Reports of Leflunomide Hepatotoxicity in Patients with Rheumatoid Arthritis

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AMERICAN COLLEGE OF RHEUMATOLOGY

Reports of Leflunomide Hepatotoxicity in Patients with Rheumatoid

Arthritis

In September 1998, leflunomide was approved for use in rheumatoid

arthritis (RA) and has been used in over 200,000 patients since. The

safety profile was established by several studies, wherein the most

common reported adverse events included diarrhea, dyspepsia, rash, hair

loss, elevated hepatic enzymes and hypertension. The combined use of

methotrexate and leflunomide was reported at the 2000 ACR meeting by

Kremer et al1. In that trial the combination was more effective than

methotrexate alone when given to 263 patients who were methotrexate non-

or partial-responders. In that trial, nearly 30% of patients exhibited an

increase in AST or ALT at any time during the 6 month trial, but only 1.5

% and 3.8% demonstrated 3-fold elevations of AST and ALT respectively.

These findings are consistent with the 3 phase III trials which lead to

FDA approval. In these trials, 14.4%-17.6% of patients had an elevated

ALT between 1.2 but less than 2 x upper limit of normal (ULN). Greater

than 3 x ULN elevations of ALT were seen in 1.5-4.4% of patients.

Guidelines on the monitoring of LFT's and response to elevations are

detailed in the package insert.

In May 2001, the manufacturer issued a " Dear Arava Prescriber " letter

detailing post-marketing reports of hepatotoxicity summarized for the

European Agency for the Evaluation of Medicinal Products (EMEA). This

report detailed the experiences of leflunomide treated RA patients

worldwide with a total drug exposure of 104,000 patient-years. The EMEA

report described 296 cases of hepatic abnormalities, including 129 cases

of serious reactions. Among the 296 reports were 232 patients with LFT

abnormalities, 2 patients with cirrhosis, 15 patients with liver failure

(of whom 9 died either from liver failure in 3 or a concomitant illness

in 6), and a total of 15 deaths.

Most putative hepatic events occurred within the first 6 months of

treatment range 3 days to over 3 years); patients were of all ages and

there was no gender predilection. Most patients had one or several

comorbidities, and most were taking another potentially hepatotoxic drug.

Of patients with elevated liver function enzymes, 58% were taking

concomitant NSAIDS and/or methotrexate. Of the serious reports, 101

patients (78%) were concomitantly treated with hepatotoxic medications.

Of the 64 serious hepatic events with a clinical liver disease diagnosis,

19 were taking concomitant methotrexate. Confounding comorbidities

included previous or concurrent alcohol abuse, hepatitis A, B and C,

interstitial lung disease, renal insufficiency, autoimmune liver disease,

and pancreatitis. Serious hepatotoxicities reported included drug induced

hepatitis, reactivation of viral hepatitis (especially hepatitis ,

fulminant hepatic failure, jaundice, cholestasis, hepatomegaly and

hepatic cirrhosis. Both patients with cirrhosis had concomitant and/or

previous methotrexate use, and one of them had pre-existing evidence of

hepatitis and cirrhosis on methotrexate therapy. Only a few liver

biopsies were performed, which showed a variety of abnormalities,

including centrilobular necrosis with portal or periportal inflammation,

steatosis, focal piecemeal necrosis, and periportal fibrosis.

Among the 15 patients with a hepatic abnormality who died, 9 had liver

failure, 3 had liver toxicity, and 1 each had hepatitis, cholestatic

jaundice, or increased liver function tests. Death was attributed to the

hepatic event in one-third (3 liver failure, 1 hepatitis, and 1

cholestatic jaundice) and to nonhepatic causes in two-thirds. Of the 15

deaths, there were 5 patients with sepsis, 4 with multiorgan failure, 3

with preexisting hepatic disease, 2 each with alcohol abuse, pre-existing

interstitial lung disease or postoperative complications, and 1 each with

pancreatitis, pulmonary embolism or s syndrome. Information

available suggests prescribing and monitoring guidelines may not have

been fully adhered to in 4 of these cases. The cause of liver dysfunction

in the 15 patients who died was possibly related to leflunomide in 10

patients and was due to other causes in 3 patients and unknown in 2

patients.

Leflunomide should be used with caution according to guidelines described

in the products package insert. At a minimum, ALT must be obtained at

baseline and monitored monthly for the first 6 months, then, if stable,

every 2-3 months. Proper monitoring in patients taking concomitant

methotrexate or other hepatotoxic drugs includes both an ALT (possibly

more sensitive to leflunomide hepatotoxicity) and AST prior to drug

initiation, and then at least monthly for 6 months and thereafter every

1-3 months. More frequent monitoring is necessary in patients who develop

elevated LFTs requiring reduction or discontinuation of the drug.

Sporadic minor elevations (>1x and < 2x ULN) of AST or ALT may occur and

should prompt repeat testing within 2-4 weeks. A trial of dose reduction

and repeat testing is warranted for moderate ALT elevation of 2-3x ULN,

with discontinuation if ALT elevation >2x ULN persists. Although LFTs are

not a perfect reflection of potential drug induced hepatotoxicity,

persistently abnormal LFTs or a LFT >3 x the upper limit of normal should

not be tolerated and should prompt drug withdrawal and drug elimination

(eg cholestyramine; 4-8 grams tid for 2-3 days; 4 gm tid for 1 day

reduces leflunomide levels by about 50%; 4 gm tid for 5 days is generally

adequate for washout unless pregnancy is desired in which case a longer

washout is needed. If leflunomide is discontinued for reasons of

hepatotoxicity and a change to another hepatotoxic DMARD is contemplated,

washout and monitoring procedures should be adhered to.

Although the combination of leflunomide and methotrexate has been

studied1, the use of this combination has not been approved by the Food

and Drug Administration. Careful attention must be given to possible

contraindications, signs of hepatotoxicity and proper monitoring when

considering use of leflunomide together with other potentially

hepatotoxic drugs such as NSAIDs and methotrexate. Physicians should

caution their patients about the use of alcohol with leflunomide and

patients with a past history of alcohol abuse should refrain from using

leflunomide. Leflunomide is not recommended for use in patients with

evidence of hepatitis B or C infection, significant hepatic impairment,

severe immunodeficiency, bone marrow dysplasia, or serious infection.

Leflunomide is contraindicated in women who are or may become pregnant.

August 2001

Matteson, MD, MPH; J. Cush, MD

Hotline Editors

Kremer JM et al. Arthritis Rheum 43(Suppl);s224, 2000

Dr. Matteson has been the recipient of an unrestricted educational grant

from Aventis; Dr. Cush is a paid lecturer and consultant for Aventis

A summary of this information, which may be useful to patients taking

leflunomide, accompanies this HOTLINE.

Hotline is provided by the ACR Communications and Marketing Committee as

a service to members. This Hotline reflects the views of the

author(s) and does not represent a position statement of the College.

Information for Patients

AMERICAN COLLEGE OF RHEUMATOLOGY

Side Effects of Leflunomide on the Liver in Patients with Rheumatoid

Arthritis

Leflunomide (brand name Arava) was released for treatment of rheumatoid

arthritis (RA) in September 1998. Like all new medications, leflunomide

was tested in clinical trials to determine its effects, good and bad,

before it was released. Since it has been on the market, it has been

shown to be an effective medication for rheumatoid arthritis in many

patients, and is generally well tolerated.

In February 2001, the European Agency for the Evaluation of Medicinal

Products reported a series of side effects affecting the liver to

Aventis, the manufacturer of leflunomide. There were 296 cases of liver

abnormalities, most relatively minor. However, there were 129 cases of

severe side effects affecting the liver in patients with rheumatoid

arthritis who were being treated with leflunomide, including 9 deaths

among 15 patients with severe liver failure.

A review of information about these cases supplied by Aventis reveals

that most occurred within the first 6 months of treatment, but can occur

after as few as 3 days or as long as 3 years. Side effects affected men

and women patients of all ages. Most patients had one or several other

diseases, such as heart disease, diabetes, or viral hepatitis B or

hepatitis C. Most patients were also taking other medications at the same

time, which could be toxic to the liver. These include methotrexate and

nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen, celecoxib,

rofecoxib, and many others).

There were several types of liver damage reported with the use of

leflunomide. These included drug induced hepatitis, reactivation of viral

hepatitis (especially hepatitis , rapid liver failure, jaundice,

enlargement of the liver, and liver cirrhosis.

The manufacturer of leflunomide, Aventis, has determined that the severe

side effects could not be related to the use of leflunomide with absolute

certainty, but that such a relationship also could not be excluded.

Leflunomide should be used with caution in all patients. Regular

laboratory tests, including blood tests of liver function, must be done

for all patients taking this medication. The tests are done more

frequently at the beginning of treatment with leflunomide, usually just

before starting treatment and then monthly for the first six months. They

may be done somewhat less frequently after the first 6 months, perhaps

every 2 months depending on how well the drug is tolerated.

Leflunomide must be used with caution in patients taking other

medications that can be toxic to the liver, such as methotrexate and

nonsteroidal anti-inflammatory drugs. Leflunomide should not be

prescribed to patients with a past history of alcohol abuse. It should be

avoided in patients who have had viral hepatitis B or C, other liver

abnormalities such as cirrhosis, or past serious infections. It must not

be taken by women who are pregnant because of the risk of birth defects.

If you are taking, or considering taking, leflunomide, please discuss

these important issues with your physician.

August 2001

http://www.rheumatology.org/research/hotline/0801leflunomide.html