Ukmi q&a xx

Medicines Q&As

Is there an interaction between warfarin and proton pump

inhibitors?

Before using this Q&A, read the disclaimer at Background
Warfarin is the anticoagulant of choice in the UK for a number of conditions including prophylaxis of
deep vein thrombosis (DVT), treatment of DVT and pulmonary embolism, atrial fibrillation,
cardioversion and dilated cardiomyopathy (1). Patients taking warfarin are monitored regularly to
check prothrombin times and INRs (international normalised ratio).
Warfarin is a mixture of 2 active isomers – the R-isomer and the S-isomer. The S-isomer is more
potent. The R- and S-isomers are both metabolised in the liver. The S-isomer is metabolised more
rapidly than the R-isomer, mainly by the cytochrome P450 isoenzyme CYP2C9. The R-isomer is
metabolised mainly by CYP1A2 and partly by CYP3A4 and CYP2C19 (2, 3, 4, 5). Therefore,
concomitant use of other drugs that are also metabolised by the liver or have an effect on the liver,
may need careful monitoring.
There are 5 proton pump inhibitors (PPIs) available in the UK – esomeprazole, lansoprazole,
omeprazole, pantoprazole and rabeprazole (1). These are all metabolised by the liver by CYP2C19
and CYP3A4 so may affect the activity of warfarin (6-41).
Answer
Esomeprazole
The Summaries of Product Characteristics (SPC) for esomeprazole preparations, state that
concomitant administration of 40mg esomeprazole to warfarin-treated patients in a clinical trial
showed that coagulation times were within the accepted range. However, post-marketing, a few
isolated cases of elevated INR of clinical significance have been reported during concomitant
treatment (6-11, 42).
In practice, there is no reason for avoiding concurrent use of esomeprazole with warfarin although
monitoring is recommended when initiating, modifying or ending concomitant treatment (4, 6-11, 42-
44).
Lansoprazole
Two isolated reports of elevations in prothrombin time and INR following co-administration of warfarin
and lansoprazole have been highlighted (43).
In clinical practice, lansoprazole does not normally interact with warfarin. It would be prudent to
monitor prothrombin time or INR when lansoprazole is added to, changed during, or discontinued
from concomitant treatment with warfarin. If any increase in the INR is seen, the dose of warfarin
should be adjusted as necessary to maintain the desired level of anticoagulation (4, 42-44).
Omeprazole
The product literature for omeprazole reports that as omeprazole is metabolised in the liver through
cytochrome P450 it can prolong the elimination of warfarin. The metabolism is mainly dependent on
CYP2C19 (18-28). Monitoring of patients receiving warfarin is recommended and a reduction of
warfarin dose may be necessary (21).
Two studies have shown that omeprazole causes a small and clinically insignificant change in the
anticoagulant effects of warfarin by decreasing its clearance, although in an isolated case report of
one patient on warfarin given omeprazole, developed a prolonged prothrombin time and bled (4, 42,
Medicines Q&As

43). The effect of the interaction between warfarin and omeprazole is small and has been described
as having minor, doubtful or limited clinical significance (4, 5, 43).
A systematic overview of warfarin and its drug and food interactions published in 2005 concluded that
potentiation of the effect of warfarin by omeprazole was highly probable. The authors of the review
concluded that use of omeprazole with warfarin should be avoided (3). It is interesting to note that the
systematic overview only referenced one of the two studies highlighted by the other reference sources
and came to a different conclusion regarding the severity of the interaction and subsequent
recommendation (3).
In practice, the response of patients should be monitored when omeprazole is added to, changed
during or discontinued from concomitant treatment with warfarin and a reduction in warfarin dose may
be necessary (4, 18-28, 43, 44).
Pantoprazole
Although no interaction has been observed during concomitant administration of pantoprazole and
warfarin in clinical pharmacokinetic studies, a few isolated changes in INR have been reported in the
post-marketing period (29-35).
A systematic overview has highlighted one study with pantoprazole and warfarin that classed the
probability of the reaction as high but concluded that there was no effect on the activity of warfarin (3).
In practice, patients given pantoprazole and warfarin concurrently should have monitoring of
prothrombin time/INR after initiation, termination or during regular use of pantoprazole (4, 29-35, 43,
44).
Rabeprazole
The SPCs do not list an interaction between rabeprazole and warfarin (36-41). No significant change
in the pharmacokinetics of warfarin was observed after single dose administration to healthy subjects
who had been receiving rabeprazole 20mg daily for 7 days (4, 43).
The American product literature says there have been reports of increased INR and prothrombin time
in patients receiving proton pump inhibitors, including rabeprazole, and warfarin concomitantly (4, 43).
In practice, there is no reason for avoiding concurrent use of rabeprazole with warfarin. It would be
prudent to monitor prothrombin time or INR at close intervals if the 2 medicines are given together (4,
43, 44).
Summary
 Generally, the evidence for an interaction between warfarin and proton pump inhibitors is poor,
but rarely and unpredictably raised INRs and bleeding may occur.  In practice, whilst there is no reason for avoiding concurrent use of any proton pump inhibitor with warfarin, close monitoring of the prothrombin time or INR may be required.  If any increase in the INR is seen, the dose of warfarin should be adjusted as necessary to maintain the desired level of anticoagulation.
Limitations
This answer has been constructed from general information sources as well as specific drug
interaction resources. Both American and British resources were used. While information was
generally similar for most PPIs, the opinions on the use of omeprazole and rabeprazole differed
slightly. The summary was based on the consensus of the majority of the resources available at the
time the answer was prepared. The answer has only addressed the interaction between oral proton
pump inhibitors and warfarin, intravenous products have not been considered.
References
1. Martin J (Ed). British National Formulary 65th Edition, March 2013. Coumarins and phenindione.
London: Pharmaceutical Press. Electronic version, 2013. Accessed vion 23/07/13. Medicines Q&As
2. Sweetman SC (Ed). Martindale: The Complete Drug Reference. Warfarin Sodium (monograph last revised and modified 15 November 2012). London: Pharmaceutical Press. Electronic version, 2011. Accessed vion 23/07/13. 3. Holbrook AM, Pereira JA et al. Systematic overview of warfarin and its drug and food interactions. Archives of Internal Medicine 2005; 165: 1095-1106. 4. Klasco RK (Ed): DRUGDEX® Drug Evaluation – warfarin. Last modified 12/07/13 MICROMEDEX(R) Healthcare Series. Accessed vion 23/07/13. 5. Uno T, Sugimoto K et al. The role of cytochrome P2C19 in R-warfarin pharmacokinetics and its interaction with omeprazole. Therapeutic Drug Monitoring 2008; 30: 276-81. 6. Summaries of Product Characteristics – Emozul 20mg & 40mg gastro-resistant capsules,hard. Consilient Health Ltd, last updated 05/09/11 7. Summary of Product Characteristics – Esomeprazole 20mg gastro-resistant tablets. Actavis UK 8. Summary of Product Characteristics – Esomeprazole 40mg gastro-resistant tablets. Actavis UK 9. Summary of Product Characteristics - Nexium 10mg gastro-resistant granules for oral suspension, sachet. AstraZeneca UK Limited, last updated 19/10/12. 10. Summary of Product Characteristics - Nexium 20mg Tablets. AstraZeneca UK Limited, last 11. Summary of Product Characteristics - Nexium 40mg Tablets. AstraZeneca UK Limited, last 12. Summary of Product Characteristics – Lansoprazole 15mg gastro-resistant capsules (Arrow). 13. Summary of Product Characteristics – Lansoprazole 30mg gastro-resistant capsules (Arrow). 14. Summary of Product Characteristics – Lansoprazole 15mg gastro-resistant capsules. Zentiva, last 15. Summary of Product Characteristics – Lansoprazole 30mg gastro-resistant capsules. Zentiva, last 16. Summaries of Product Characteristics – Lansoprazole 15mg & 30mg gastro-resistant capsules. 17. Summary of Product Characteristics - Zoton FasTab. Pfizer Limited, last updated 06/07/12. 18. Summaries of Product Characteristics - Losec MUPS Tablets 10mg, 20mg & 40mg. AstraZeneca 19. Summary of Product Characteristics - Losec Capsules 10mg, 20mg & 40mg. AstraZeneca UK 20. Summary of Product Characteristics – Boots Acid Reflux 10mg gastro-resistant tablets. The Boots 21. Summaries of Product Characteristics - Mepradec 10mg & 20mg gastroresistant capsules. Discovery Pharmaceuticals Ltd, last updated 16/02/10 22. Summaries of Product Characteristics - Mezzopram 10mg, 20mg &40mg dispersible gastroresistant tablets. Sandoz Ltd, last updated 04/05/11. 23. Summary of Product Characteristics - Omeprazole 10mg capsules. Actavis UK Ltd, last updated 24. Summary of Product Characteristics - Omeprazole 20mg capsules. Actavis UK Ltd, last updated 25. Summaries of Product Characteristics - Omeprazole 10mg & 20mg capsules. Sandoz Limited, 26. Summary of Product Characteristics - Omeprazole 40mg capsules. Sandoz Limited, last updated 27. Summary of Product Characteristics - Omeprazole 20mg gastro-resistant capsules. Zentiva, last 28. Summary of Product Characteristics – Zanprol 10mg tablets. Omega Pharma Ltd, last updated 29. Summary of Product Characteristics – Pantoloc Control 20mg gastroresistant tablets. Novartis Medicines Q&As
30. Summaries of Product Characteristics – Pantoprazole 20mg & 40mg gastro-resistant tablets. Wockhardt UK Ltd, last updated 06/08/12. 31. Summaries of Product Characteristics – Pantoprazole 20mg & 40mg gastro-resistant tablets. 32. Summary of Product Characteristics – Pantoprazole 20mg gastro-resistant tablets. Actavis UK 33. Summary of Product Characteristics – Pantoprazole 40mg gastro-resistant tablets. Actavis UK 34. Summaries of Product Characteristics – Pantoprazole 20mg & 40mg gastro-resistant tablets. 35. Summaries of Product Characteristics – Pantoprazole 20mg & 40mg gastro-resistant tablets. 36. Summary of Product Characteristics - Pariet 10mg & 20mg. Eisai Ltd, last updated 19/04/13. 37. Summaries of Product Characteristics – Rabeprazole 10mg & 20mg gastro-resistant tablets. 38. Summary of Product Characteristics – Rabeprazole 10mg gastro-resistant tablets. Aurobindo Pharma - Milpharm Ltd, last updated 15/11/12. 39. Summary of Product Characteristics – Rabeprazole 20mg gastro-resistant tablets. Aurobindo Pharma - Milpharm Ltd, last updated 22/11/12. 40. Summaries of Product Characteristics – Rabeprazole 10mg & 20mg gastro-resistant tablets. Consilient Health Ltd, last updated 13/12/12. 41. Summaries of Product Characteristics – Rabeprazole 10mg & 20mg gastro-resistant tablets. 42. Blume H, Donmath F et al. Pharmacokinetic drug interaction profiles of proton pump inhibitors. 43. Baxter K (Ed). Stockley’s Drug Interactions. Coumarins + Proton Pump Inhibitors (Updated 2 November 2012). London: Pharmaceutical Press. Electronic version. Accessed via on 23/07/13. 44. Agewall S, Cattaneo M, Collet JP et al on behalf of ESC Working Group on Cardiovascular Pharmacology and Drug Therapy and ESC Working Group on Thrombosis. Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy. European Heart Journal 2013; 34: 1708-15.
All Summaries of Product Characteristics accessed vion 23/07/13.
Quality Assurance
Prepared by
Katie Smith, East Anglia Medicines Information Service
Contact

Date Prepared
7th August 2013
Checked by
Sarah Cavanagh, East Anglia Medicines Information Service
Date of check
9th August 2013
Search strategy
 Embase: 1980 to Present; WARFARIN/it [it=Drug Interaction] AND [[ ESOMEPRAZOLE/it
[it=Drug Interaction] OR LANSOPRAZOLE/it [it=Drug Interaction] OR OMEPRAZOLE/it [it=Drug Interaction] OR PANTOPRAZOLE/it [it=Drug Interaction] OR RABEPRAZOLE/it [it=Drug Interaction]] OR PROTON PUMP INHIBITOR/it [it=Drug Interaction]] [Limit to: Publication Year 20011-2013 and Human and English Language] Medicines Q&As
 Medline: 1950 to Present; search terms = WARFARIN/ AND DRUG INTERACTIONS/ AND [[OMEPRAZOLE/ OR esomeprazole.af OR lansoprazole.af OR pantoprazole.af OR rabeprazole.af] OR PROTON PUMP INHIBITORS/] [Limit to: Publication Year 2011-2013 and Humans and English Language]  In-house database/resources: BNF, Martindale, Drug Interactions  Electronic Medicines Compendium: esomeprazole, lansoprazole, omeprazole, pantoprazole,  MICROMEDEX(R) Healthcare Series – DrugDex: warfarin monograph  IDIS: "WARFARIN 20120208" and "ANTIULCER-PROTON PUMP INHIB 56260600" or "ESOMEPRAZOLE 56260605" or "LANSOPRAZOLE 56260603" or "OMEPRAZOLE 56260602" or "PANTOPRAZOLE 56260606" or "RABEPRAZOLE 56260604" and Descriptor(s): "DRUG INTERACTION 50" Years: 2011-2013

Source: http://www.sefap.org/media/upload/pdf/qa_nhs-_interaccion_ibp_-_warfarina_agosto_2013_editora_10_123_1.pdf

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