Drug Topics - March 2009 - (Page 44) Continuing Education RHEUMATOID ARTHRITIS should be stored in the refrigerator but allowed to reach room temperature before injection to minimize pain. Patients may inject doses of etanercept into the front of the mid-thigh, the outer area of the upper arm, or the abdomen (except for within two inches of the navel). Twice-weekly injections of etanercept 10 mg and 25 mg were compared to an average oral methotrexate dose of 19 mg/week for 12 months in a randomized, double-blind, placebo-controlled trial of 632 patients with early RA. At six months, the patients in the 25 mg etanercept group had a much more rapid response to therapy with subsequent higher percentages of patients achieving ACR 20, ACR 50, and ACR 70 improvements in disease activity compared to those receiving methotrexate (P<0.05). A higher percentage of patients treated with 25 mg of etanercept (72 percent) had no evidence of erosion compared to those receiving methotrexate (60 percent, P=0.007). The researchers noted that, consistent with previous studies, the 25 mg dose of etanercept was more effective than the 10 mg dose. Infliximab is a chimeric (i.e., derived from human and murine or mouse components) monoclonal antibody that blocks TNF-alpha from binding to its receptor. It must be given by intravenous infusion over at least two hours at weeks zero, two, and six, and then every eight weeks, and it cannot be administered in the same line as any other medication. The initial dose is 3 mg/kg; however, this may be increased to 10 mg/kg in patients who are unresponsive. Additionally, a shorter dosing frequency (i.e., every four weeks) may be considered; however, there is an increased risk of infection. Infliximab should be given in combination with methotrexate to prevent formation of human antichimeric antibodies, which are believed to be associated with infusion reactions and enhanced clearance of the drug. In a randomized, controlled trial of 428 patients with active RA, the effects of methotrexate were compared to the combination of methotrexate and infliximab (3-10 mg/ kg given every four to eight weeks). Overall, combination therapy with the TNF-alpha antagonist infliximab, at all doses and dosing frequencies, was associated with statistically significant reductions in the signs and symptoms of RA, as evidenced by improvements in ACR 20, ACR 50, and ACR 70 when compared to methotrexate monotherapy. In addition, more patients had progression of joint damage from baseline in the methotrexate-only group compared to all groups treated with both methotrexate and infliximab (P<0.001). Adalimumab is the first fully human recombinant monoclonal antibody studied for treatment of RA. This agent binds to TNF-alpha and blocks it from interaction with the TNF-alpha receptor. Due to its long half-life of 10 to 20 days, adalimumab is administered as a 40-mg subcutaneous injection every other week; with an inadequate response, it may be increased to weekly administration. The injection may be administered in the abdomen or the front of the thigh. In a 24-week randomized, double-blind, placebo-controlled trial of 271 patients with active RA currently receiving methotrexate, adalimumab in doses of 20 mg, 40 mg, and 80 mg, given in injections every other week, were compared to placebo. All patients continued their doses of methotrexate. At 24 weeks, the primary outcome of an ACR 20 response was achieved in 47.8 percent of patients receiving adalimumab 20 mg, 67.2 percent receiving 40 mg, and 65.8 percent receiving 80 mg, compared to 14.5 percent receiving methotrexate plus placebo (P<0.001). An ACR 70 response was achieved in 26.9 percent of patients receiving adalimumab 40 mg and 19.2 percent receiving 80 mg of adalimumab, compared to 4.8 percent of patients receiving methotrexate plus placebo (P<0.001, P=0.020, respectively). These findings suggest that adalimumab is a feasible treatment option to improve RA symptoms. Adverse effects of TNF-alpha antagonists While these agents do not have toxicities that require laboratory monitoring, as do many of the nonbiologic DMARDs, TNF-alpha antagonists are associated with serious side effects that deserve special attention. All these agents have a boxed warning indicating a risk for infection, including activation of latent tuberculosis (TB), invasive fungal infections, sepsis, and other opportunistic infections. The ACR advises these agents not be initiated or resumed in patients with active infections. Infections have been reported to occur in all organ systems and are caused by viral, bacterial, fungal, and protozoal pathogens. Thus, healthcare providers are advised to use caution when prescribing TNF-alpha antagonist therapy for patients with a history of recurrent infections or for those who are prone to infection. Patients should be monitored throughout therapy for the development of any infection. In addition, all patients should be screened for latent TB with a purified protein derivative (PPD) tuberculin skin test or chest x-ray before the initiation of therapy. If a patient tests positive, anti-TB therapy should be instituted before treatment with a TNF-alpha antagonist, but it does not have to be completed. All patients, regardless of PPD findings, should be closely monitored throughout therapy for active TB infection. TNF-alpha antagonist therapy is also associated with a risk for reactivation of the hepatitis B virus (HBV), especially in patients who are chronic carriers of the virus. Recent recommendations from the ACR state that biologic agents are contraindicated in chronic hepatitis B and C. In an effort to minimize the risk of infection, patients should receive age-appropriate vaccinations, according to the recommendations of the Centers for Disease Control and Prevention (CDC). The ACR recommends the hepatitis B vaccine series be completed before the initiation of therapy in patients at risk of the condition. It should be noted that patients receiving TNF-alpha antagonist therapy may concomitantly receive vaccinations, with the exception of live immunizations. W W W.D R U GTO P I C S .C O M 44 DRUG TOPICS March 2009 http://WWW.DRUGTOPICS.COM
For optimal viewing of this digital publication, please enable JavaScript and then refresh the page. If you would like to try to load the digital publication without using Flash Player detection, please click here.