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ostmarketing surveillance for drug safety

o the Editor:The recent commentary by Griffin et al1 concerning a

eport on peripheral neuropathy and leflunomide patientslaims that, as of October 2003, none of the 6 postmarketingtudies committed to by Aventis (Bridgewater, NJ) at the timef approval had been started, at least according to a Food andrug Administration (FDA) database. In fact, all 6 of these

tudies were initiated between 1998 and 2003, and resultsrom completed and ongoing studies have been published.2-4

ventis has performed many postmarketing studies in closeooperation with regulatory authorities around the world sup-orting the positive benefit-risk profile of leflunomide.

The report by Bonnel and Graham5 in the same issue raiseseveral methodologic concerns that make the interpretation ofhe selective data presented difficult, especially in a rheuma-oid arthritis (RA) population.

The event of interest in the report, peripheral neuropathy,as been reported during leflunomide treatment in postmar-eting experience as stated in the prescribing information.he authors selected events in the FDA database identified aseripheral neuropathy occurring in patients treated with le-unomide. Peripheral neuropathy was not defined by stan-ardized criteria other than subjective physician assessmentnd electrodiagnostic testing, if the latter was available. Spon-aneous report information, the data source for this article, isften lacking the kind of detail necessary for a complexiagnosis. Baseline electromyography and nerve conductiontudies were not available in these patients. This is importantecause peripheral neuropathy is a common manifestation inhe RA population.6 Subjective improvement appears to behe outcome measure, because no electromyography or nerveonduction study results were noted after drug discontinua-ion. Reasons for drug discontinuation were also not pro-ided. Information regarding symptom time to onset wasoted to be lacking in 42% of the reports; however, theaplan-Meier curve in Fig 1 of the report of Bonnel andraham5 shows the time to onset of symptoms in reports on

ll 80 patients after the start of leflunomide therapy.It is problematic that the authors selected anakinra as the

omparator, a drug launched 3 years after leflunomide andne with significantly lower exposure. An estimation of re-orting rates through June 2003 (the latest date for which datare available) with the use of disease-modifying antirheu-atic drug comparators with similar or greater patient expo-

ure is presented here. The numbers of cases of peripheral

euroathy came from the FDA Adverse Event Reporting d

LINICAL PHARMACOLOGY & THERAPEUTICS

ystem database and exposure was estimated from IMSmerica, Ltd, data. The reporting rates of PN (per 100,000erson-years of exposure) are as follows: 25.74 for lefluno-ide, 42.02 for etanercept, 23.67 for infliximab, and 1.01 forethotrexate. The reporting rate for methotrexate is consid-

rably lower than that for the newer disease-modifying anti-heumatic drugs, consistent with the underreporting of eventshat is known to occur with well-established therapies over time.

Since 1998, worldwide patient experience with lefluno-ide has exceeded 770,000 patients and has confirmed a

avorable benefit/risk profile for the treatment of adult pa-ients with RA. Potential safety signals generated from activend intensive postmarketing surveillance have been furtherested and analyzed in large observational cohort studies.hysician and patient information has been continually up-ated to reflect current knowledge about the safety of thismportant pharmaceutical product.

William L. Holden, PhDLinda J. Scarazzini, MD

AventisGlobal Pharmacovigilance and Epidemiology

Bridgewater, NJ

E-mail: william.holden@aventis.com

Both authors are full-time employees of Aventis.

eferences. Griffin MR, Stein CM, Ray WA. Postmarketing surveillance for

drug safety: surely we can do better. Clin Pharmacol Ther 2004;75:491-4.

. Silverman E, Prieur A, Spiegel LK, et al. Efficacy and safety ofleflunomide (LEF) versus methotrexate (MTX) in the treatment ofpediatric patients with juvenile rheumatoid arthritis. Ann RheumDis 2004;63(Suppl 1):195.

. Wolfe F. Low rates of serious liver toxicity to leflunomide (LEF)and methotrexate (MTX): A longitudinal surveillance study of14,997 LEF and MTX exposures in RA. Arthritis Rheum 2002;46:S375.

. Kremer JM, Genovese MC, Cannon GW, Caldwell JR, Cush JJ,Furst DE, et al. Concomitant leflunomide therapy in patients withactive rheumatoid arthritis despite stable doses of methotrexate: arandomized, double-blind, placebo controlled trial. Ann InternMed 2002;37:726-33.

. Bonnel RA, Graham DJ. Peripheral neuropathy in patients treatedwith leflunomide. Clin Pharmacol Ther 2004;75:580-5.

. Rosenbaum R. Neuromuscular complications of connective tissuedisease. Muscle Nerve 2001;24:154-69.

oi:10.1016/j.clpt.2004.07.012

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