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Kansas City,Mo-Sept.11,1998--The FDA has approved Hoechst Marion (Hoechst AG) Roussel's Arava (Tm) (Leflunomide) for the treatment of active RA in adults.
The FDA indicated in it reports in 1998 that the medication was no better than the gold-standard methotrexate but different patients needed options.
Arava is indicated in adults for the treatment of active RA to reduce signs and symptoms and to retard structural damage as evidenced by x-ray erosions and joint-space narrowing. This marks the first time that a DMARD has been indicated for retardation of structural damage in RA based on X-ray analysis.
The efficacy of Arava was demonstrated by improvement at endpoint in measures such as tender and swollen joint counts,physician and patient global assessments, a function/disability measure and pain intensity.
Laval,QC--April 3, 2000-Aventis Pharma Inc., today announced the launch of Arava (TM),a novel drug for adults with active RA. Arava acts  by treating the underlying cause of the disease as opposed to just treating symptoms which include joint inflammation, swelling, stiffness, and pain.
"This is the first specifically-designed DMARD to come to the market in 10 years and having this new treatment option available is good news for those who are afflicted with this autoimmune disease", said Jean Bourgouin,MD,Vice-President of Scientific Affairs at Aventis Pharma.
"We further anticipate that patients taking Arava will have a better quality of life,given the drug's ability to slow down the progression of the disease".    

In clinical studies involving more than 1,800 patients world-wide, Arava was shown to be effective as a therapy for long-term use. "The data,as evidenced by x-ray,clearly showed that Arava slows disease progression"said Dr. Bourgouin.  
Arava was generally well tolerated in these studies with the most common transient side effects being diarrhea,elevated liver enzymes,hair loss, and rash.
In a one-year,phase III,placebo-controlled trial,482 patients were given one of 3 treatments. Arava 20mg/day after a loading dose of 100 mg/day for 3 days, placebo (with an increase to 15 mg/week for continued active disease.
Sixty % of the MTX patients were increased to 15 mg/week during weeks seven through nine. The efficacy and safety of Arava at the one-year primary end-point was presented at the ACR last year.
In a second year continuation of the trial to look for maintained effect at 2 years,MTX dose could be increased as high as 20mg/week. 235 patients continued for the second year of therapy (Arava was compared only to MTX because of the predictably small number of patients continuing on placebo).
"The data showed that clinical and radiographic improvement observed with Arava and MTX at one year was maintained at two years,providing evidence of the durability and consistency of Arava efficacy and safety"said Dr Vibele Strand,clinical associate professor at Stanford University.
"Additionally,at two years,Arava DEMONSTRATED STATISCALLY SIGNIFICANTLY IMPROVEMENTS IN ACR 20 RESPONSE rates compared to the active control,Methotrexate Disease progression was stabilized with both Arava and MTX at 2 years".
In the same study improvement in physical function with Arava remained consistent over 2 years.Improvement was statiscally significant compared to methotrexate.
This improvement was assessed through a series of validated questionnaires designed to measure patients' functional ability in terms of their ability to conduct daily activities (e.g.,walking,eating,dressing,washing) and their function in daily life. These questionnaires included the Health Assessment Questionnaire (HAQ) and the Problem Elicitation Technique (PET).
In a separate scientific analysis presented at ACR,Arava was assessed to determine the consistency of its effect for slowing RA disease progression. Results from three large mutinational,  controlled trials were compared and analyzed. Arava consistently retarded the structural damage across all three clinical trials regardless of patient disease duration. The treatment effect was observed at both 6 months and at one year.
Pregnancy must be excluded before the start of treatment with Arava. Arava is contraindicated in pregnant women or women of child-bearing potential who are not using reliable contraception. Before using Arava patients must be fully counseled on the potential for serious risks to the fetus.
Pregnancy must be avoided during Aravaa treatment or prior to the completion of a drug elimination procedure with cholestyramine after Arava treatment. It is recommended  that all women of child bearing potential undergo this elimination procedure upon discontinuing Arava as the drug may increase the risk of fetal death or teratogenic effects when administered to a pregnant women.
In addition men wanting to father a child should consider discontinuing Arava and taking cholestyramine eight grams three times daily for 11 days to minimize any possible risk to the fetus.
Arava was associated with elevations in liver enzymes,primarily ALT and AST,in a significant number of patients in clinical trials' Although these effects were generally reversible with dose reduction or discontinuation of treatment,marked elevation (greater than3 times the upper limit of normal) occurred as well.
Therfore,at minimum.ALT levels should be measured at the beginning of therapy (baseline) and monitored initially at monthly intervals, then,if stable, at intervals determined by the individual clinical situation. Arava is not recommended in patients with significant hepatic impairement or positive hepatitis B or C serologies given the risk of increased hepatoxicity.
Adverse reactions associated with the use of Arava include diarrhea,elevated liver enzymes (ALT and AST),alopecia,and rash. The higher incidence of liver toxicity and the resulting death of 130 patients world-wide have prompted the public advocacy group,"Public Citizen" to ask the FDA to investigate the concern further,and requested a ban on the drug..
The FDA said further studies will be conducted with respect to this concern but no immediate action is contemplated. Arava officials have indicated they are unaware of any extra-ordinary concern related to the medication in general.
Arava have recently,been tried on certain J.R.A. patients with a positive clinical trial result. This is important as some JRA patients are not tolerant to MTX  therapy.
Arava reduces inflammation by suppressing the immune cells responsible for the inflammation. It does this by preventing  the formation of DNA and RNA in the immune cells by inhibiting an enzyme (dihydroorotate dehydrogenase --DHODH) that is necessary for the production of a critical component of DNA and RNA,pyrimidine (nucleic acid).--it is thought,it suppresses the formation of rapidly dividing cells from forming.
Arava may be more suitable for patients who are intolerant to or failed MTX therapy. I personally tried Arava 20 mg./daily (without MTX) and it did not help me. MTX (22.5 mg./weekly) did aid my RA. Drug efficacy is different for each patient. Some patients will fail Arava,Enbrel or Remicade and work wonders for others.
Recent reports about 13 deaths world-wide attributed to patients taking  Arava,and liver toxicity originated from an European web site. Those patients  affected had a pre-existing liver disease,and/or were on other hepatotoxic drugs as well as Arava. 
Even the advocacy group,"Public Citizen" got involved, and petitioned the FDA to conduct a study,and  they made a further request to ban the drug. (Actual facts will show the reports biased,and not fully explained in the articles). The ACR website addresses the concern.

Leflunomide doesn't work for everyone. About 40 to 65 % of the people who take this medication show improvement. Leflunomide therapy begins usually with one 100 mg tablet for three days,and then 20 milligrams tablets once a day.
Leflunomide may not soon replace methotrexate as the DMARD of choice,but certainly is a potentially effective addition for peole who do not respond to methotrexate alone. Combination trials,with methotrexate have proven successful.
In one early trial,the researcher concluded that lefluenomide was slightly superior to methotrexate,but I personally,dispute that statement.through experience with the drug.
Leflunomide is a welcome addition in the arsenal of weapons to fight RA,especially,those patients who can not tolerate methotrexate. I rate leflunomide similar to sulphasalazine through personal experience.


ACR criteria For Response:
1)at least a 20% improvement in both tender and swollen joint count,and 2) at least a 20% improvement in three of the following five criteria: patient's assessment of disease activity,investigator's assessment of disease activity,pain intensity,functional/disability measure,and acute phase reactants.
San Francisco,CA--11/15/01--Remicade (infliximab) in combination with Arava (leflunomide) has been shown to be safe and effective therapy for RA in patients unable to tolerate metrotrexate (MTX).
This finding comes from data collection on patients with RA from a variety of RA practises including single physicians,group RA practises and academic practises. The results were presented during the 65th Annual Meeting of  the American College of rheumatology (ACR).
Clinical data so far suggest that lefluenomide appears to be an alternative to MTX and sulfasalazine in patients with RA.
Leflunomide is a new DMARD approved for the treatment of active RA to reduce signs and symptoms of the disease and to retard structural damage. Earlier data show that continuing lefluenomide therapy for more than 12 months can result in clinically meaningful improvements in disease-specific measures of physical function.
Infliximab is a chimeric,monoclonal antibody that binds with high affinity and specificity to TNF alpha and neutralize its biological activity. It is well tolerated when administered either as monotherapy or with MTX.
The study aimed to evaluate the safety and tolerability of the infliximab/leflunomie combination. eighty patient were identified as having recently begun concomitant treatment with these agents. Generrally it appeared that patients were begun on lefluenomide at 20 mg daily withe the majority of them starting at 3 mg/kg every eight weeks. The majority of these patients also continued to use predisone at doses ranging from 2.5 to 40 mg/day.
Follow-up efficacy data were available on 33 patients and show that mean swollen and tender joint counts improved in 47% and 56% of patients, respectively. There was a mean functional class improvement of 20%. furthermore,the mean predisone dose was reduced by 33% (baseline,7.6 mg/day,post-infliximab,5.1 mg/day).
Of the 48 patients receiving concomitant infliximab and lefluenomide on whom safety data were available,there was no report of serious adverse events. the most common side effects seen were nausea and vomiting (6%),anaphylactoid reaction (6%),headache (4%),myelodysplasia (unrelated) (4%),alopecia (2%), arthralgia/myalgia (2%),diarrhea (2%),and flu (2%).
Investigators of this study are continuing to monitor these and other patients to better determine the clinical efficacy of infliximab and leflunomide combination therapy.