Long term treatment with rifampicin for pruritis has implications for warfarin use.

  BL Bound, L Johnstone and G A McKay

  1Medical SHO, 2Clinical Pharmacist, 3Consultant Physician, University Medical Unit, Wards 29 & 30, Glasgow Royal Infirmary, Castle Street, Glasgow G4 0SF

  Author for correspondence:

Dr G A McKay, Consultant Physician, University Medical Unit, Wards 29 & 30, Glasgow Royal Infirmary, Castle Street, Glasgow G4 0SF, UK

Email: gerard.mckay@ggc.scot.nhs.uk

SMJ 2009 54(1): 58

Abstract

Warfarin is an established treatment method for anticoagulating patients following diagnosis of deep vein thrombosis (DVT).  We present a patient who was on rifampicin treatment for pruritis, secondary to primary biliary cirrhosis (PBC), who was diagnosed with a DVT post operatively.  A therapeutic INR was not obtained following fourteen days of warfarin treatment due to a drug interaction with rifampicin.  We review the use of rifampicin for pruritis in PBC and the mechanism of interaction between warfarin and rifampicin.

 

Case Report

A 57-year-old lady was referred by her GP with a 3-day history of left thigh and calf pain.  On examination she was tender over her left thigh and posterior calf with left leg swelling.  Four weeks previously, she was admitted for elective laparatomy with a view to resecting a presumed Hepatocellular Carcinoma (HCC) (due to high AFP of 265 and a 2.2cm liver lesion identified on CT scan).  In theatre no lesion consistent with HCC was identified and she therefore underwent laparotomy alone.  She received DVT prophylaxis during the admission, but had been less mobile during the 3 weeks since discharge.  Her past medical history included primary biliary cirrhosis and polyarthritis.  Her medications included Ursodeoxycholic acid 500mg bd, Rifampicin 300mg bd, Omeprazole 20mg bd and Calciferol 7.5mg/ml once/month.

 

Blood results showed an elevated D dimer of 6780, PT ratio 1.2 and platelets were 90.  Ultrasound Doppler of the left leg revealed extensive recent-looking occlusive thrombus in the deep venous system of the left lower limb, at which time she was commenced on warfarin, with a view to 3-month anticoagulation given the clear precipitant.  She remained on treatment dose dalteparin (12,500 units) from admission, pending a therapeutic INR.  Physiotherapists also provided input with regards to poor mobility.

 

During admission her INR increased only slowly with increasing doses of warfarin; this was due to the known interaction with rifampicin.  The patient was on rifampicin for itch secondary to primary biliary cirrhosis and had been on this for almost ten years; she was reluctant to stop treatment as the itch was previously very severe and had markedly improved on rifampicin.

 

This patient remained on warfarin and dalteparin for a total of 14 days, resulting in an INR of 1.6 and a warfarin dose of 20mg.  Figure 1 illustrates the 14 days of warfarin treatment and the patients’ INR response to this.  After discussion with Haematologists it was decided that warfarin should be discontinued and for treatment to continue with dalteparin alone, treatment length to be 3-4 months and dose to be decreased by 20% after one month of treatment.  Platelet count after 13 days of dalteparin was 112 and although this was low, it had been stable and did not decrease during treatment; therefore this was reassuring that there was no evidence of Heparin Induced Thrombocytopenia.  The patient was happy with this plan and on subsequent review in medical clinic 3 months later, dalteparin was discontinued.

 

  Figure 1. Daily Warfarin dose and INR during concomitant Rifampicin therapy.

Discussion

Pruritis and use of Rifampicin in Primary Biliary Cirrhosis

Primary Biliary Cirrhosis (PBC) is a chronic autoimmune disease of the liver, characterised by destruction of the interlobular bile ducts and leading to progressive ductopenia and chronic cholestasis.1,2  Pruritis is a disabling and distressing symptom of chronic cholestasis and is estimated to occur in up to 80% of patients with PBC.3,4  Symptoms may be so severe as to significantly impact on the patients quality of life and to warrant liver transplantation.2

 

Rifampicin has been recommended for second line treatment of pruritis in PBC by recent American Guidelines, in patients who fail on or are intolerant to the side effects of cholestyramine.2  The mechanism of action of rifampicin in improving pruritis is unclear; It is hypothesized that it may reduce hepatic uptake or alter the metabolism of bile salts and other pruritogens.1,4  

 

Khurana et al. performed a meta – analysis of five randomised controlled trials (total of 61 patients) comparing efficacy of rifampicin with placebo or alternative treatment for pruritis secondary to chronic cholestasis; They concluded that rifampicin was a safe and effective for treatment of pruritis.5  Tandon et al. subsequently reviewed use of bile acid binding agents, opioid antagonists or rifampicin in treatment of cholestasis associated pruritis, using four of the above mentioned trials for data extraction.4  Rifampicin was significantly more likely to reduce pruritis than control (SMD -1.62, 95% CI -0.35 to -0.18).4

 

Our patient was successfully commenced on rifampicin for pruritis in 1998 and had therefore been on treatment for 10 years.  She was reluctant to discontinue rifampicin due to the sustained improvement in pruritis and consequently this was not an option during the management of her DVT.  Case reports have described hepatitis and liver dysfunction with rifampicin therapy and it has been suggested that longer term trials are performed to review the safety and efficacy of rifampicin; long-term use of rifampicin is not well documented in the literature.1,5

 

Interaction between Rifampicin and Warfarin

Warfarin is a racaemic mixture of the isomers R-warfarin and S-warfarin, the S isomer is around seven times more active in terms of anticoagulation.  Both isomers are extensively metabolised in the liver by the cytochrome P450 isoenzymes (predominantly cytochrome P4502C9).  Rifampicin is known to be a potent inducer of these enzymes and hence accelerates the metabolism of warfarin.  Pharmacokinetic studies have shown that the clearance of R-warfarin is increased threefold and the clearance of S-warfarin two fold by concomitant administration of rifampicin.6  Plasma levels of warfarin are significantly reduced by rifampicin to the extent where they are undetectable in some cases.7,8  Average half life of warfarin is usually 36 hours but was reduced to 0.47 hours in one patient who had been taking warfarin and rifampicin together for 25 days.8

 

The clinical significance of this interaction is well documented.  Previous cases have reported warfarin doses of 20mg daily or more being necessary to achieve therapeutic anticoagulation.8-11  Despite these high doses, INR remained sub therapeutic in some patients.  In one case a dose of 25mg of warfarin per day achieved a maximum INR of 1.9 in a patient also taking rifampicin 600mg per day.11  We could only find one case report in the literature describing the treatment in this situation to be the discontinuation of warfarin and replacement with low molecular weight heparin (LMWH) while the patient remained on rifampicin therapy.12 

 

It takes approximately one week for maximal enzyme induction to occur when rifampicin is commenced, hence drug interactions become apparent after this time.9,11  This patient  had been taking rifampicin long term, therefore liver enzymes would already be maximally induced and the interaction was apparent immediately from the initiation of warfarin.  Rifampicin is not known to interact with any of the patient’s other medicines.  The patient was not taking any other medications which are known to decrease the anticoagulant effect of warfarin, although the concomitant dosing of omeprazole may have been expected to cause a minor increase in the anticoagulant effect by inhibiting the metabolism of R-warfarin.  Liver function remained stable throughout admission.  The maximum INR achieved in this patient was 1.8 on day 4 of warfarin therapy.  INR subsequently decreased further and was 1.6 at a dose of 20mg daily of warfarin.  After 14 days of therapy warfarin was discontinued and the decision to continue LMWH for 3-4 months was made.       

 

When warfarin and rifampicin are given concomitantly a 2-3 fold increase in the usual warfarin dose should be expected.8,11  Frequent monitoring of the INR will be required and consideration should be given to substitution with LMWH if high doses of warfarin consistently fail to achieve therapeutic anticoagulation.  Discontinuation of rifampicin also carries a risk of over-anticoagulation.  Patients should be monitored carefully during this time and warfarin dosage should be gradually reduced over several weeks.11

 

Conclusion

This case highlights the significant interaction between rifampicin and warfarin.  It raises the question of whether short-term anticoagulation with warfarin should be attempted or if LMWH should be the first line treatment option in patients taking rifampicin.  Rifampicin is a potent inducer of the cytochrome P450 enzymes which are involved in the metabolism of numerous drugs.  The potential for drug interactions should be considered when initiating long-term rifampicin therapy and revisited when subsequently introducing additional medication.

 

References

  1. Prince MI, Burt AD, Jones DEJ. Hepatitis and liver dysfunction with rifampicin therapy for pruritis in primary biliary cirrhosis. Gut 2002;50:436-439

  2. Heathcote EJ. Management of primary biliary cirrhosis. Hepatology 2000;31:1005-1013

  3. Bachs L, Pares A, Elena M, et al. Comparison of rifampicin with phenobarbitone for treatment of pruritis in biliary cirrhosis. Lancet 1989;1:574-576

  4. Tandon P, Rowe BH, Vandermeer MA, et al. The efficacy and safety of bile acid binding agents, opioid antagonists, or rifampicin in the treatment of cholestasis-associated pruritis. Am J Gastroenterol 2007;102:1528-1536

  5. Khurana S, Singh P. Rifampicin is safe for treatment of pruritis due to chronic cholestasis:  a meta-analysis of prospective randomized-controlled trials. Liver International 2006;26:943-948

  6. Heimark LD, Gibaldi M, Trager WF, O’Reilly RA, Goulart DA. The mechanism of the warfarin-rifampin drug interaction in humans. Clin Pharmacol Ther 1987;42:388-94

  7. O’Reilly RA. Interaction of Chronic Daily Warfarin Therapy and Rifampin. Ann Internal Medicine 1975;83:506-508

  8. Casner PR. Inability to attain oral anticoagulation: Warfarin-Rifampin interaction revisited. Southern Medical Journal 1996;89(12):1200-3

  9. Romankiewicz JA. Rifampin and Warfarin: A Drug Interaction. Ann Internal Medicine 1975;82:224-225

  10. Self TH, Mann RB. Interaction of Rifampin and Warfarin. Chest 1975;67;490-491

  11. Lee CR, Trasher KA. Difficulties in Anticoagulation Management during co-administration of Warfarin and Rifampin. Pharmacotherapy 2001;21(10):1240-1246

  12. Kim KY, Epplen K, Foruhari F, Alexandropoulos H. Update on the interaction of rifampin and warfarin.(review) Progress in Cardiovascular Nursing 2007;22(2):97-100

Back to February Contents