=882&AspxAutoDetectCookieSupport=1

Anticoagulants + Celery

Apigenin content of Celery, may inhibit thromboxane A2 formation

leading to reduced platelet aggregation & Celery contains

coumarin derivatives, which may produce additional anticoagulant

effects




TIPS for Patients on Anticoagulants

Do not double the dose to compensate a missed one. Do not forget to discuss with your surgeon or dentist about the regular use of

Anticoagulant prior to any surgery. Talk to your Physician or Pharmacist before taking any other medications,

including prescription and OTC (Over-The-Counter) medicines. Contact your doctor if you develop severe diarrhea, an infection or a fever. Seek immediate medical advice if there is signs of bleeding such as blood in

your stools or urine, nose-bleeds, bleeding gums, excessive menstrual bleeding or excessive bruising.

Be careful with knives and try to minimize the risk of falling. Always adhere to the prescribed dosage schedule. Wear or carry an identification stating that You are on Anticoagulant.

Conclusion

Drug interactions can result in significant morbidity and mortality and thus minimizing the risk for drug interactions should be a goal in drug therapy.

The patients with clotting disorders should bring a list of all of the drugs they are taking including prescription drugs, over-the-counter drugs, and any supplements, herbal or otherwise, during their visit to the doctor or pharmacist.

The risk of adverse effects could be reduced by healthcare professionals through the screening, education, and follow up on suspected drug interactions.

If possible, the patients are recommended to fill all their prescriptions at one pharmacy.

Pharmacists can play a crucial role in identifying possible drug interactions by asking patients on Anticoagulants about their herbal and other alternative medicine product use.

References

Stockley’s Drug Interactions, 9e Karen Baxter Goodman & Gilman's: The Pharmacological Basis of

Therapeutics, 12e Laurence L. Brunton, Bruce A. Chabner, Björn C. Knollmann Basic & Clinical Pharmacology, 12e Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor A Manual of Adverse Drug Interactions J.P. Griffin, P.F. D'Arcy Clinical Manual of Drug Interaction Principles for Medical

Practice Gary H. Wynn, . Jessica R Oesterheld, . Kelly L Cozza, . Scott CArmstrong

References http://www.micromedexsolutions.com http://

reference.medscape.com/drug-interactionchecker https://www.drugs.com/drug_interactions.html http://www.webmd.com/interaction-checker/ http://

www.rxlist.com/drug-interaction-checker.htm http://

umm.edu/health/medical/drug-interaction-tool http://ukhealthcare.uky.edu/Library/DrugReferenc

e/Druginteractionchecker/

http://www.micromedexsolutions.com/

http://reference.medscape.com/drug-interactionchecker



https://www.drugs.com/drug_interactions.html

https://www.drugs.com/drug_interactions.html

http://www.webmd.com/interaction-checker/

http://www.webmd.com/interaction-checker/

http://www.rxlist.com/drug-interaction-checker.htm

http://www.rxlist.com/drug-interaction-checker.htm

http://umm.edu/health/medical/drug-interaction-tool

http://umm.edu/health/medical/drug-interaction-tool

http://ukhealthcare.uky.edu/Library/DrugReference/Druginteractionchecker/



Health & Medicine

Drug interactions of Dabigatran