The yearlong, comprehensive review of safety data for LEF included analysis of the following databases:

• A database of 2,900 subjects on LEF in controlled clinical trials with a median exposure of over six months.
• Three independent medical claims databases comprising over 5,400 subjects treated with LEF for a mean of over 12 months.
• Data from the National Databank of Rheumatic Diseases on over 5,000 subjects treated with LEF for a mean of over 12 months.
• A database of hospitalizations for acute liver failure from a consortium of 17 liver transplant centers.
• The Adverse Event Reporting System (AERS) that represents the database of all Medwatch reports received by the FDA.

The FDA Division of Arthritis, Analgesic and Ophthalmic Drug Products reached the following conclusions regarding LEF and liver injury:

• LEF is associated with a three-fold elevation of liver enzymes in 2-4% of subjects compared to 1-2% in the placebo-treated groups as is currently identified in the drug label
• Hospitalization for apparent drug-related hepatitis was identified in the databases at a rate of approximately 0.02% or 1/5000 patients
• There were no cases of hepatocellular necrosis with jaundice (an event with a mortality association of greater than 10%) in the databases of 13,700 subjects

There are few cases of LEF-induced serious liver injury or acute liver failure in postmarketing surveillance. Through the Medwatch system, the FDA has received several reports of possible LEF-induced acute hepatic failure. The majority of these reports were highly confounded by the concomitant use of agents known to be potential hepatotoxins, co-morbidity affecting the liver or otherwise inadequate case information so that no conclusions about the relationship between these reports of serious liver injury or acute liver failure and the use of LEF could be drawn.

The FDA presentation concluded that the incidence of elevated liver function tests is in the range of 2-4% but serious hepatotoxicity, such as hepatocellular jaundice and acute liver failure, is rare based on:

• The small number of post-marketing reports of acute liver failure
• The absence of acute liver failure as well as a less severe degree of acute liver injury, (hepatocellular necrosis with jaundice) in a database of over 13,000 subjects
• Data suggesting that hospitalization for drug-induced liver injury may occur with a frequency of well under 0.02%
• Review of the FDA Medwatch database showing that the reporting rate for acute liver failure and fatal hepatotoxicity associated with LEF is well below that for previously identified drugs with serious hepatotoxicity such as INH, valproate, trovafloxacin bromfenac and troglitazone

The committee unanimously voted to recommend that LEF remain on the market and commented that it continued to represent a valuable therapeutic in the armamentarium for the treatment of rheumatoid arthritis.

In addition, the committee received data supporting the efficacy of LEF for the improvement of physical function. Such data, based on assessments using the Health Assessment Questionnaire, reflect symptomatic improvement. The committee voted to recommend that labeling be updated to include information on the demonstrated improvement in physical function.

The FDA will review these nonbinding recommendations forwarded by the Arthritis Advisory Committee.

The Bottom Line:

While elevations in liver function tests are seen in 2-4% of LEF treated patients, serious hepatotoxicity is extremely rare.

• The Arthritis Advisory Committee of the FDA recommends that LEF remain on the market.
• LEF should receive additional labeling for improvement in physical function in patients with RA.

H. Pylori testing for patients on NSAIDs?
The relationship between the two most important risk factors for peptic ulcer disease, infection with Helicobacter pylori and use of NSAIDs, has been an area of debate. It has been reported that treatment of H pylori both lowers the incidence of NSAID-induced ulcers (Lancet 1997;350:975) or had no effect on ulcer development and actually impaired ulcer healing (Lancet 1998;352:1016). Two recent reports seem to favor an interaction between these two risk factors. Chan and colleagues reported that screening for and treatment of H pylori reduced the risk of NSAID-induced ulcers over a 6 month period from 34.4% to 12.1% among NSAID naïve patients commencing long-term NSAID therapy (Lancet 2002;359:9). This difference was highly significant, as was the difference in complicated ulcers (27% versus 4.2%).

Huang and colleagues performed a meta-analysis of published literature to address this issue. They found a synergistic relationship between the two risk factors. For patients with either NSAID use or H pylori infection, the presence of the other risk factor increased the risk of developing ulcer by approximately 3.5 fold. Compared with H pylori negative NSAID non-users, those with both risk factors had a risk of ulcer of 61 (95% CI 9.98-373).
Bottom Line: Clinicians should be aware of these two important risk factors for peptic ulcer disease. Concomitant with an understanding of the risks for individual patients, based upon the presence of comorbidities and other factors, it would seem prudent to consider appropriate screening and treatment of patients.

Aseptic Meningitis
Aseptic meningitis has long been recognized as a rare side effect that can occur in association with the use of various traditional NSAIDs. A recent paper, based upon information from the FDA Adverse Event Reporting System (AERS), reported 5 cases of aseptic meningitis associated with the use of rofecoxib . In all cases, symptoms occurred within 1 and 12 days following exposure to rofecoxib. In one case, 2 rechallenges were positive. Several other cases of aseptic meningitis in patients taking rofecoxib and celecoxib have been received through AERS, but causality in those cases cannot be clearly defined. As a result of these reports, the FDA asked Merck to add aseptic meningitis to the list of potential adverse effects on the package insert for rofecoxib.

Bottom Line: Rare cases of aseptic meningitis, which appear to be idiosyncratic reactions rather than hypersensitivity reactions or sequelae of inhibition of prostaglandins, have been reported with traditional NSAIDs and now with the COX-2 selective agent rofecoxib. Health care providers should be aware of this potential adverse effect in patients receiving these medications.

Aspirin-sensitive asthma
Aspirin-sensitive asthma is an important clinical concern, with an estimated prevalence among asthmatic patients of 2-6% by history and 8-34% on oral challenge. The association is stronger among asthmatic patients with nasal polyposis. The cross-reactivity between aspirin and other NSAIDs suggested that alteration in prostaglandin synthesis were relevant; this was supported by elevated concentrations of urinary leukotrienes after aspirin challenge in affected patients. With the introduction of the COX-2 selective inhibitors, it was hypothesized they may be safer for patients with aspirin sensitivity, because they spare prostaglandins synthesized via COX-1. However, patients with aspirin sensitivity were specifically excluded from the clinical trials of these drugs. Since then, anecdotal observations, open assessment, and small controlled trials seemed to support this contention. Recently, several reports provide support for the lack of cross reactivity between aspirin and COX-2 inhibitors

Stevenson et al studied 60 patients with confirmed aspirin-sensitivity in a double-blind placebo controlled study. On aspirin challenge, 32 of the 60 patients experienced bronchospasm and upper airway symptoms, while 28 experienced only upper airway symptoms. By contrast, none of the patients experienced nasal symptoms, changes in nasal examination or significant change in FEV1 with rofecoxib (25 mg) challenge.
Bottom Line: While appropriate caution is indicated, COX-2 inhibitors may be a therapeutic option for patients with aspirin-sensitive airway symptoms.

On August 17, 2001 the FDA convened a meeting of the Arthritis Advisory Committee (AAC) and the sponsors of etanercept (Immunex) and infliximab (Centocor) to review and update past and current safety observations related to the use of TNF inhibitors.  Representatives of the Center for Biologics Evaluation and Research (CBER) reported to the committee on their analysis of adverse events reported to the FDA through Medwatch and the Adverse Event Reporting System (AERS).  Representatives from Immunex and Centocor addressed the AAC regarding their safety database as well as their current and future pharmacosurveillance efforts to educate physicians and patients regarding these matters.  Serious and unusual adverse events potentially related to TNF inhibitors were reviewed.  The table below summarizes available data from the meeting.

As of July 2001 over 270,000 patients have been exposed to etanercept or infliximab worldwide.  Whereas infliximab is marketed for use in Europe (representing 18% of worldwide use), etanercept is available on a more limited basis in Europe (accounting for ~6% of its worldwide use). Whereas > 90% of etanercept use has been in RA, most of the worldwide use of infliximab has been in Crohns disease more so than RA.  Foremost in the discussion were concerns raised by reports of tuberculosis (M.Tb) and other opportunistic infections infrequently observed in patients taking TNF inhibitors. M.Tb has been reported in 82 infliximab-treated and 11 etanercept-treated patients worldwide.  Importantly, 80% of the infliximab cases were from outside of the US, predominantly from Europe and Norway.  M.Tb cases with infliximab occurred during treatment for RA (67.5%), Crohns disease (26%) and other indications (4.5%).  In comparison, 11 reports of M.Tb and 8 cases of atypical mycobacterial infections were seen in etanercept treated patients. Infliximab-related cases were discovered in the first 6 months of use, suggesting reactivation of latent M.Tb, with nearly 80% of these occurring outside the USA.  Nearly one-third of cases had an extrapulmonary or miliary presentation.

Risk factors for M.Tb (and other opportunistic infections) appear to include current and past residence in endemic regions (e.g., Europe for M.Tb, Ohio River Valley for histoplasmosis, San Joaquin Valley for coccidioidomycosis) and chronic prednisone (>15 mg/day) use. The American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC) also include recent immigrants (from high prevalence countries), IV drug users, those exposed to M.Tb, lab personnel, and patients with silicosis, diabetes mellitus, chronic renal failure, leukemia, lymphoma, and HIV (+) as high risk populations.  However, most of the RA patients (Table 1) had no identifiable risk factor other than treatment with a TNF inhibitor.  A majority of RA patients in the table below were receiving prednisone and other DMARDs at the time of reported infection.  Although chronic prednisone use is a risk factor for serious or opportunistic infections, it is unknown whether methotrexate or other DMARDs significantly influences the incidence of opportunistic infections in RA. 

Data from preclinical animal models indicate that TNF, nitric oxide and other proinflammatory cytokines play an important and specific role in the containment and isolation of viable tubercle bacilli, presumably by promoting macrophage activity and granuloma formation.  Likewise, TNF knockout mice are more susceptible to infection with intracellular pathogens such as candida, listeria and M.Tb.  Thus, the inhibition of TNF by these biologic agents may facilitate reactivation of latent M.Tb in some patients.

The package insert for infliximab has been revised by Centocor warning that M.Tb and other opportunistic infections have been observed with infliximab use, and advising physicians to employ PPD skin testing in patients who will receive or are receiving infliximab. Studies have shown no support for chest X-ray (CXR) or skin controls (e.g., Mumps, candida) as screening measures for latent M.Tb.  Discussants at the meeting considered whether these findings indicated a class effect and if these recommendations would apply to all TNF inhibitors. This issue awaits further study for each drug.  It is unclear if skin testing should be use in those on etanercept.  However, some rheumatologists (who are concerned about a class effect) may use skin testing in their etanercept-treated patients until further studies become available. Immunex recommends that physicians follow ATS/CDC guidelines on the use of targeted skin testing.

Other safety issues were raised at the meeting. The number of cases of demyelinating disorders, multiple sclerosis, optic neuritis, pancytopenia, and aplastic anemia are presented below (Table1).  New information regarding reports of patients with seizures, colonic perforations, lupus-like manifestations and lymphoma in patients receiving TNF inhibitors was also presented.  It was universally felt that prospective observational programs are needed to further confirm the long-term safety of TNF inhibitors.  Both sponsors detailed their comprehensive pharmacosurveillance programs (>15,000 patients to be observed prospectively) to address these specific issues.

Rheumatologists should carefully monitor patients on these agents using sponsor recommended guidelines.  Patients taking TNF inhibitors who exhibit serious adverse events, including M.Tb, opportunistic infection or other unusual or life-threatening clinical disorders, should be reported to the FDA through the sponsor or by filling out forms available at the Medwatch Web site (http://www.Medwatch.com)

The August 22/29, 2001 issue of the Journal of the American Medical Association features a meta-analysis entitled "Risk of cardiovascular events associated with selective COX-2 inhibitors" which has stirred considerable and immediate media attention and raises concerns about possible thromboembolic risks facing patients taking COX-2 inhibitors and physicians who prescribed them.

This meta-analysis studied two large randomized post-marketing trials of rofecoxib and celecoxib (VIGOR, CLASS respectively), as well as other published and unpublished data submitted to the relevant FDA committees. The VIGOR study with 8076 patients was designed to evaluate gastrointestinal toxicity of rofecoxib vs. naproxen in a large rheumatoid arthritis cohort2. Low dose aspirin use was not permitted. There were 46 cases of serious thrombotic cardiovascular events (e.g., MI, TIA and stroke) in the rofecoxib group, and 20 events in the naproxen group (RR 2.38; p <0.001). The CLASS study with 8059 patients evaluated GI toxicity of celecoxib vs. ibuprofen vs. diclofenac3. Aspirin use was permitted. There were no significant differences in cardiovascular events between groups in the CLASS study. The cardiovascular risk seen in the rofecoxib and celecoxib studies was then compared to a meta-analysis of two previous unrelated studies using aspirin vs. placebo for prevention of cardiovascular events (the US Physicians Health Study and the UK Doctors Study). This analysis suggested that the annualized MI rate for the placebo group from the US/UK studies was 0.52%, statistically significantly lower that for both rofecoxib (0.74%; p=0.04) and celecoxib (0.80%; p = 0.02).

The meta-analysis of Mukherjee et al has important limitations. It is well appreciated that selective COX-2 inhibitors do not significantly inhibit platelet aggregation, one of several factors influencing thrombotic cardiovascular disease. Conventional NSAIDs inhibit both thromboxane and PGI2. It has been suggested that by decreasing antithrombotic PGI2 production and not affecting thromboxane production, selective COX-2 inhibitors could cause an increase in thrombotic cardiovascular events. This hypothesis was not directly studied by Mukherjee et al. At the same time, all NSAIDs, including selective COX-2 inhibitors, may have important effects in reducing the inflammatory component of atherogenesis and actually reduce cardiovascular risk. Patients in the COX-2 trials were heterogeneous; the CLASS study included patients with both OA and RA; patients with RA have a higher risk for MI, a fact that likely had important, but unknown meaning for the study conclusions. Finally, none of the studies examined in the meta-analysis was actually designed to evaluate differences in the rates of cardiovascular events.

Current evidence indicates that available selective COX -2 inhibitors are associated with a significant reduction in major NSAID related GI toxicity, especially in high-risk patients. These GI toxicities have been and continue to be a major source of morbidity and mortality in patients with arthritis. The decision to use selective COX-2 inhibitors is multidimensional, and must balance possible risks for major cardiovascular events against the benefits of these agents. For the individual patient, it is important to consider factors that affect the risk/benefit ratio of the therapeutic choice and the patient's willingness to accept therapy recommendations. These factors include risks for major GI toxicity, cardiovascular events, renal failure, cost and others. These are balanced against measures that can ameliorate these risks, including where appropriate, concomitant low dose aspirin, gastric mucosal protection, and use of effective analgesics and antiinflammatories with minimal GI toxicities. A well-designed study focusing on cardiovascular risk and benefit of selective COX-2 inhibitors will be needed to properly examine this issue.