Warfarin interacts majorly with drugs such as Tamoxifen, Simvastatin, Penicillins, cephalosporins, Macrolide antibiotics, Fluoroquinolones, Sulphonamides, Azole antifungals, Amiodarone, Enoxaparin, Danaparoid, Antiplatelets, Fish oil, Vitamin K rich foods, Green tea, Pomegranate etc.

1. Drug Interactions of Anticoagulants
– Part 1
(Drug Interactions of Warfarin (Coumarins)
Dr. P.NAINA MOHAMED PhD
Pharmacologist

2. 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).

3. 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 – Argotroban
Dabigatran etexilate (Oral)

4. Warfarin
 Warfarin is used to treat patients with Deep Vein Thrombosis (DVT) or Pulmonary Embolism.
 Warfarin is also used to prevent thrombosis in high risk patients with Atrial Fibrillation, Heart
attack and knee or hip surgeries.
 Warfarin can cause serious interactions with many commonly used medicines and it also can
interact with certain foods.
 Regular blood monitoring of INR (International Normalized Ratio) is recommended to check for
effectiveness and safety.
Warfarin
Inhibition of
vitamin K epoxide
reductase (VKOR)
enzyme
Decreased
availability of
vitamin K in tissues
Inhibition of
Glutamyl
carboxylase
Blockade of
carboxylation of
Coagulation
factors II, VII, IX and X
Coagulation factors
unable to bind to
the endothelial surface
of blood vessels
Coagulation factors
become
biologically inactive
Prevention of
clotting

5. Warfarin & Tamoxifen
 Consider using lower warfarin doses and closely monitor the INR
(International Normalized Ratio) when Tamoxifen and Warfarin use is
necessary.
http://journals.sagepub.com/doi/pdf/10.1345/aph.1M176
Warfarin + Tamoxifen
Tamoxifen may inhibit
CYP2C9-mediated warfarin
metabolism
Elevated risk of bleeding

6. Warfarin & Simvastatin
 Concurrent use of Warfarin and Simvastatin warrants the monitoring of
Prothrombin time ratio or International normalized ratio (INR).
 Monitor the patients also for signs and symptoms of myopathy or
rhabdomyolysis (muscle pain, tenderness, or weakness).
http://journals.sagepub.com/doi/pdf/10.1345/aph.1K167
Warfarin + Simvastatin
Warfarin and Simvastatin
compete for CYP3A4
mediated metabolism
Increased risk of
Bleeding and
Rhabdomyolysis

7. Warfarin &
Penicillins
 More frequent monitoring of INR is recommended, if concomitant use is
necessary.
 Substitute Penicillins with an antibiotic with a low-risk profile for bleeding, such
as clindamycin and cephalexin.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712345/
Warfarin + Penicillins
(Amoxicillin, Cloxacillin,
Ticarcillin, Methicillin, etc)
Penicillins alter the
intestinal flora that
synthesize vitamin K
Elevated risk of bleeding

8. Warfarin &
Cephalosporins
 More frequent monitoring of INR is recommended, if concomitant use is
necessary.
 Substitute Cephalosporins with an antibiotic with a low-risk profile for bleeding,
such as clindamycin and cephalexin.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712345/
Warfarin +
Cephalosporins
(Cefixime, Cefepime,
Ceftazidime, etc)
Cephalosporins alter the
intestinal flora that
synthesize vitamin K
Elevated risk of bleeding

9. Warfarin &
Macrolide Antibiotics
 More frequent monitoring of INR is recommended, if concomitant use is
necessary.
 Substitute Macrolides with an antibiotic with a low-risk profile for bleeding, such
as clindamycin and cephalexin.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712345/
Warfarin + Macrolide
Antibiotics (Azithromycin,
Clarithromycin,
Roxithromycin, etc)
Macrolide Antibiotics alter
the intestinal flora that
synthesize vitamin K
Elevated risk of bleeding

10. Warfarin &
Fluoroquinolones
 More frequent monitoring of the patient's INR is recommended, if
concomitant use is required.
http://journals.sagepub.com/doi/pdf/10.1345/aph.1K605
Warfarin +
Fluoroquinolones
(Ciprofloxacin, Levofloxacin,
Moxifloxacin, etc)
Fluoroquinolones alter the
intestinal flora that
synthesize vitamin K
Elevated risk of bleeding

11. Warfarin &
Sulphonamides
 More frequent monitoring of INR is recommended, if concomitant use is
necessary.
 Substitute Sulphonamides with an antibiotic with a low-risk profile for bleeding,
such as clindamycin and cephalexin.
https://www.ncbi.nlm.nih.gov/pubmed/20386005/
Warfarin + Sulphonamides
(Sulfamethoxazole,
Sulfisoxazole, etc)
Sulphonamides alter the
intestinal flora that
synthesize vitamin K &
Inhibit CYP2C9-mediated
metabolism of warfarin
Elevated risk of bleeding

12. Warfarin &
Azole Antifungals
 More frequent monitoring of INR is recommended, if concomitant use is
necessary.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574587/
Warfarin + Azole Antifungals
(Fluconazole, Ketoconazole,
Posaconazole, Miconazole,
Itraconazole, etc)
Azole antifungals alter the
intestinal flora that synthesize
vitamin K & Inhibit CYP3A4-
mediated metabolism of warfarin
Elevated risk of bleeding

13. Warfarin &
Chemotherapeutic Agents
 Warfarin may not be the optimal anticoagulant for cancer patients for any
indication, especially during treatment with chemotherapy.
 Monitor the INR (International Normalized Ratio) closely and monitor for signs of
bleeding when warfarin is used concomitantly with chemotherapeutic agents.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219727/
Warfarin + Chemotherapeutic
Agents (Cyclophosphamide,
Methotrexate, Doxorubicin)
Increased risk for
elevated INR
Bleeding

14. Warfarin & Amiodarone
 Coadministration of Warfarin and Amiodarone increases the prothrombin time
by 100% after 3 to 4 days.
 Decrease the warfarin dose by one-third to one-half and monitor the
prothrombin time, if concurrent use is required.
http://www.sciencedirect.com/science/article/pii/S0012369215346365
Warfarin +
Amiodarone
Decreased
metabolism
Serious Bleeding

15. Warfarin & Enoxaparin
 If coadministration of Warfarin and Enoxaparin is required, closely monitor
the patient for signs and symptoms of bleeding, and neurological
impairment in patients who are receiving neuraxial anesthesia or
undergoing spinal puncture.
 Prothrombin time/INR should also be monitored closely if enoxaparin and
warfarin are taken concomitantly, especially during medication initiation or
discontinuation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265267/
Warfarin +
Enoxaparin
Additive
anticoagulation
Increased risk
of bleeding

16. Warfarin & Danaparoid
 More frequent monitoring of Prothrombin time/INR is recommended,
When concomitant use is required.
Warfarin +
Danaparoid
Additive
anticoagulation
Elevated risk of
bleeding

17. Warfarin &
Antiplatelet agents
 Monitor patients closely for signs or symptoms of bleeding.
http://www.onlinejacc.org/content/54/2/95
Warfarin + Antiplatelet
agents (Aspirin,
Clopidogrel, etc)
Additive effects Increased risk of

18. Warfarin & Fish oil
 Warfarin patients should be educated about and monitored for possible
drug-supplement interactions.
https://www.ncbi.nlm.nih.gov/pubmed/14742793
Warfarin + Fish oil
(Omega 3 Fatty
Acids)
supplements
EicosaPentaenoic Acid
(EPA) of fish oil decreases
the availability of the
Thromboxane precursor
in the phospholipids of
the cell membrane
Decreased
Thromboxane
A2 levels
Decreased
platelet
aggregation
Elevated risk of Bleeding

19. Warfarin &
Vitamin K rich Foods
 Large changes in dietary consumption of foods high in vitamin K should
be avoided or accompanied by careful monitoring of the international
normalized ratio (INR).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911546/
Warfarin + Vitamin K
rich Foods (Kale,
Spinach, Brussels
sprouts, Collard greens,
Mustard greens, etc)
Antagonism of warfarin
Altered anticoagulant
effectiveness

20. Warfarin & Green tea
 It is recommended to question Warfarin Patients routinely about their
intake of vitamin K-containing foods and beverages.
https://www.ncbi.nlm.nih.gov/pubmed/10332534
Warfarin + Green tea
Vitamin K content of Green tea
antagonize warfarin action
Reduced anticoagulant
effectiveness

21. Warfarin &
Pomegranate
 It is recommended to instruct the patient to avoid pomegranate, before
initiating Warfarin.
https://www.ncbi.nlm.nih.gov/pubmed/19637955
Warfarin +
Pomegranate
Pomegranate inhibits CYP3A4/
CYP2C9 mediated metabolism
warfarin
Increased plasma
concentrations of
Increased risk of bleeding

22. 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
Increased risk of bleeding

23. 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
Decreased function of plateletsIncreased risk of Bleeding

24. 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
by platelets
Decreased function of
platelets
Increased risk of Bleeding

25. 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
Decreased warfarin plasma
concentrations leading to Reduced
anticoagulant effectiveness

26. 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
aggregation
Increased risk of bleeding

27. Anticoagulants & Garlic
 Monitor bleeding time and signs and symptoms of excessive bleeding, if
garlic is taken with an anticoagulant.
http://onlinelibrary.wiley.com/doi/10.1002/mnfr.200700072/epdf
Anticoagulants + Garlic
Garlic has Anti-platelet,
Antithrombotic and
Fibrinolytic activities
Increased risk of bleeding

28. Anticoagulants +
Papaya
 The patient should be monitored closely for symptoms of bleeding and
the INR should be closely monitored, if taken concomitantly.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025393/
Anticoagulants + Papaya
Papain of Papaya may
damage the mucous
membranes of the
gastrointestinal tract
Increased bleeding risk

29. 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
Increased risk of bleeding

30. Warfarin & Tobacco
Smoking
 Close monitoring of warfarin therapy is recommended when there is a
change in smoking status of patients.
http://www.sciencedirect.com/science/article/pii/S0012369211602389
Warfarin + Tobacco
smoking (Polycyclic
aromatic hydrocarbons)
Induction of CYP1A2-
mediated metabolism of
Warfarin
Decreased Warfarin
efficacy

31. Warfarin & Alcohol
 Patients on Warfarin should avoid large amounts of alcohol.
http://circ.ahajournals.org/content/119/8/e220
Warfarin+ Alcohol
Alcohol possess
Antiplatelet activity
Elevated risk of
bleeding

32. TIPS for Warfarin Patients
 Limit the intake of Vitamin K rich foods kale, collards, broccoli, spinach and other green
leafy vegetables.
 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 Warfarin
prior to any surgery.
 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 Warfarin.
 Stick with the same brand of warfarin to maintain INR levels stable.

33. 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 Warfarin patients about their herbal and other alternative medicine
product use.

34. 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 C.
Armstrong

35. 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/DrugReference/Dru
ginteractionchecker/