Leflunomide and methotrexate can be used together safely

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Nov 14, 2002

Leflunomide and methotrexate can be used together safely

Albany, NY - Leflunomide can be used safely in conjunction with methotrexate

in patients with rheumatoid arthritis, as long as liver enzymes and blood

counts are monitored regularly, according to a new double-blind,

placebo-controlled study. Patients receiving leflunomide plus methotrexate

were more likely to experience clinical improvement than those on placebo

and methotrexate, the researchers report in the ls of Internal Medicine

[1].

The combination of leflunomide and methotrexate has long been considered

tricky, because both drugs are potentially hepatotoxic; the American College

of Rheumatology last year warned against use of these 2 together until more

information was available, and the European labeling for leflunomide

discourages its use with methotrexate. But leflunomide is significantly

cheaper than the biologic therapies, and many rheumatologists believe that

when methotrexate alone is no longer sufficient, it is worth trying

leflunomide with methotrexate before moving on to biologic agents. A number

of healthcare organizations are also advocating this practice.

Large study needed to help confirm results from small open trial

Reporting the new study, Dr Kremer (Center for Rheumatology, Albany,

New York) and colleagues say they previously saw considerable clinical

improvement in patients taking a combination of methotrexate and leflunomide

in a small open study, with reversible elevations in aminotransferase

levels. " We therefore sought to determine whether similar results could be

achieved in a large, double-blind investigation of the combination of these

2 antimetabolic agents. "

At 20 centers in the US and Canada, 263 patients receiving stable doses of

methotrexate (between 15 mg/week and 20 mg/week in most cases) but still

with active RA were randomized to leflunomide 100 mg/day for the first 2

days followed by 10 mg/day or to matching placebo. If substantial adverse

events (AEs) occurred, the dose of leflunomide could be reduced to 10 mg

every other day. If 10 mg/day was tolerated but active disease was still

present at week 8 or thereafter, an increase to 20 mg/day of leflunomide or

matching placebo was required. If substantial AEs occurred while the patient

was taking 20 mg of the study drug per day, a 1-time dose reduction to 10

mg/day was allowed at the discretion of the investigator. All patients

received at least 1 mg of folate supplementation per day.

The primary end point was the rate at which the intention-to-treat sample

achieved a 20% improvement in ACR criteria at the end of the study, which

was 24 weeks in duration. At this time, 46.2% of the leflunomide group (60

of 130 patients) and 19.5% of the placebo group (26 of 133 patients) met

ACR20 criteria (p<0.001). Of those receiving the active drug, 39% of

patients were receiving 10 mg of leflunomide once daily, 55% were taking 20

mg once daily and 6% were receiving 10 mg every other day.

Adjustment of leflunomide dose can normalize elevated liver enzymes

Patients in the leflunomide group were more likely than those in the placebo

group to experience elevated levels of liver aminotransferase enzymes, but

values normalized in all patients in the active drug group " in most cases

with no adjustment of leflunomide dose (58.5%) or with 1 dose decrease

(29.3%), " the researchers note. As 39% of patients achieved an adequate

clinical response while receiving 10 mg of leflunomide, Kremer et al say

patients should start with this maintenance dose when leflunomide is added

to methotrexate.

They recognize that " one of the safety concerns when combining methotrexate

with leflunomide is potential hepatotoxicity. " But, they add, regular

monitoring in those taking methotrexate " has resulted in the virtual

elimination of methotrexate-associated hepatotoxicity " when drug doses are

adjusted following abnormal liver function tests (LFTs). " We suspect the

same principles will apply when new disease modifying antirheumatic drugs

with potential hepatotoxicity are combined with methotrexate. " Nevertheless,

they caution that " experience with the combination of leflunomide and

methotrexate is still limited, [so] it is imperative that liver enzymes be

monitored during the longer treatment intervals needed to maintain control

of this chronic disease. "

Neither leucopoenia nor neutropenia were observed in any of the patients in

the study, and the incidence of infections (including serious infections

requiring hospitalization) was lower in the leflunomide group than in the

placebo group. But again, Kremer et al make the point that these

observations " will need to be sustained over longer treatment intervals

before we can conclude with certainty that this combination does not

increase risk for infectious complications. "

In conclusion, they say the combination of leflunomide and methotrexate " can

be used effectively and safely with careful monitoring. It represents a

logical alternative for patients who have an incomplete response to

monotherapy with maximally tolerated weekly doses of methotrexate. "

Nainggolan

Source

1. Kremer JM, Genovese MC, Cannon GW, et al. Concomitant leflunomide therapy

in patients with active rheumatoid arthritis despite stable doses of

methotrexate. A randomized, double-blind, placebo-controlled trial. Ann

Intern Med 2002 Nov 5; 137(9):726-33.