Peripheral neuropathy and leflunomide

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Peripheral neuropathy and leflunomide

Jul 21, 2004 9:00 Zosia Chustecka

Rockville, MD - The disease-modifying antirheumatic drug leflunomide (Arava,

Aventis) is associated with peripheral neuropathy in some patients, say FDA

researchers who reviewed 80 case reports received by the agency. They

describe details of the reports in the June 2004 issue of Clinical

Pharmacology and Therapeutics [1].

Patients who stopped using leflunomide within 30 days of symptom onset

were more likely to have improvement of symptoms or complete recovery than

were patients who continued to use the drug for longer periods of time.

Peripheral neuropathy is listed under the " adverse-events " section of the

prescribing information for leflunomide, with the comment that it has been

reported " rarely " during postmarketing surveillance. No cases were seen

during preapproval clinical trials (involving 816 patients), although

complaints of paresthesia were noted in 3% to 4% of patients. The FDA

researchers comment that their review was prompted by a report of 2 cases in

Rheumatology [2], which was reported at the time by rheumawire.

Not possible to estimate incidence

In the 4 years following the launch of leflunomide in the US in September

1998, the FDA received reports of 80 cases of peripheral neuropathy

temporally associated with use of the drug (49 cases [61%] from the US, the

remainder from other countries). During that time, an estimated 250 000

patients in the US received at least 1 prescription for the drug.

As these cases are reported as part of a voluntary and spontaneous

adverse-event reporting system, in which underreporting is likely, it's not

possible to give an estimate of the incidence of this adverse effect or to

compare reliably the risk of neuropathy for 1 drug with another, the

researchers comment.

Nevertheless, they provide some figures for another drug used in rheumatoid

arthritis, the interleukin-1 antagonist anakinra (Kineret, Amgen). From the

start of marketing in November 2001 until September 2003, the FDA received

only 1 case report of peripheral neuropathy in the setting of anakinra use.

During this period, an estimated 79 000 patients used the drug.

Recovery if drug is stopped within 30 days

All of the 80 reports describe new-onset peripheral neuropathy, presenting

with symptoms such as peripheral numbness, tingling or burning, severe pain,

cold sensation in distal extremities, or extreme weakness. The symptoms

typically appeared after about 6 months of leflunomide treatment, the

researchers comment, although this ranged from 3 to 1126 days. In most

cases, the onset of neuropathy occurred during a period of improved disease

control (most of the patients were taking the drug for rheumatoid arthritis,

although not all the reports listed the indication).

Examination of the neuropathy from nerve conduction and electromyographic

studies were reported for 36 patients (46%). The underlying nerve injury was

specified in 16 patients (axonal 12, demyelinating 2, mixed 2), and the

predominant type of nerve injured was mentioned in 23 patients (sensory 13,

motor 1, sensorimotor 9). A sural nerve biopsy performed in 1 patient showed

axonal loss with no evidence of vasculitis.

There was a lack of information on patient outcome, the FDA researchers

comment, but for most patients recovery had not occurred as of the date of

the last follow-up. " Patients who stopped using leflunomide within 30 days

of symptom onset were more likely to have improvement of symptoms or

complete recovery than were patients who continued to use the drug for

longer periods of time, " they note. This marked reduction in reversibility

suggests that axonal death may occur relatively quickly after that time,

they add.

" Given the inherent limitations of spontaneous case report data, additional

studies would be useful to better establish the nature and extent of an

associated between leflunomide use and peripheral neuropathy, " the FDA

researchers comment. However, they add that it may be difficult to undertake

such studies " because of the relatively low national level of leflunomide

use. "

Sources

1. Bonnel RA and Graham DJ. Peripheral neuropathy in patients treated

with leflunomide. Clin Pharmacol Ther 2004; 75:580-585

2. Carulli MT and Davies UM. Peripheral neuropathy: an unwanted

side-effect of leflunomide? Rheumatology 2002; 41:952-953