DRUG INTERACTIONS WITH WARFARIN - IJN College Workshop Drug Interactions...• Warfarin –drug...

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


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


29/3/2018 2.0 8mg daily 4d

2/4/2018 2.0 8.5mg daily 4d


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


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


Case Study 2

Name: KS

Age: 52

Gender: Male


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


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%


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


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


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


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


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


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


Case Study 4Name: SR

Age: 75

Gender: Female


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


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


Take-home messages:

• Warfarin – drug interactions unpredictable

• Response differ in different patients

• Closely monitor INR

Thank you

DRUG INTERACTIONS WITH WARFARIN - IJN College Workshop Drug Interactions...• Warfarin –drug...

Documents

Transcript of DRUG INTERACTIONS WITH WARFARIN - IJN College Workshop Drug Interactions...• Warfarin –drug...