Aventis is working with FDA to update Arava labeling based on postmarketing information from methotrexate combination studies on the rheumatoid arthritis drug.

"Aventis currently is in discussion with the FDA regarding the addition of information relating to this study to the prescribing information," the company says in its written response to a petition filed by Public Citizen's Health Research Group calling for the drug's removal (¹ [A#00640130023], p. 29).

The six-month, Phase IIIb study (US 4001) enrolled 263 rheumatoid arthritis patients with active disease that had an inadequate response to methotrexate monotherapy. Patients received leflunomide/methotrexate or placebo/methotrexate.

At the end of the study, patients were allowed to enter a six-month, open-label extension trial. Placebo patients were switched to Arava without a loading dose. All patients remained blinded to their original randomized treatment arm.

"The safety findings of this Phase IIIb combination therapy study - the type and frequency of adverse events - were consistent with those reported in clinical trials evaluating Arava monotherapy," Aventis said. "No clinical hepatic adverse events...were reported during the six-month, placebo-controlled study or the subsequent six-month, open-label extension."

"Most" of the alanine transaminase and aspartate transaminase elevations were mild (<2 times="" the="" upper="" limit="" of="" normal)="" "as="" they="" were="" in="" the="">Phase III monotherapy studies," Aventis said.

In addition, "the incidence of clinically significant (>2 x ULN) ALT elevation and the subset of marked ALT elevations (>3 x ULN) after adding Arava to ongoing methotrexate therapy was within the range observed with Arava monotherapy in the Phase III trials."

In its March 28 petition, HRG maintains that Arava offers no advantages for rheumatoid arthritis patients "since it lacks an increased efficacy and appears to pose an increased likelihood of serious adverse events such as liver toxicity when compared to methotrexate."

HRG estimates that Arava has been associated with 130 severe hepatic reactions, resulting in 56 hospitalizations and 22 deaths between September 1998 and September 2001.

The figures appear to correlate with Aventis' numbers: the company received 126 reports of serious and non-serious adverse hepatic events from September 1998 to September 2001 "that were classified as possibly associated with Arava use." Between September 2001 and March 2002, Aventis said it received 24 reports.

Aventis maintains, however, that it is difficult to compare the adverse event profile of a newly approved drug with one that has been on the market for many years, noting that adverse event reporting typically drops off after the first two years a drug is on the market.

"It is impossible to directly compare a 25-year-old drug with a drug approved only four years ago when using spontaneous adverse event reporting as an index of safety," the company declared.

FDA considered labeling changes to reflect reports of hepatic injury associated with Arava in early 2001, but the changes were never made (² Also see "Aventis Discussing Arava Label Changes With FDA; EU Revises Monitoring" - Pink Sheet, 19 March, 2001., p. 28). The agency's review came as EU labeling was revised to include more active monitoring of liver alanine transaminase levels.

Aventis maintains that Arava labeling adequately addresses the potential for liver toxicity. U.S. labeling recommends ALT monitoring both at baseline and at monthly internals or as determined by a physician.

"Since first marketed, the prescribing information for Arava has contained information about hepatotoxicity in the Warnings section, including monitoring recommendations. The rare serious hepatic events observed in the postmarketing period do not alter the positive benefit-risk profile of Arava," Aventis said.

In the past, "when a post-marketing Arava experience has produced an indication that there may be events not seen in clinical trials (or an increased frequency of previously observed events), Aventis has worked with the FDA to update the prescribing information and to notify physicians."

For example, in March 2000, Aventis sent a "Dear Doctor" letter following reports of rare dermatologic events, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Arava's warnings and adverse reactions sections of labeling were revised to include the conditions, as well as erythema multiforme.

The company maintains that HRG's petition generally "mischaracterizes and selectively cites clinical trial and postmarketing data," thereby exaggerating Arava's association with severe adverse events.

"The safety data from randomized controlled trials show the overall percentage of patients with adverse events who were treated with Arava was generally comparable to that of patients who received methotrexate and sulfasalazine. Importantly, nothing in the postmarketing experience changes the acceptable benefit-risk profile established by the controlled clinical studies."

In its petition, HRG argues that a risk management program to keep Arava on the market would be inappropriate, given the poor success of other programs in protecting patients from serious adverse events.

Aventis also argues that HRG inaccurately alleges that the company failed to report two clinical trial deaths associated with vasculitis. "First, the eventual deaths of these two patients occurred long after they withdrew from the clinical trial, as is clear from the publication on which HRG relies," the company responded.

"Second, both cases were reported to the FDA during the trial and at the time the vasculitis was diagnosed, and both were detailed in the NDA submission. Third, both deaths were, in fact, reported by Aventis to the FDA after the trials were concluded."

Aventis also disputes HRG's assertion that labeling makes no mention of hypertension as a postmarketing adverse event. "This argument is specious. Table 5 of the prescribing information identifies adverse events occurring in 3 percent or greater of clinical trial patients; hypertension is specifically mentioned under the heading 'Cardiovascular.'"

FDA approved Arava in September 1998 for the treatment of active rheumatoid arthritis to reduce signs and symptoms and to retard structural damage as evidenced by X-ray erosions and joint space narrowing (³ Also see "Hoechst Arava Arthritis Therapy Launched At $3,000 Per Year AWP" - Pink Sheet, 14 September, 1998., p. 3).

Aventis Arava Labeling Update Expected Based On Methotrexate Combo Study

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