DRUG INTERACTIONS WITH WARFARIN

27 OCTOBER 2018

Types of Warfarin – Drug Interactions

Pharmacodynamics:

• Antiplatelets

• NSAIDs

• Vitamin K production (Antimicrobials)

Pharmacokinetics:

• Protein displacement

• CYP450 liver enzymes – metabolism

Unknown mechanisms

Case Study 1

Name: IS

Age: 48

Gender: Female

Alcohol / Nicotine: nil

Past medical history: hyperlipidemia, gastritis, childhood asthma, CRHD, severe MR, mild MS

Case Study 1Past 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

Date INR Warfarin Dose Duration Remarks

8/9/2017 2.5 2.5mg daily 4w

2/10/2017 2.7 2.5mg daily 4w

7/12/2017 3.3 Started on Bactrim

9/12/2017 3.6 Patient seen by doctor/only comes to hospital to check INR, gets warfarin supply outside, therefore dose prescribed unknown

11/12/2017 4.5

14/12/2017 2.9

19/12/2017 2.7

26/12/2017 2.4 1.5mg alternate 2mg daily

3d

30/12/2017 2.6

2/1/2018 2.3 1.5mg alternate 2mg daily

3d

9/1/2018 2.9

20/1/2018 2.6

↓31%

Drug-drug interaction: warfarin and co-trimoxazoleInteraction effect warfarin exposure

Probable mechanism

• 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 Established; Fair

Clinical Management

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

Case Study 1

Post-op issues:

• 6/3/2018 sternal wound debridement

• treat as chronic osteomyelitis with po rifampicin 600mg daily and poBactrim 1.92g BD for three months

Date INR Warfarin Dose Duration Remarks

13/3/2018 Started on Bactrim and Rifampicin during ward admission

18/3/2018 3.0 4.5mg daily 2d Patient discharged from ward

20/3/2018 2.1 5mg daily 3d

23/3/2018 1.8 6mg daily 3d SC Fondaparinux 2.5mg daily x3d

26/3/2018 1.4 8mg daily 3d SC Fondaparinux 2.5mg daily x3d

29/3/2018 2.0 8mg daily 4d

2/4/2018 2.0 8.5mg daily 4d

6/4/2018 1.7 9mg daily 3d SC Fondaparinux 2.5mg daily x2d

9/4/2018 2.7 9mg daily 4d Bactrim dose increased

13/4/2018 3.1 9mg daily 3d

16/4/2018 3.4 8.5mg daily 4d

20/4/2018 3.1 8.5mg daily 1w

24/4/2018 2.6 9mg alternate 8.5mg daily 6d

27/4/2018 2.1 9mg daily 5d

3/5/2018 2.2 9.5mg daily 11d

14/5/2018 2.5 9.5mg daily 2w

18/5/2018 3.3 9mg daily 4d

25/5/2018 2.7 9mg daily

06/6/2018 3.4 9mg daily

11/6/2018 2.3 9mg daily 2w

25/6/2018 2.4 9mg daily 2w Missed 1 dose

↑100% in 4 weeks

Date INR Warfarin Dose Duration Remarks

13/7/2018 2.1 9mg daily 3d Completed rifampicin yesterday and Bactrim today

16/7/2018 1.8 10mg daily 3d Referred to consultant cardiologist

19/7/2018 2.5 9mg daily 5d

27/7/2018 5.1 Omit warfarin 3d Referred to consultant cardiologist

30/7/2018 1.9 9mg daily 3d

2/8/2018 3.6 8mg daily 4d

7/8/2018 8.0 Omit warfarin Patient admitted for monitoring

10/8/2018 4.3 Omit warfarin Patient discharged without warfarin

13/8/2018 1.4 3mg daily + SC fondaparinux 2.5mg daily for 3d

4d Patient follow up with consultant cardiologist

17/8/2018 1.8 3.5mg daily 1w Referred to cardiology dr

24/8/2018 2.7 3.5mg M-F, 3mg Sat/Sun 11d

4/9/2018 4.8 Omit 2d then 2.5mgx1d

7/9/2018 2.1 3mg daily 5d

12/9/2018 3.5 2.5mg x M-T, 3mg x F-S 1w

19/9/2018 3.3 2.5mg x M-T, 3mg x F-S 9d

27/9/2018 2.8 2.5mg x M-T, 3mg x F-S 1w

4/10/2018 3.4 2.5mg x M-T, 3mg x F-S 2w

↓70% in 2m

Dosing and INR trend

Started Rifampicin and Bactrim

Stopped Rifampicin and Bactrim

↓70% in dose, INR stabilized 57 days after stoppage of abx

Dose increased by 100%, INR stabilized in a month

Drug-drug interaction: warfarin and rifampicinInteraction 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)

• 25-50% reduction of the warfarin dose should be considered within 1 to 2 weeks after rifampicin is discontinued

Micromedex, Lexicomp & Drug interactions practice tool

Case Study 2

Name: KS

Age: 52

Gender: Male

Alcohol / Nicotine: nil

Past medical history: hyperlipidemia, hypertension, epilepsy

Case Study 2Past 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

Date INR Warfarin Dose Duration Remarks

Dec 2016 Patient started on carbamazepine

Mar 2017 Patient had AVR (Mech) procedure, started on warfarin

10/4/2017 1.7 7mg x2d then 6.5mg daily 1w First follow up in INR clinic

17/4/2017 1.5 7mg daily 8d

25/4/2017 1.8 7.5mg daily 9d

3/5/2017 2.3 8mg daily 4w Seen by cardiothoracic consultant

31/5/2017 2.3 8mg daily 6w

10/7/2017 1.8 8mg daily 4w

10/8/2017 1.2 9mg daily + SC Fonda 2.5mg 2d 3w Referred to cardiothoracic consultant

30/8/2017 2.0 9mg daily 3m Seen by cardiothoracic consultant

29/11/2017 1.6 10mg daily 2w Referred to Senior Registrar

14/12/2017 2.6 10mg daily 3w

4/1/2018 1.9 10mg daily 2w

18/1/2018 1.7 10mg daily 3w Referred to cardiothoracic consultant

26/1/2018 1.8 11mg daily 1w Stopped carbamazepine since 22/1/2018

2/2/2018 3.3 10mg daily 1w

8/2/2018 3.9 Omit x1d then 9mg daily 12d

20/2/2018 2.4 7.5mg daily 1w Missed 1 dose

27/2/2018 2.8 7.5mg daily 2w

13/3/2018 3.4 7mg daily 8d

21/3/2018 2.7 7mg daily 3m Seen by cardiothoracic consultant

6/6/2018 2.6 7mg daily 12w

Managing DRUG INTERACTION

50 days since he stopped taking CBZDose reduction so far: -30%

Dosing and INR trend

Stopped carbamazepine

Dose reduction of 30%, INR stabilized after 50 days

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

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 ThrombHaemost 2016; 14: 765–71.

Case Study 3

Name: KL

Age: 72

Gender: Female

Height: -

Weight: -

BMI: -

Allergy / ADR: NKA

Alcohol / Nicotine: nil

Past medical history: hyperlipidemia, hypertension

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

Date INR Warfarin Dose Duration Remarks

25/6/2018 2.2 7mg daily 6w

8/8/2018 2.6 7mg daily 8w Patient started on fenofibrate; unaware of drug interaction with warfarin

4/10/2018 4.4 Omit 1d then 6.5mg daily 5d

9/10/2018 2.1 6mg daily 7d

16/10/2018 2.7 6mg daily 2w

Managing DRUG INTERACTION

12 days after dose reductionDose reduction so far: -14%

Dosing and INR trend

Started fenofibrate

Dose reduction of 14%

Drug-drug interaction: warfarin and fenofibrateInteraction 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

Case Study 4Name: SR

Age: 75

Gender: Female

Alcohol / Nicotine: nil

Past medical history: diabetes mellitus, hypertension

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

Managing DRUG INTERACTION

43 days after dose reductionDose reduction: -53%

5/12/17 - Started amiodarone & w4.5 x 1/52

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 x 1w)

Dosing and INR trendStarted amiodarone

Dose reduction of 53%, INR stabilized after 70 days

Drug-drug interaction: warfarin and amiodaroneInteraction effect ↑ INR

Probable mechanism

decreased warfarin metabolism; hyper- or hypothyroidism

Severity Major

Onset • Delayed (3–7 days)

• ~ 90 days

Substantiation Excellent

Clinical Management

Intensive monitoring and empiric 35 to 65% warfarin dosage reduction are recommended

Micromedex, Lexicomp & Drug interactions practice tool

Take-home messages:

• Warfarin – drug interactions unpredictable

• Response differ in different patients

• Closely monitor INR

Thank you