Potential Drug Interactions
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Drug interactions with warfarin may occur via several mechanisms, including impairment of absorption, induction or inhibition of metabolism, competition for protein-binding sites, and platelet inhibition. Drugs that inhibit or induce P-450 2C9 (responsible for metabolism of S-warfarin) may have the greatest effect on INR.
-
INR should be monitored more frequently in pediatric patients who are already on warfarin therapy and are starting on antibiotics.
-
Warfarin dosing can be adjusted to permit use of some medications that have an effect on warfarin metabolism. Please consult Hematology for adjustment recommendations.
Table 6. Commonly used Drugs in Children that affect INR Values
|
Drug |
INR Effect |
Mechanism |
|
Amiodarone |
Increase |
Decreases warfarin metabolism |
|
Antifungal agents |
Increase |
Fluconazole, ketoconazole, and miconazole (vaginal) decrease warfarin metabolism |
|
Barbiturates |
Decrease |
Increase warfarin metabolism |
|
Carbamazepine |
Decrease |
Increase warfarin metabolism |
|
Cephalosporins |
Increase |
Inhibits production of vitamin K dependent clotting factors |
|
Ciprofloxacin |
Increase |
Displace warfarin from binding sites (possible mechanism; not fully known) |
|
Clarithromycin |
Increase |
Decrease warfarin metabolism |
|
Contraceptives (Oral) |
Increase |
Increase clotting factor synthesis; may inhibit oxidative metabolism |
|
Corticosteroids |
Increase |
Produce hypercoagulability; may have ulcerogenic effects |
|
Delaviridine |
Increase |
May inhibit warfarin metabolism |
|
Erythromycin |
Increase |
Decrease warfarin metabolism |
|
Ibuprofen |
Increase |
May inhibit warfarin metabolism in addition to platelet inhibition |
|
Indomethacin |
Increase |
May inhibit warfarin metabolism in addition to platelet inhibition |
|
Isoniazid |
Increase |
May inhibit warfarin metabolism |
|
Losartan |
Increase |
May inhibit warfarin metabolism |
|
Omeprazole |
Increase |
May inhibit of warfarin metabolism |
|
Metronidazole |
Increase |
Inhibits metabolism of S-isomer |
|
Nicardipine |
Increase |
May inhibit warfarin metabolism |
|
Pantoprazole |
Increase |
May inhibit warfarin metabolism |
|
Penicillins |
Increase |
May enhance warfarin metabolism; May reduce GI flora synthesis of vitamin K |
|
Phenytoin / fosphenytoin |
Decrease |
Increase warfarin metabolism; induces warfarin metabolism; displaces warfarin from protein-binding sites; enhances metabolism of clotting factors |
|
Rifampin |
Decrease |
Induces hepatic enzymes, increases warfarin metabolism |
|
Sulfamethoxazole - Trimethoprim (Bactrim) |
Increase |
Sulfonamide component may stereo-selectively inhibit S-isomer metabolism |
|
Vitamin K (ADEK, Centrum, Viactiv) |
Decrease |
Effects of oral anticoagulants are directly antagonized by the excessive ingestion of foods or dietary supplements containing vitamin K |
|
Zafirlukast |
Increase |
May inhibit warfarin metabolism |
|
Other important interactions |
||
|
Drug |
Effect |
Mechanism |
|
Aspirin, NSAIDs |
Increased risk of bleed |
Inhibition of platelet aggregation |
|
Anti-platelet agents (dipyridamole, clopidrogel, ticlopidine, cilostazol) |
Increased risk of bleed |
Inhibition of platelet aggregation |
References
Ansell, J., Hirsh, J., Hylek, E., Jacobson, A., Crowther, M., & Palareti, G. (2008). Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 133(6 Suppl), 160s-198s. https://doi.org/10.1378/chest.08-0670
Bolton-Maggs, P., & Brook, L. (2002). The use of vitamin K for reversal of over-warfarinization in children. Br J Haematol, 118(3), 924. https://doi.org/10.1046/j.1365-2141.2002.03631_5.x David, M., et al. (2004, May). Warfarin Therapy in Children. Thrombosis Interest Group of Canada. Retrieved Oct 21, 2008 from http://www.tigc.org/eguidelines/warfarinchildren04.htm.
Horton, J. D., & Bushwick, B. M. (1999). Warfarin therapy: evolving strategies in anticoagulation. Am Fam Physician, 59(3), 635-646.
Lexicomp Online, Pediatric and Neonatal Lexi-Drugs. Kcentra. Retrieved Oct 2008, from https:online.lexi.com.
Lexicomp Online, Pediatric and Neonatal Lexi-Drugs. Warfarin. Retrieved Oct 2008, from https:online.lexi.com. Monagle, P., Chan, A. K. C., Goldenberg, N. A., Ichord, R. N., Journeycake, J. M., Nowak-Göttl, U., & Vesely, S. K. (2012). Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 141(2 Suppl), e737S-e801S. https://doi.org/10.1378/chest.11-2308
Monagle, P., Cuello, C. A., Augustine, C., Bonduel, M., Brandão, L. R., Capman, T., Chan, A. K. C., Hanson, S., Male, C., Meerpohl, J., Newall, F., O'Brien, S. H., Raffini, L., van Ommen, H., Wiernikowski, J., Williams, S., Bhatt, M., Riva, J. J., Roldan, Y., . . . Vesely, S. K. (2018). American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism. Blood Adv, 2(22), 3292-3316. https://doi.org/10.1182/bloodadvances.2018024786
Roach, E. S., Golomb, M. R., Adams, R., Biller, J., Daniels, S., Deveber, G., Ferriero, D., Jones, B. V., Kirkham, F. J., Scott, R. M., & Smith, E. R. (2008). Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke, 39(9), 2644-2691. https://doi.org/10.1161/strokeaha.108.189696
These pathways do not establish a standard of care to be followed in every case. It is recognized that each case is different, and those individuals involved in providing health care are expected to use their judgment in determining what is in the best interests of the patient based on the circumstances existing at the time. It is impossible to anticipate all possible situations that may exist and to prepare a pathway for each. Accordingly, these pathways should guide care with the understanding that departures from them may be required at times.