"We believe the new physical function indication will reinforce for physicians the clinically meaningful benefits of Arava treatment," said Francois Nader, M.D., Senior Vice President, Medical Affairs, Aventis North America. RA can have devastating effects on a person's ability to carry out daily activities like buttoning a shirt, opening a door and even walking. For people with rheumatoid arthritis, demonstrating an improvement in the ability to perform daily activities is an important indicator of treatment success."  Arava® (leflunomide), an oral disease-modifying antirheumatic drug (DMARD), is a first-line therapy to reduce signs and symptoms, inhibit structural damage as evidenced by X-ray erosions and joint space narrowing, and improve physical function in active rheumatoid arthritis in adults. RA is one of the most common forms of arthritis, a potentially crippling autoimmune disease that affects more than two million Americans, 70 percent of whom are women.

 

The FDA also approved revisions and additions to the Arava safety information, which include revised liver function and hematology monitoring recommendations. When used as directed, Arava is a safe and effective drug among the very limited therapies available to treat RA..  The FDA approval was based on data from three long-term, Phase III pivotal trials. Improvement in physical function was assessed through a series of validated and widely accepted tools measuring patients ability to conduct daily activities (e.g., walking, eating, dressing and washing), their function in daily life, and their sense of well-being.  A marked, clinically meaningful improvement in physical function was demonstrated in the same three studies that previously had demonstrated improvement in signs and symptoms of rheumatoid arthritis and retardation of structural damage evidenced by X-ray erosions and joint space narrowing.  The data showed that efficacy was sustained for two years in patients continuing treatment in the three multinational, multicenter, double-blind, parallel group studies.

 

Safety Information Pregnancy Contraindication: Pregnancy must be excluded before the start of treatment with Arava. Arava is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Before starting treatment with Arava, patients must be fully counseled on the potential for serious risks to the fetus.  Pregnancy must be avoided during Arava treatment or prior to the completion of a drug elimination procedure with cholestyramine after Arava treatment. It is recommended that all women of childbearing 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 woman.  If this drug is used during pregnancy or if the patient becomes pregnant when taking this drug, the patient should be apprised of potential hazard to the fetus. In addition, men wishing to father a child should consider discontinuing use of Arava and taking cholestyramine eight grams three times daily for 11 days to minimize any possible risk to the fetus.

 

Hepatic: Rare cases of severe liver injury, including cases with fatal outcome, have been reported during treatment with leflunomide. Most cases of severe liver injury occur within 6 months of therapy and in a setting of multiple risk factors for hepatotoxicity (liver disease, other hepatotoxins).  Arava is not recommended in patients with significant hepatic impairment or evidence of infection with hepatitis B or C viruses given the risk of increased hepatotoxicity.  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 reductions or discontinuation of treatment, marked elevations (greater than three times the upper limit of normal) occurred as well. Therefore, at minimum, ALT levels must be measured at the beginning of therapy (baseline) and monitored initially at monthly intervals during the first six months, then, if stable, every 6 to 8 weeks thereafter.

 

Arava is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. Rarely, severe infections including sepsis, which may be fatal, have been reported. Rare cases of pancytopenia, agranulocytosis, thrombocytopenia, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported in post-marketing experience.  At minimum, patients taking Arava should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6 to 8 weeks thereafter.  Adverse reactions associated with the use of Arava in clinical trials include diarrhea, elevated liver enzymes (ALT and AST), alopecia, and rash.

 

Two-Year Treatment of Active Rheumatoid Arthritis (RA) with Leflunomide (Lef) Compared with Placebo (Pl) or Methotrexate (MTX):   Patients who completed the 1-year North American Leflunomide Study were continued in the same treatment groups for an additional 12 months to assess the durability of the treatment effect.  Of the 482 patients in the 1-year study 235 patients (Lef 98/182, Pl 36/118, MTX 101/182) continued into year 2 (2-year cohort).  This study looks at treatment response at 12 and 24 months for the 2-year cohort.  The Lef group had a 77% ACR 20 and a 57% ACR 50 response at 12 months and a 79% ACR 20 and 56% ACR 50 response at 24 months. The MTX group had a 60% ACR 20 and 32% ACR 50 at 12 months and a 67% ACR 20 and a 43% ACR 50 at 24 months. Of the patients entering year 2, 85% of the Lef group and 79% of the MTX group completed trial.

 

It is clinically relevant to know if patients will continue to respond to a medication.  This data supports the concept that both methotrexate and leflunomide are well tolerated and effective over 24 months.   It is interesting that the of the ~50% of patients in the MTX and Lef group that entered into the second year, only ~75% met ACR 20 response at 12 months.  Thus, the "durability" of the response might represent some patients worsening and some improving during the second year of the study. A comparison of Lef and MTX was done by the manufacturer,but comparison trials may not disclose the full details.  For example,when patients do not respond to MTX oral at (e.g.,) 19 mg oral,it is recommended that patients be given 25 mg subcutaneous injection before determining MTX is efficious or not. In the trials, a lower dose of methotrexate was given to the patients for comparison purposes with LEF (not 25 mg). LEF is a good alternative for patients that cannot tolerate MTX,but most patients will find methotrexate to be more efficacious,overall. It depends on the individual patient response.

 

Leflunomide was approved by the FDA and became available as a new DMARD agent for rheumatoid arthritis in October 1998. In clinical trials, its efficacy was similar to that of methotrexate and will represent a viable alternative to patients who have failed or were intolerant to methotrexate. The most recent clinical trial data were presented at the 1999 American College of Rheumatology meetings.  The mechanism of action is not fully understood but may be related to its ability to inhibit tyrosine kinase activity and inhibit de novo pyrimidine biosynthesis through the inhibition of the enzyme dihydroorotate dehydrogenase. In vitro studies have demonstrated the inhibition of mitogen and IL-2 stimulated T cells.  The half-life of the active metabolite of leflunomide is 15 days. Leflunomide and its active metabolite are extensively protein bound and undergo further metabolism before excretion in the urine and in the feces (direct biliary excretion). To achieve steady state, it is recommended to start with a loading dose of 100mg daily for three days and then 20 mg daily. The dose may be reduced to 10mg daily if not tolerated or in patients having difficulty metabolizing or excreting the drug.

 

Usual time to maximal effect: Onset of action 4-8 weeks, with some evidence that onset of action may be sooner than methotrexate. Additional data have supported that leflunomide is well tolerated and effective over 24 months. In clinical trials, leflunomide has been associated with a 2-4% incidence of liver transaminase elevations 3 times the upper limit of normal that reversed with cessation of the drug. Routine monitoring should include complete blood count and hepatic panel every 2 weeks for the first month and then on a monthly basis. Other toxicitys have included mild diarrhea, GI upset and alopecia of insufficient severity to cause cessation of the drug. Some rheumatologists have tried MTX and LEF in combination therapy,when MTX or LEF alone did not give the desired results. Close monitoring is essential.