Do guidelines for the prescribing and monitoring of leflunomide need to be modified?

S. Rajakulendran and C. Deighton

Department of Rheumatology, Derby Royal Infirmary

Correspondence to: Dr. C. Deighton, Department of Rheumatology, London Rd, Derby, DE1 2QY. Email: chris.deighton{at}sdah-tr.trent.nhs.uk

SIR, Leflunomide is the newest of the non-biological disease-modifying anti-rheumatic drugs (DMARDs), having been licensed for use in the UK 3 years ago. As rheumatologists incorporate leflunomide into their clinical practice, it is evident that there is variation amongst clinicians in the place of the drug in their practice, and in the initiation regime and monitoring of the drug. We conducted a survey amongst rheumatologists on the Midlands Rheumatology Society mailing list to evaluate the current prescribing practice with leflunomide. The results of the survey were compared with the recommendations in the most recent Summary of Product Characteristics (SPC) for leflunomide [1].

A questionnaire was sent to 72 consultant rheumatologists in the Midlands area. The survey questioned the following: the preferential hierarchy of DMARDs in practice, and the place of leflunomide; the initiation of leflunomide and whether the loading dose of 100 mg for 3 days was used; advice on alcohol consumption; use of a washout procedure on changing leflunomide to another DMARD; use of combination therapy with methotrexate; and the frequency of monitoring blood and blood pressure.

Fifty-seven (79%) of the rheumatologists returned the questionnaire. Of these, three did not prescribe leflunomide. Twenty-five (46.3%) of the responders who prescribed leflunomide used it as the third drug in their typical DMARD hierarchy. Of these, 17 (68%) used sulphasalazine as the first-choice drug and methotrexate as the second. Five (20%) used methotrexate as first-line DMARD and four (16%) used sulphasalazine as the second. Nine (16.7%) of the consultants used leflunomide as the second DMARD, seven of these using methotrexate first and two varying between either sulphasalazine or methotrexate as the first-line drug. These results are similar to those described in a recent survey of DMARD preferences in UK rheumatologists [2].

Twenty-two of the 54 prescribers (40.7%) never used the loading dose, 12 (22.2%) usually did, 14 (25.9%) usually did not and six (11.1%) always did. The main factors influencing caution in using the loading dose were gastrointestinal side-effects and other toxicity. Some consultants had adopted a starting dose of 10 mg/day increasing to 20 mg/day if tolerated. Thirty-two (59.3%) advised patients that occasional alcohol consumption was acceptable, 12 (22.2%) advised no alcohol restriction, and only 10 (18.5%) followed the recommendation of the SPC of avoiding alcohol. Some consultants commented that patients may refuse leflunomide if there was an alcohol ban.

Against SPC recommendations, 26 (48.1%) never used a cholestyramine or activated charcoal washout for swapping leflunomide to another DMARD and 16 (29.6%) used one occasionally. Not all consultants indicated whether the full 11 days washout was used but some commented that they used shorter washout periods as few patients tolerated the 11 days. Although the SPC warns against combination therapy, 31 (57.4%) and 8 (14.8%) combined leflunomide with methotrexate occasionally and usually, respectively. Combination therapy was never used by 14 (25.9%) consultants. The main concern raised with combination therapy was the potential for liver toxicity.

Thirty-five (64.8%) monitored bloods fortnightly in the first 6 months, in keeping with SPC recommendations. The remainder had variable monitoring regimes, ranging from fortnightly for 2 months then monthly, to fortnightly for 2 months, monthly for 4 months, then 3-monthly. Blood pressure monitoring was conducted fortnightly and monthly in 23 (42.6%) and 22 (40.7%), respectively. One responder never checked the blood pressure.

In summary, this survey has demonstrated that for most rheumatologists in the Midlands leflunomide has established a firm footing in their clinical practice, and usually follows the failure of sulphasalazine and methotrexate. This survey confirmed the marked variation in the prescribing and monitoring of leflunomide. In some regards, the majority of consultants are disregarding the SPC and national guidelines [3]. This applies to the infrequent use of the loading dose, failure to ban alcohol, not using a washout to transfer patients from leflunomide to another DMARD, and combining the drug with methotrexate. The percentage of rheumatologists who were monitoring full blood counts less frequently than the SPC recommends was 35.2%, and one person was not checking blood pressure at all.

These discrepancies between clinical practice and the recommendations of the SPC can be interpreted in two ways. The first interpretation is that the SPC is too restrictive, and increasing experience with the drug is influencing confidence in deviating from recommendations. If this is the case, then information needs to be collected to be able to modify the SPC. The second interpretation is that consultants have become too relaxed in their approach to the prescribing and monitoring of leflunomide, and this may lead to medicolegal consequences. We would like to suggest that the former is closer to the truth than the latter, and that urgent attention needs to be given to modifying the SPC.

There are already data on the safe and efficacious use of combinations of leflunomide and methotrexate [4, 5], despite warnings about possible adverse liver reactions [6]. Full blood count abnormalities are infrequent [7–12], suggesting that fortnightly blood tests for 6 months is excessive. More information is required on the efficacy and toxicity of using or avoiding the loading dose [13]. More data are needed on the safety of alcohol with leflunomide, and the need for washing patients out prior to switching from leflunomide to another DMARD.

The difficulty with SPCs is that, once a recommendation has been made, evidence is needed before it can be modified with confidence. We believe that for leflunomide there is already enough data and a sufficient groundswell of clinical practice and experience to modify the SPC.

Conflict of interest: the authors have declared that this research was supported by a small unrestricted grant from Aventis Pharmaceuticals.

References

  1. Arava Summary of Product Characteristics. Aventis Pharmaceuticals, July 2002.
  2. Jobanputra P, Wilson J, Douglas K, Burls A. A survey of British rheumatologists’ DMARD preferences for rheumatoid arthritis. Rheumatology 2004;43:206–10.[Abstract/Free Full Text]
  3. British Society for Rheumatology. National guidelines for the monitoring of second line drugs (online), July 2000. http://www.msecportal.org/portal/editorial/PublicPages/bsr/536883013/3.doc
  4. Weinblatt ME, Kremer JM, Coblyn JS et al. Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum 1999;42:1322–8.[CrossRef][ISI][Medline]
  5. Kremer JM, Genovese MC, Cannon GW et al. Concomitant leflunomide in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2002;137:726–36.[Abstract/Free Full Text]
  6. The European Agency for the Evaluation of Medicinal Products. Post-authorisation evaluation of medicines for human use. EMEA public statement on leflunomide (Arava)—severe and serious hepatic reactions. Document reference EMEA/H/5611/01/en. London, 12 March 2001.
  7. Strand V, Cohen S, Schiff M et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Int Med 1999;159:2542–50.[CrossRef][ISI]
  8. Smolen JS, Kalden JR, Scott DL et al. and the European Leflunomide Study Group. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind randomised multicentre trial. Lancet 1999;353:259–66.[CrossRef][ISI][Medline]
  9. Emery P, Breedfeld C, Lemmel EM et al. and the multinational leflunomide study group. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology 2000;39:655–65.[Abstract/Free Full Text]
  10. Cohen S, Cannon GW, Schiff M et al. Two-year blinded randomized controlled treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group. Arthritis Rheum 2001;44:1984–92.[CrossRef][ISI][Medline]
  11. Scott DL, Smolen JS, Kalden JR et al. Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine. Ann Rheum Dis 2001;60:913–23.[Abstract/Free Full Text]
  12. Kalden JR, Schattenkirchner M, Sorensen H et al. The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: a five-year follow up study. Arthritis Rheum 2003;48: 1513–20.[CrossRef][ISI][Medline]
  13. Sinha A, Amos N, Lawson TM. Leflunomide—the Welsh experience. Rheumatology 2003;42(Suppl. 1):97–8.
Accepted 29 June 2004





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