797FM.3.1 ORAL ANTICOAGULANTS – WARFARIN, ACENOCOUMAROL AND PHENINDIONE, WHEN DOSES ARE ADJUSTED BY THE ANTICOAGULATION CLINIC AND PRESCRIBED BY THE GENERAL PRACTITIONER Shared Care Protocol

This protocol provides prescribing and monitoring guidance for oral anticoagulant therapy with warfarin, acenocoumarol or phenindione. It should be read in conjunction with the shared care responsibilities, the Summary of Product Characteristics (SPC) available on www.medicines.org.uk/emc and the BNF.

BACKGROUND FOR USE This agreement outlines the ways in which the responsibilities for prescribing of oral anticoagulation with warfarin, acenocoumarol or phenindione are shared where the anticoagulation monitoring service recommends doses and the general practitioner (GP) prescribes them. Sharing of care assumes communication between the anticoagulant monitoring service, GP and patient. The intention to share care should be explained to the patient by both the patient’s GP and the healthcare professional initiating treatment. It is important that patients are consulted about treatment and are in agreement with it. Patients treated with oral anticoagulants are under regular follow-up, which provides an opportunity to discuss drug therapy. It is the responsibility of both the anticoagulation monitoring service and the GP to maintain competencies relevant to their roles. The anticoagulation monitoring service is responsible for ongoing audit of the quality assurance components of the service. The doctor who prescribes the medication legally assumes clinical responsibility for the drug and the consequences of its use.

SUPPORTING INFORMATION The vitamin K antagonist (VKA) oral anticoagulant of choice is warfarin. A small number of patients are intolerant of warfarin and many of these are able to switch to direct oral anticoagulant (DOAC) drugs. Patients unable to tolerate warfarin who are unsuitable for DOAC drugs should have a risk assessment performed regarding the advisability of continued anticoagulation. Patients who definitely require ongoing VKA treatment should be switched to acenocoumarol. Phenindione should be very rarely, if ever required – see section on equivalent doses under switching therapy.

Licensed indications Warfarin Acenocoumarol Phenindione (SINTHROME®) Prophylaxis of embolism in ✓ ✓ ✓ rheumatic heart disease Prophylaxis of stroke in atrial ✓ ✓ ✓ fibrillation Prophylaxis after insertion of ✓ ✓ ✓ prosthetic heart valves Prophylaxis and treatment of ✓ ✓ ✓ venous thrombosis and pulmonary embolism Transient ischaemic attacks ✓ Not licenced Not licensed

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Patients with a therapeutic time in range less than 65%, especially if associated with frequent monitoring and erratic INR swings that are not due to poor medication adherence, should be considered for suitability for a direct oral anticoagulant (DOAC).

ROLES AND RESPONSIBILITIES Where the anticoagulation monitoring service is not the patient’s GP, the responsibilities for care that are specified in this shared care protocol for oral anticoagulation apply. In this situation the anticoagulation monitoring service should request shared care using the form provided in the local shared care document.

GP or hospital will refer the patient to an anticoagulation monitoring service provider.

Secondary care specialist/referrer for oral anticoagulation 1. Determine the need for anticoagulation. 2. If rapid anticoagulation is required with a VKA, it is the responsibility of the specialist identifying the need for rapid oral anticoagulation to refer urgently to secondary care for initiation. 3. Where slow oral anticoagulation with a VKA is appropriate refer the patient to the anticoagulation monitoring service of their choice and inform the GP where the GP practice is not a registered ‘any qualified provider’ (AQP) site.

Anticoagulant monitoring service 1. Initiate and take over management of oral anticoagulant treatment. Inform patient’s GP. 2. Provide written and verbal counselling advice on warfarin. Patients should be provided with patient information and education in an accessible and understandable format both at the initiation of oral anticoagulant treatment and reinforced at subsequent patient attendances and/or review as required. 3. If the anticoagulation monitoring service is initiating the warfarin to provide the first prescription for warfarin, titrate the dose and establish patient on a stable dose of oral anticoagulant. 4. Where a dose change warrants a change in the prescribed strengths of warfarin tablets that cannot be met with patient’s existing warfarin supply, the anticoagulation monitoring service provider must make an initial supply. 5. Provide the patient with a patient held yellow oral anticoagulant therapy record book or equivalent detailing the reason for anticoagulant therapy, target international normalised ratio (INR) range and duration of therapy and issue an oral anticoagulant alert card for them to keep on their person at all times. 6. Provide ongoing monitoring of INRs and appropriate dosing and follow up. Communicate electronically the INR results, dose prescribed and date of next INR test promptly to the patient and patient’s GP within 24 hours. 7. In cases of over anticoagulation, administer oral vitamin K in accordance with British Committee for Standards in Haematology (BCSH) guidelines and clinic protocols. 8. For all patients with an INR >5.0 the cause should be investigated. For every patient with a recorded INR of 8 or more a significant event report giving details of possible cause, management and outcome is to be completed and patient’s GP informed – AQP contract requirement. 9. Where a stop date has been clearly documented by the referrer who is not the patient’s GP then the responsibility to discontinue warfarin or other VKA resides with the anticoagulation monitoring service provider and the GP should be notified oral anticoagulation (OAC) has been stopped. 10. Where continuation of OAC is either in doubt or is not in line with national guidance this should be flagged up to the GP or referrer if this is not the patient’s GP. 11. The anticoagulation monitoring service provider must actively follow up any patient who does not attend (DNA) for regular monitoring within the agreed time period as stated in anticoagulation service specification.

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12. If a patient DNA on 2 or more consecutive occasions or there are more than 42 days in a DNA period, the anticoagulation monitoring service will contact the patient’s GP directly. 13. Report adverse events on the yellow card scheme if appropriate. 14. Ensure clear arrangements for back up advice and support are in place and patient informed. 15. Discuss and regularly review benefits and side effects of treatment with the patient. To assess treatment at regular intervals and conduct annual treatment review. To check patient is well controlled (i.e. degree of INR control should be more than 65% of time in therapeutic range in last 6 - 12 months excluding first 6 weeks of treatment) and no known contraindications to continuing treatment apply or have been identified during monitoring. The outcome of annual review is to be communicated in writing to the patient’s GP (see suggested template Appendix 1).

General practitioner specific responsibilities 1. Unless initiated in secondary care before referral, the prescriber should have a documented discussion with the patient regarding the need for oral anticoagulation as well as the risks and benefits of long term treatment with warfarin. 2. Prior to referral carry out full clinical review and undertake initial full blood count (FBC), coagulation screen, urea & electrolytes (U&Es) and liver function tests (LFTs) and communicate results to the anticoagulation monitoring service. There is a standardised referral form that can be imported into the GP’s clinical system which can be used when referring to any anticoagulant monitoring service clinic to ensure capture of all essential information. Refer patient to their chosen anticoagulation monitoring provider for initiation of treatment, following a holistic assessment of the patient’s suitability for anticoagulation. The prescriber must assess the appropriateness of treatment against the patient’s current health and social status, taking into account the patient’s preferences for treatment. 3. The current chosen anticoagulation monitoring service provider should be recorded in the patient’s notes. 4. Prescribe oral anticoagulant on prescription once patient is initiated on treatment. 5. Ensure that the patient’s INR is being regularly transferred and recorded in their medical records. 6. Inform anticoagulation monitoring service if situation regarding need for anticoagulation changes following specialist advice. 7. Monitor for clinical conditions that may lead to a deterioration in health and INR stability and alert anticoagulation monitoring service in the event of any significant changes in patient’s clinical condition. 8. GP to conduct a review of the benefits versus risks of ongoing anticoagulation therapy at least annually. Details of the review should be recorded in the patient’s notes. 9. When co-prescribing, choose medicines least likely to interact with oral anticoagulant as per the interaction chart (Appendix 2). If there is a known potential interaction following any medication changes that may affect the stability of the patient’s INR, either refer the patient back to the anticoagulant clinic for an appropriate INR follow up or make arrangements for an INR check to be made and communicate results to anticoagulation monitoring service. It is the responsibility of the clinician or GP who is prescribing any potentially interacting drug to ensure arrangements are in place for appropriate INR follow up to be completed in a timely manner. 10. To inform AQP provider of any relevant change in medical condition and/or recent hospital admissions likely to affect anticoagulation status and warranting an earlier review of INR control. 11. Alert anticoagulation monitoring service if a decision to stop oral anticoagulant treatment has been made or if the patient leaves the practice. It is the GP’s decision when to stop treatment where they are the original referrer and of any decision to stop treatment on advice of other specialist clinician.

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12. Liaise with patient to report any significant adverse events to anticoagulation monitoring service clinic. 13. The anticoagulation AQP will conduct an annual review of the patient’s stability and adherence to warfarin therapy but it is the GP’s responsibility to review patient’s suitability to continue warfarin. Patients with a time in therapeutic range (TTR) less than 65% associated with frequent INR monitoring/erratic swings in INR trend that is not due to medication adherence should be considered for suitability of a direct oral anticoagulant (DOAC). Information on TTR will be sent to the GP following annual review by the service provider.

Patient's responsibilities 1. Attend anticoagulation monitoring service regularly and if unable to attend, re-organise appointments as soon as is practical. 2. Regular INRs are required – at least every 12 weeks (at least every 8 weeks for prosthetic heart valve patients). 3. Patients who are self-managing their INRs agree to be reviewed as specified by the anticoagulation monitoring service. 4. Where the GP advises an increased frequency of tests due to interacting drugs it is the patients responsibility to have an INR test done as advised and, if requested, to arrange an urgent appointment with the anticoagulation monitoring service. 5. Report any missed doses when attending for an INR check. 6. Advise anticoagulation monitoring service about any changes in prescribed medication or medical condition and check with the anticoagulation monitoring service or community pharmacist before taking or stopping any over the counter medicines or supplements. 7. Share any concerns with their anticoagulation monitoring service or GP that they may have in relation to treatment with oral anticoagulant. 8. Report to the anticoagulation monitoring service or GP if they do not have a clear understanding of their treatment. 9. Take oral anticoagulants as directed and stated in the yellow oral anticoagulant therapy record book or equivalent hand held record. 10. Report any adverse effects to their anticoagulation monitoring service and/or GP whilst treated with oral anticoagulant.

Hospital pharmacy duration of supply At initiation of treatment, it is standard practice to issue 28 tablets of warfarin 1 mg and 3 mg strengths. Warfarin is usually supplied in original packs which are not split.

CONTRAINDICATIONS AND PRECAUTIONS – see guideline 775FM Treatment of Atrial Fibrillation (AF) Absolute contraindications: • Known large oesophageal varices. • Significant thrombocytopenia (platelet count <50 x 109/L) - refer to haematologist. • Within 72 hours of major surgery with risk of severe bleeding - defer and reassess risk postoperatively. • Previously documented hypersensitivity to either the drug or excipients – consider cardiology opinion. • Acute clinically significant bleed - defer and re-assess suitability for restarting warfarin as soon as acute bleed is over and within 1 - 3 months. • Decompensated liver disease or deranged baseline clotting screen (INR ≥1.5) – refer to gastroenterology/hepatology or haematology as appropriate. • Pregnancy or within 48 hours postpartum - seek urgent haematological advice. • Severe renal impairment (GFR <30 mL/min/1.73 m2).

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Relative contraindications to OAC: • Previous history intracranial haemorrhage. • Recent major extracranial bleed within the last 6 months where the cause has not been identified or treated – decision for oral anti-thrombotic therapy should be deferred. • Recent documented peptic ulcer (PU) within last 3 months – decision for oral anti- thrombotic therapy should be deferred until treatment for PU completed. In all cases with history of PU give PPI cover whilst on anti-thrombotic. • Recent history recurrent and severe falls in patient at higher bleeding risk (see below).

A patient at higher bleeding risk is assessed by having 3 or more of the following risk factors: • Age >65 years. • Previous history bleed or predisposition to bleeding (e.g. diverticulitis). • Uncontrolled blood pressure. • Severe renal impairment (i.e. serum creatinine >200 micromol/L, eGFR <30 mL/min/1.73 m2 or on dialysis). • Acute hepatic impairment (e.g. bilirubin >2 x ULN + LFTs >3 x ULN), chronic liver disease (e.g.cirrhosis). • Low platelet count <80 x 109/L or a thrombocytopenia or anaemia of undiagnosed cause. • On concomitant drugs associated with an increased bleeding risk e.g. SSRIs, oral steroids, NSAIDs, methotrexate or other immune-suppressant agents. • Dementia or marked cognitive impairment with poor medicines compliance and no access to carer support. • Chronic alcohol abuse – especially if associated with binge drinking.

DOSAGE AND TIME TO RESPONSE (see also references 1 and 2). Patients who do not require rapid anticoagulation with loading doses of warfarin i.e. asymptomatic atrial fibrillation, can be given a slow induction regimen e.g. 2 - 3 mg warfarin daily for a week. Subsequent doses are determined by the INR and sensitivity to warfarin. Most patients should achieve therapeutic anticoagulation (i.e. within desired therapeutic range) within 3 - 4 weeks. Individuals have different dosage requirements of warfarin. The response in individuals cannot be predicted. This is partly due to the patient’s different metabolism of warfarin and partly due to other factors such as disease states and interacting drugs. The average dose of warfarin required daily is around 4 - 6 mg but may vary markedly because of several factors. Warfarin should be given once daily ideally at approximately the same time each day.

Once stabilised on warfarin the frequency of INR monitoring will be dictated by the latest INR reading taking into account their recent INR trend and dosing history.

SWITCHING THERAPY Acenocoumarol (Sinthrome®) 1 mg is equivalent to warfarin 1.5 to 2 mg. Phenindione 50 mg is equivalent to warfarin 3 mg (see dosage conversion table below). Patients currently on phenindione who are allergic to or unable to take a coumarin (warfarin/acenocoumarol) should be referred for consideration of a DOAC.

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Dosage conversion table3

Approximate dosage conversions Phenindione dose Acenocoumarol Warfarin dose (Sinthrome®) dose 20 mg 0.5 mg 1 mg 35 mg 1.0 mg 2 mg 50 mg 1.5 mg 3 mg 70 mg 2.0 mg 4 mg 80 mg 2.5 mg 5 mg 100 mg 3.0 mg 6 mg 120 mg 3.5 mg 7 mg 135 mg 4.0 mg 8 mg 150 mg 4.5 mg 9 mg 170 mg 5.0 mg 10 mg

The risk of potential adherence problems or confusion would need to be taken into account when switching therapies (e.g. elderly, cognitively impaired, language problems) and every effort should be made to ensure that the dosing regimen is as simple as possible.

MONITORING SCHEDULE for VKA – by GP It is recommended as good practice to consider checking BP, FBC and U&Es at least annually to fulfil GPs responsibilities listed above i.e. points 7, 8 and 10. The following parameters relate to the clinical care of patients anticoagulated with VKAs (baseline assessments are compulsory for referral but recommended ongoing monitoring requirements are not considered mandatory). Note this monitoring schedule does not apply to DOACs which require regular monitoring of U&Es, the frequency of monitoring determined according to the patient’s renal function status.

Parameter Frequency of test Action Clinical review Baseline assessment (compulsory) Change in patient’s clinical LFTs and baseline Pre& then treatment annually only condition, particularly clotting screen treatm,Annually associated with changes in Full blood count Pre treatment then annually renal function may U&Es Pre treatment then annually necessitate more frequent testing. BP Pre treatment then every 6 - 12 months

MONITORING SCHEDULE – by anticoagulant monitoring service A full clotting screen is mandatory prior to initiation of oral anticoagulation (prothrombin time/INR and APTT). Normal coagulation profile is required for initiation of oral anticoagulation to proceed. Discuss with haematology if any abnormal results. The frequency of INR monitoring following starting of warfarin will initially need to be every 5 - 7 days until stabilised on treatment. For ongoing monitoring where there is no change in medical status or drug therapy, the frequency of monitoring can be guided by the criteria shown below or use of computerised decision support software (CDSS).

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One INR high Recall in 7 to 14 days (stop treatment for 1 to 3 days) (maximum 1 week in prosthetic valve patients) One INR low: Recall in 7 to 14 days One INR therapeutic: Recall in 1 to 2 weeks Two INRs therapeutic Recall in 2 to 3 weeks Three INRs therapeutic Recall in 3 to 4 weeks Four INRs therapeutic Recall in 4 to 5 weeks Five INRs therapeutic Recall in 6 to 8 weeks

More than 5 INRs therapeutic - recall period can be increased in a step-wise fashion to a maximum of 12 weeks between appointments if stable (maximum 8 weeks for prosthetic valve patients).

SIDE EFFECTS of VKAs Main side effect with all VKAs is increased bleeding risk. Other side effects to warfarin reported but are uncommon include hypersensitivity rashes, alopecia, diarrhoea, rarely unexplained drop in haematocrit, “purple toes”, skin necrosis, calciphylaxis, jaundice, hepatic dysfunction. For further details on profile for adverse effects of VKAs, refer to the individual SPC for warfarin, phenindione, Sinthrome®.

NOTABLE DRUG INTERACTIONS (REFER TO BNF AND SPC) See Appendix 2

BACK-UP INFORMATION/ADVICE A list of anticoagulant monitoring clinics is available on the CCG websites. If haematological advice is needed:

Contact Details Telephone: Wycombe General Stoke Mandeville

Haematology 01494 425224 (secretaries) 01296 315516 (leave message for In an emergency contact consultant consultant call back) Haematologist on-call 01494 526161 In an emergency contact Haematologist on bleep 740 via switchboard on 01296 315000 Hospital Pharmacy 01494 425254 01296 315285 Medicines Resource 01494 425355 01494 425355 Centre

SHARED CARE AGREEMENT FORM Available on DocGen. When not available, use the Word version linked here.

REFERENCES 1. Joint Formulary Committee (2018). British National Formulary. 75th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain. 2. British Committee Standards Haematology Guidelines on Oral Anticoagulation (warfarin) fourth edition. 3. Guy’s and St. Thomas’ NHS Foundation Trust Medicines Information Centre May 2012.

See also: Guideline 191FM Protocol for Over-anticoagulation with Warfarin Guideline 775FM Guidelines for the Treatment of Atrial Fibrillation (AF)

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Title of Guideline Oral Anticoagulants – Warfarin, Acenocoumarol and Phenindione, when Doses are Adjusted by the Anticoagulation Clinic and Prescribed by the General Practitioner Guideline Number 797FM Version 3.1 Effective Date June 2018 Review Date June 2021 Original Version Produced January 2009 Amended October 2020 Approvals: Medicines Management Sub Committee 8th March 2018 Clinical Guidelines Subgroup 11th April 2018 Authors Satinder Bhandal, Jane Butterworth, Dr Renu Riat, Maria Smith SDU(s)/Department(s) responsible for updating the MMT at CCG, BHT Haematology SDU guideline Uploaded to the Intranet 28th June 2018 and 9th October 2020

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Appendix 1 Suggested Template for Treatment/Annual Review of Patients On Oral Anticoagulants as Vitamin K Antagonist AQP Provider details…………………. Date of Tx /Annual Review……….. Patient Details Patient full name Date of birth Patients address Registered GP name & surgery address Indication for oral anticoagulation Target INR range Date oral anticoagulation initiated Treatment duration / treatment stop date Reason for review – Annual Review / End of Treatment Review/ Other (state)………………………….. Clinical Review Details Results Comments Average time INR in therapeutic range Assess reasons if poor INR control and (TTR) in the last 12 months if on long- provide supporting information if any reasons term treatment identified for poor TTR control (TTR <65%) INR time in therapeutic range (TTR) in and/or measures taken to improve TTR the latest 6 months (ex 1st 6 weeks tx) Average frequency of INR monitoring □ self testing/management pt Stable pts should not need more frequent (excluding 1st 6 weeks of initiation of □ 8 - 12 weekly monitoring than every 4 - 6 weeks treatment) □ 6 - 8 weekly □ 4 - 6 weekly □ <4 weekly Assessment of medication adherence / □ Never or rarely missed doses Document if any evidence of unintentional dosing history □ Occasionally reported missed doses non-compliance if poor INR control (also □ Frequently missed doses reported consider adherence with other meds being □ No reported missed doses but erratic prescribed that can affect INR control) or unintentional non-compliance suspected Has there been any unintentional INRs Yes/No. If yes how many? Unintentional includes INRs <1.5 not due to ≤1.5 recorded in last 6 months? warfarin being stopped deliberately e.g. prior to surgery Have there been any documented INRs Yes/No. If yes how many? Provide supporting information on >5 recorded in last 6 months? circumstances for cause raised INR Has patient failed to attend for INR follow Yes/No. Give details if yes Record action taken up on more than 1 occasion in last 6 months? Is patient taking any other known drugs e.g. aspirin containing products, oral Check need for other concurrent medicines increasing his bleeding risk as over-the- NSAIDs; dietary supplements known to including use of OTC to minimise any counter medicines or supplements? increase bleeding risk/affect INR control potential drug interactions and bleeding risk Does patient drink alcohol? Yes/No. If yes record number units/week Ensure patient is aware of safe limits alcohol use with warfarin and risks associated with binge drinking. Has there been any evidence of Yes/No. If yes give details Ensure patients are aware to have regular spontaneous bruising or bleeding BP checks (minimum 6 monthly) reported by the patient in last 6 months? Have any other risks during monitoring of Yes/No. If yes give details Give details if yes e.g. is patient prone to anticoagulant treatment or any factors significant bruising; erratic swings in INR affecting INR control been identified since trend etc last review? Would patient benefit from alternative Yes/No Give reasons for decision OAC strategy e.g. self-monitoring or consideration DOAC? Does patient or carer have clear Yes/No. Check patient has yellow OAT The annual review is an opportunity to understanding/indication of benefits and card and record any healthcare advice reinforce key messages and check their risks of treatment? given including signposting to other understanding of treatment and importance networks/organisations for further of drug adherence. advice/support RECOMMENDATION Warfarin well controlled/no safety concerns identified. No further action required by GP. Warfarin poorly controlled/safety concerns identified. Further review by GP required. Guideline 797FM.3.1 9 of 12 Uncontrolled if printed

Appendix 2 Recommendations for prescribing commonly used drugs in Primary Care that potentially interact with warfarin

1. ANTIBACTERIAL AND ANTIFUNGAL DRUGS

Clinically important interaction with significant increases in INR seen with fluconazole and miconazole (including stat doses, buccal and topical formulations). Fluconazole has dose related effect on INR. (Approx. 20% Antifungals to >50% warfarin dose reductions needed.) Reduce dose by at least 20% if co-prescribing fluconazole and, in all cases, check INR day 2 – 4 and day 7 - 10. Nystatin and amphotericin are possible alternative non-interacting options. st nd Most cephalosporins, such as cefalexin (1 generation) and cefaclor (2 generation), do not normally interact with warfarin, although some of the 2nd Oral rd and 3 generation cephalosporins have been associated with independent cephalosporins bleeding risks as they can act as vitamin K antagonists and cause thrombocytopenia. Usually no interaction seen with azithromycin although, very rarely, unpredictable raised INRs have been reported. There is, however, good evidence that azithromycin usually offers a non- interacting and safer alternative to clarithromycin and erythromycin. It is good practice to check INR on day 3 - 5 from start of treatment. Established and potentially serious interaction seen with clarithromycin but it Macrolide is unpredictable and not common. All patients requiring clarithromycin antibiotics should have INR checked within day 2 - 4 because the reaction when it occurs is rapid and usually causes a marked increase on INR. Increases in INR are usually seen with erythromycin although they are not always clinically significant. Marked increases in INR can, however, occur. Reduce dose by 20% in high risk patients only (those sensitive to warfarin, i.e. <3 mg/day and/or if age >75 years), but in all cases check INR day 3 - 5. An established and clinically important interaction seen. The effect on INR can be markedly increased and prolonged by metronidazole. If concurrent Metronidazole use cannot be avoided, recommend reducing dose by at least 30% and check INR within 3 - 5 days and then weekly for 3 - 4 weeks following discontinuation of drug. No clinically significant interaction normally occurs but clinically significant impact on INR is occasionally seen in the elderly and patients sensitive to Oral penicillins warfarin. Check INR within 3 - 5 days if patient is >75 years of age and taking <3 mg warfarin/day or if on intensive/prolonged treatment >7 days. Occasional but unpredictable increases in INR seen which can be marked Quinolone with ciprofloxacin and ofloxacin. Check INR between days 3 - 5 of starting antibiotics antibiotic. Rifampicin causes a marked reduction in anticoagulant effect within 5 - 7 days of starting treatment and persisting for at least 7 - 10 days after the Rifampicin rifampicin has been stopped in most patients. Warfarin dose usually at least doubled and in some cases increased 5 – 6 fold to compensate. Increase warfarin dose by 50% and check INR within 3 days of starting antibiotic. Normally no interaction seen but rarely unpredictable and possibly marked Tetracyclines increases in INR can occur. Check INR within 3 - 5 days of starting treatment. Normally no interaction occurs but very occasionally transient increases in Trimethoprim INR have been observed. Check INR only in those patients sensitive to warfarin on <3 mg/day requiring more than a 3 day antibiotic course.

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Appendix 2 continued

2. OTHER COMMONLY PRESCRIBED DRUGS

Wide individual variability in level of interaction seen. Impossible to predict Allopurinol who is likely to be affected. Check INR within 3 - 5 days of initiating treatment and 2 - 3 weeks later. Significant increase in INR seen in all patients. Reduce warfarin dose by approx 25 - 30% and check INR within 4 - 7 days. Weekly monitoring Amiodarone recommended for first 4 weeks of starting amiodarone. Interaction persists for many weeks following drug withdrawal (6 - 16 weeks). Low dose aspirin (75 mg daily) does not appear to interact directly to a clinically relevant extent but ALL antiplatelet drugs are associated with an independent increased risk of bleeding. Bleeding risks associated with Aspirin and other aspirin use are dose related. Consider PPI cover if combination with aspirin anti-platelet unavoidable. Risks of bleeding similar with clopidogrel. Systemic drugs absorption of topical salicylate preps does occur and may increase effect of warfarin – clinical significance depends upon area of application and frequency of use. Anticoagulation not usually affected by beta-blockers, except possibly with Beta-blockers propranolol. Check INR if co-prescribing propranolol within 1 - 2 weeks of starting drug. Carbamazepine can cause a marked reduction in INR. Doses of warfarin Carbamazepine usually need to be doubled to compensate for interaction. Check INR within and 7 – 10 days and monitor INR every 1 - 2 weeks for following 4 - 6 weeks. oxcarbazepine Oxcarbazepine appears to be a relatively non-interacting alternative. Can significantly reduce the INR. Separating the administration of the two Colestyramine drugs by at least 3 - 6 hours has been shown to minimise the interaction. Check INR within 5 - 7 days of starting treatment. Effect of steroids on INR unpredictable and usually dose related. High dose Corticosteroids steroids can cause marked INR increases. (Also independent bleeding risk associated with steroid use.) Check INR within 5 – 10 days of use. All fibrates increase the effects of warfarin (established and clinically serious Fibrates interaction). Reduce dose by 30 – 50% and check INR within 3 – 5 days. In practice, both transient increases and decreases in INR have been seen in some patients. Consider checking the INR within 7 – 10 days following Flu vaccine vaccination in high risk individuals (i.e. all mechanical heart valve patients; AF and CHA2DS2VASc score >5 and VTE in last 3 months). Avoid cimetidine. Interactions with other H2 antagonists are rare but, as H2 antagonists isolated reports of unpredictable raises in INR have been observed, it would be prudent to check INR within 2 weeks of concurrent use. Avoid piroxicam. Slight – moderate increases in INR can occur with other NSAIDs although not usually clinically significant, especially if being used Non selective ‘prn’ for acute pain of <5 days duration. Ibuprofen associated with lowest GI NSAIDs bleeding risk. Plasma concentrations of topical NSAIDs low compared to oral therapy. Consider H2 antagonist/PPI cover if co-prescribing oral NSAID necessary. Check INR within 10 - 14 days of concurrent use. Good evidence supports celecoxib as being the least likely COX II NSAID to interact with warfarin. However, as there are isolated reports of raised INRs Selective NSAIDs with both celecoxib and some other NSAIDs, check INR within 10 days of concurrent use. No documented interactions have been observed with meloxicam. Evidence for interactions with warfarin and PPIs is poor and, if occurs, is Proton pump rarely clinically significant. However as unpredictable clinically significant inhibitors raised INRs have been reported check INR within 10 days of starting or stopping PPI. Guideline 797FM.3.1 11 of 12 Uncontrolled if printed

Appendix 2 continued

No interaction seen with occasional, when required, doses of paracetamol, but regular daily use is associated with increases in INR in a dose Paracetamol and dependent manner. Full extent of interaction associated with chronic tramadol concurrent use takes 7 - 14 days to develop. Check INR within 7 - 14 days if prescribed for regular use. With tramadol, unpredictable interaction infrequently seen but clinically significant if it occurs. Check INR 5 – 7 days. Can cause marked increases in INR. Warfarin may also affect serum Phenytoin phenytoin levels. Check INR weekly for first few weeks following starting/stopping treatment and also monitor for phenytoin toxicity. No interaction usually occurs with SSRIs, but unpredictably raised INRs SSRI seen occasionally with fluoxetine, venlaflaxine and sertraline. Citalopram is antidepressants the least likely SSRI to affect INR. SSRIs also associated with independent and venlafaxine bleeding risk because of their effect on platelet function. Check INR within 10 - 14 days of starting an SSRI. Simvastatin and, less frequently, atorvastatin can cause modest but occasionally clinically significant increases in INR. Check INR at 10 - 14 Statins days and again at 21 - 28 days. Rosuvastatin has the potential to affect INR, check INR within 7 days. Full extent of interaction in all cases may take 3 - 4 weeks to develop. No interactions have been seen with pravastatin. Established clinically important interaction which affects some but not all patients. Marked increases in INR seen - at least 50% dose reductions in Tamoxifen warfarin required if interaction occurs. Check INR within 3 - 5 days and then weekly for first 4 - 6 weeks of starting treatment. Starting levothyroxine or increasing the dose in a patient stabilised on Thyroid and warfarin will increase INR. Conversely, anti-thyroid drugs will decrease INR. antithyroids Check INR in all cases within 2 - 3 weeks of starting or changing therapy. Amitriptyline and other tricyclics can cause unpredictable, modest increases Tricyclic or decreases in INR, but these can make stable INR control difficult to antidepressants achieve. Check INR within 10 - 14 days if concurrent use unavoidable.

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