DRUG INTERACTIONS WITH WARFARIN 27 OCTOBER 2018

Transcription

1 DRUG INTERACTIONS WITH WARFARIN 27 OCTOBER 2018

2 Types of Warfarin Drug Interactions Pharmacodynamics: Antiplatelets NSAIDs Vitamin K production (Antimicrobials) Pharmacokinetics: Protein displacement CYP450 liver enzymes metabolism Unknown mechanisms

3 Case Study 1 Name: IS Age: 48 Gender: Female Alcohol / Nicotine: nil Past medical history: hyperlipidemia, gastritis, childhood asthma, CRHD, severe MR, mild MS

4 Case Study 1 Past surgical history: appendicectomy, removal of ovaries 16/01/2016 mitral valve repair 26/11/2016 MVR (mechanical) Target INR: 2.5 to 3.5 Post-op issues: 28/11/2017 xiphisternal osteomyelitis sternal wound debridement and removal of sternal wire started on iv cloxacillin and discharged with oral Bactrim 1920mg BD for 6 weeks

5 Date INR Warfarin Dose Duration Remarks 8/9/ mg daily 4w 2/10/ mg daily 4w 7/12/ Started on Bactrim 9/12/ Patient seen by doctor/only 11/12/ comes to hospital to check INR, gets warfarin supply outside, 14/12/ % therefore dose prescribed 19/12/ unknown 26/12/ mg alternate 2mg daily 30/12/ /1/ mg alternate 2mg daily 9/1/ /1/ d 3d

6 Drug-drug interaction: warfarin and co-trimoxazole Interaction effect Probable mechanism warfarin exposure CYP2C9 inhibitor (trimethoprim) may decrease the metabolism of CYP2C9 substrate (warfarin) Sulfonamide displacement of warfarin from protein binding sites Severity Major Onset Rapid (2 to 5 days) Anticipated offset (2 to 14 days) Substantiation Clinical Management Established; Fair Pre-emptive warfarin dose reductions of 10 % to 20 % (up to 40% of the mean daily dose may be considered Micromedex, Lexicomp & Drug interactions practice tool

7 Case Study 1 Post-op issues: 6/3/2018 sternal wound debridement treat as chronic osteomyelitis with po rifampicin 600mg daily and po Bactrim 1.92g BD for three months

8 Date INR Warfarin Dose Duration Remarks 13/3/2018 Started on Bactrim and Rifampicin during ward admission 18/3/ mg daily 2d Patient discharged from ward 20/3/ mg daily 3d 23/3/ mg daily 3d SC Fondaparinux 2.5mg daily x3d 100% in 4 weeks 26/3/ mg daily 3d SC Fondaparinux 2.5mg daily x3d 29/3/ mg daily 4d 2/4/ mg daily 4d 6/4/ mg daily 3d SC Fondaparinux 2.5mg daily x2d 9/4/ mg daily 4d Bactrim dose increased 13/4/ mg daily 3d 16/4/ mg daily 4d 20/4/ mg daily 1w 24/4/ mg alternate 8.5mg daily 6d 27/4/ mg daily 5d 3/5/ mg daily 11d 14/5/ mg daily 2w 18/5/ mg daily 4d 25/5/ mg daily 06/6/ mg daily 11/6/ mg daily 2w 25/6/ mg daily 2w Missed 1 dose

9 Date INR Warfarin Dose Duration Remarks 13/7/ mg daily 3d Completed rifampicin yesterday and Bactrim today 16/7/ mg daily 3d Referred to consultant cardiologist 19/7/ mg daily 5d 27/7/ Omit warfarin 3d Referred to consultant cardiologist 30/7/ mg daily 3d 2/8/ mg daily 4d 7/8/ Omit warfarin Patient admitted for monitoring 10/8/ Omit warfarin Patient discharged without warfarin 13/8/ mg daily + SC fondaparinux 2.5mg daily for 3d 4d Patient follow up with consultant cardiologist 17/8/ mg daily 1w Referred to cardiology dr 24/8/ mg M-F, 3mg Sat/Sun 11d 4/9/ Omit 2d then 2.5mgx1d 70% in 2m 7/9/ mg daily 5d 12/9/ mg x M-T, 3mg x F-S 1w 19/9/ mg x M-T, 3mg x F-S 9d 27/9/ mg x M-T, 3mg x F-S 1w 4/10/ mg x M-T, 3mg x F-S 2w

10 Dosing and INR trend Dose increased by 100%, INR stabilized in a month Stopped Rifampicin and Bactrim Started Rifampicin and Bactrim 70% in dose, INR stabilized 57 days after stoppage of abx

11 Drug-drug interaction: warfarin and rifampicin Interaction effect anticoagulant effectiveness of warfarin Probable mechanism CYP2C9 inducer (rifampicin) may increase the metabolism of CYP2C9 substrate (warfarin) Severity Moderate Onset Delayed (1 3 weeks) Anticipated offset (1 5 weeks) Substantiation Good; Fair Clinical Management high doses of warfarin may be needed (double or triple) Micromedex, Lexicomp & Drug interactions practice tool 25-50% reduction of the warfarin dose should be considered within 1 to 2 weeks after rifampicin is discontinued

12 Case Study 2 Name: KS Age: 52 Gender: Male Alcohol / Nicotine: nil Past medical history: hyperlipidemia, hypertension, epilepsy

13 Case Study 2 Past surgical history: CABG x 3, AVR (mechanical) & LAA Ligation on 25/3/17 Target INR: 2 to 3 Medication changes: Patient had 2 episodes of seizure since July 2016, started on carbamazepine since Dec 2016 Warfarin dose started from 6.5mg daily titrated up to 11mg daily Carbamazepine stopped by neurologist on 22/1/18 as pt has been seizure-free for a year To start levetiracetam (Keppra) if patient experiences seizures in the future

14 Date INR Warfarin Dose Duration Remarks Dec 2016 Patient started on carbamazepine Mar 2017 Patient had AVR (Mech) procedure, started on warfarin 10/4/ mg x2d then 6.5mg daily 1w First follow up in INR clinic 17/4/ mg daily 8d 25/4/ mg daily 9d 3/5/ mg daily 4w Seen by cardiothoracic consultant 31/5/ mg daily 6w 10/7/ mg daily 4w 10/8/ mg daily + SC Fonda 2.5mg 2d 3w Referred to cardiothoracic consultant 30/8/ mg daily 3m Seen by cardiothoracic consultant 29/11/ mg daily 2w Referred to Senior Registrar 14/12/ mg daily 3w 4/1/ mg daily 2w 18/1/ mg daily 3w Referred to cardiothoracic consultant 26/1/ mg daily 1w Stopped carbamazepine since 22/1/2018 2/2/ mg daily 1w 8/2/ Omit x1d then 9mg daily 12d 20/2/ mg daily 1w Missed 1 dose 27/2/ mg daily 2w 13/3/ mg daily 8d 21/3/ mg daily 3m Seen by cardiothoracic consultant 6/6/ mg daily 12w

15 Managing DRUG INTERACTION 50 days since he stopped taking CBZ Dose reduction so far: -30%

16 Dosing and INR trend Stopped carbamazepine Dose reduction of 30%, INR stabilized after 50 days

17 Drug-drug interaction: warfarin and carbamazepine Interaction effect INR Probable mechanism Increase in warfarin metabolism through CYP2C9 induction Severity Moderate to severe Onset Delayed (10 to 35 days) Anticipated offset (14 to 40 days) Substantiation Good Clinical Management Increase in warfarin dose of 50 to 100% may be required Decrease warfarin dose by 50% when stopping carbamazepine Micromedex, Lexicomp & Drug interactions practice tool

18 Swedish cohort study 2016 Experienced subtherapeutic anticoagulative effect within 3-5 weeks of starting carbamazepine Warfarin dose by 49% Differed widely among patients Close INR monitoring recommended Take several weeks to reach new warfarin steady-state conc Mannheimer B, Andersson ML, Ja rnbert-pettersson H, Lindh JD. The effect of carbamazepine on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population. J Thromb Haemost 2016; 14:

19 Case Study 3 Name: KL Age: 72 Gender: Female Height: - Weight: - BMI: - Allergy / ADR: NKA Alcohol / Nicotine: nil Past medical history: hyperlipidemia, hypertension

20 Case Study 3 Indication for anticoagulation: AVR (Mechanical) Target INR: 2 to 3 Medication changes: Warfarin dose: stable at 7mg daily Commencement of Fenofibrate 145mg daily since 08/08/2018 Duration of supply for warfarin with 7mg daily: 8 weeks

21 Date INR Warfarin Dose Duration Remarks 25/6/ mg daily 6w 8/8/ mg daily 8w Patient started on fenofibrate; unaware of drug interaction with warfarin 4/10/ Omit 1d then 6.5mg daily 5d 9/10/ mg daily 7d 16/10/ mg daily 2w

22 Managing DRUG INTERACTION 12 days after dose reduction Dose reduction so far: -14%

23 Dosing and INR trend Started fenofibrate Dose reduction of 14%

24 Drug-drug interaction: warfarin and fenofibrate Interaction effect INR Probable mechanism Additive effect on anticoagulation? inhibition of metabolism of S-warfarin (mild-moderate inhibitor of the CYP2C9)? protein-binding displacement Severity Major Onset 5 10 days Delayed offset Substantiation Fair Clinical Management Decrease warfarin dose by one-third at the start of treatment Micromedex, Lexicomp & Drug interactions practice tool

25 Case Study 4 Name: SR Age: 75 Gender: Female Alcohol / Nicotine: nil Past medical history: diabetes mellitus, hypertension

26 Case Study 4 Indication for anticoagulation: MVR (Mechanical) Target INR: 2.5 to 3.5 Medication changes: Stable warfarin dose: 5.5mg weekdays, 5mg weekends Started amiodarone 200mg bd on 5/12/2017; discharged with 4.5mg x 1/52 Dose reduce to 2.5mg daily after 70 days

27 Managing DRUG INTERACTION 43 days after dose reduction Dose reduction: -53% 16/12/17 - INR 4.5 (prescribed with prednisolone and azithromycin in ED) 14-18/1/18 admitted for SOB & pneumonia, d/c 2.5mg 5/12/17 x 1w) - Started amiodarone & w4.5 x 1/52

28 Dosing and INR trend Started amiodarone Dose reduction of 53%, INR stabilized after 70 days

29 Drug-drug interaction: warfarin and amiodarone Interaction effect Probable mechanism Severity INR decreased warfarin metabolism; hyper- or hypothyroidism Major Onset Delayed (3 7 days) ~ 90 days Substantiation Clinical Management Excellent Intensive monitoring and empiric 35 to 65% warfarin dosage reduction are recommended Micromedex, Lexicomp & Drug interactions practice tool

30 Take-home messages: Warfarin drug interactions unpredictable Response differ in different patients Closely monitor INR Thank you