Enbrel & Remicade

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Postmarketing Adverse Event Data Updated for

Enbrel, Remicade

GAITHERSBURG, MD (Reuters Health) Aug 17 - The US Food

and Drug Administration's Arthritis Drugs Advisory

Committee heard updated postmarketing adverse event

data on Friday for two rival rheumatoid arthritis

drugs: Centocor's Remicade (infliximab) and Immunex's

Enbrel (etanercept).

Overall, there have been more reported events

concerning Enbrel than Remicade,the panel was

informed. But Immunex maintained that the higher

number of reports could be a product of its efficient

collection system rather than its drug's safety

profile.

In addition, while the number of reports was higher

for Enbrel, Remicade has been more closely associated

with certain serious infections, including

tuberculosis.

Centocor said earlier this week that it would add a

" black box " warning to Remicade concerning TB and

other infections. Enbrel does not carry a boxed

warning and Immunex has said that it does not expect

it will need to add one.

Remicade was approved in October 1998 for Crohn's

disease and in November 1999 for rheumatoid arthritis.

Enbrel was approved in November 1998 for rheumatoid

arthritis. The FDA panel appeared to be in agreement

on Friday that, despite the necessity for caution in

using the drugs, their benefits continue to outweigh

their risks.

The FDA has received 2300 adverse event reports on

Remicade, which has been taken by an estimated 147,000

patients worldwide. Twenty-six percent of those

reports were related to infections.

There have been 18,500 reports on Enbrel, 22% of them

infection-related, with 102,000 patients worldwide

receiving the drug since it was approved. Recent

reports suggest that Enbrel may be contributing to

higher lymphoma rates, but Immunex said the incidence

still seems to be much lower than might have been

expected.

Both Remicade and Enbrel inhibit tumor necrosis

factor-alpha, but they have slightly different

chemical properties and actions. Remicade is a

chimeric mouse-human monoclonal antibody, while Enbrel

fuses several human proteins.

Because they are different, adverse events with one

should not necessarily be expected for the other, said

Miles Braun, director of the Division of Epidemiology

in the FDA's Center for Biologics Evaluation and

Research. When approved, both Enbrel and Remicade had

precautions on infection risks in their labeling. Once

on the market, infections, including TB, were reported

to the FDA's MedWatch database, along with reports on

multiple sclerosis, intestinal perforation, and

malignancies, including aplastic anemia and lymphoma.

In the years since approval, warnings have been added

to both products' labels,

with some events more clearly associated with Remicade

and others with Enbrel.

Remicade's new label will indicate that patients

should be tested for TB before

starting therapy and that the drug has been associated

with opportunistic infections,

sometimes fatal.

Remicade has been associated more with TB, with 92

cases reported, according to

the FDA. More than half were in Europe, and 77% of

patients were taking

concomitant immunosuppressive therapy, a potential

risk factor, noted FDA

medical reviewer Jong-Hoon Lee. The reviewer estimated

a TB incidence of 24 per

100,000 in the US for rheumatoid arthritis patients

taking Remicade, and only 6 per

100,000 among rheumatoid arthritis patients in

general.

Jerry Boscia, vice president of clinical R&D for

Centocor, said that Remicade

patients might be at higher risk for TB if they are

also receiving methotrexate and

immunosuppressive agents. He added that the data

suggest that many of those who

developed TB did so early in Remicade therapy,

indicating that the drug may have

stimulated a latent infection.

Remicade was associated nine reports to the FDA of

histoplasmosis, 11 of

listeriosis, and 10 of Pneumocystic carinii pneumonia,

Lee said. The new label for

the drug states that in regions in which

histoplasmosis is endemic, benefits and risks

should be carefully weighed before starting Remicade.

FDA medical reviewer Siegel cited 14 cases of

opportunistic infections

reported for Enbrel patients, including 5 cases of

Pneumocystic carinii pneumonia.

Four patients were taking concomitant methotrexate or

corticosteroids, which

Siegel said might have increased infection risk.

Enbrel has been more closely associated than Remicade

with new onset of multiple

sclerosis, with 17 cases reported to the FDA so far.

The company said an expert

neurological panel it convened found no positive link

between Enbrel and MS, but

urged Immunex to closely monitor all reports.

There have been 18 cases of lymphoma reported to the

agency for Enbrel,

compared with 10 for Remicade. But Siegel said that

the reported rate for both

drugs — about 9 per 100,000 — seems to be the same as

that in the general

population. However, he pointed out that there is

underreporting to the FDA on all

adverse events.

Both Immunex and Centocor, which is a &

company, plan several

prospective studies to further evaluate the causes and

incidence of infections and

malignancies, and they have also started registries to

track adverse events in patients

taking their products. And both firms said they have

hotlines for patients and

physicians to use in reporting suspected adverse

events.

The advisory panel on Friday commended the FDA and the

manufacturers on their

adverse event collection efforts and urged continued

surveillance.

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