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    <recommendedItem id="20100101_19_252"
                     title="MS Walking Drug Gets FDA Nod"
                     score="0.001"
                     href="http://www.medpagetoday.com/Neurology/MultipleSclerosis/tb/18112?impressionId=1265792173892"
                     
      &lt;p&gt;WASHINGTON  --  The FDA has approved the first drug that improves walking in patients with multiple sclerosis, the tablet dalfampridine (Ampyra).&lt;/p&gt;
&lt;p&gt;The approval was based on clinical trial data that found patients could walk better with the drug than those treated with placebo.&lt;/p&gt;
&lt;p&gt;Patients who exceed recommended dosage, 10 mg twice a day, or who have moderate to severe kidney disease, may experience seizures the FDA said.&lt;/p&gt;
&lt;p&gt;Adverse events reported during clinical trials include urinary tract infection, insomnia, dizziness, headache, nausea, weakness, back pain, balance disorder, swelling of the nose or throat, constipation, diarrhea, indigestion, throat pain, and burning, tingling, or itching skin.&lt;/p&gt;
&lt;p&gt;The drug is manufactured by Elan of Dublin, Ireland and distributed by Acorda Therapeutics Inc. of Hawthone, NY.&lt;/p&gt;

    </recommendedItem>
    <recommendedItem id="20100101_19_219"
                     title="Oral MS Drugs Effective in Phase III Trials (CME/CE)"
                     score="-0.001"
                     href="http://www.medpagetoday.com/Neurology/MultipleSclerosis/tb/18069?impressionId=1265792173892"
                     
      Two oral drugs under investigation for multiple sclerosis reduced relapse rates and delayed onset of disability in separate trials reported online this week in the &lt;em&gt;New England Journal of Medicine&lt;/em&gt;.&lt;br&gt;
&lt;br&gt;Fingolimod, a novel agent also known as FTY-720, was more effective than both placebo and the standard of care for MS, interferon-beta-1a (Avonex), in two independent trials.&lt;br&gt;
&lt;br&gt;The studies, called FREEDOMS and TRANSFORMS, were reported by Ludwig Kappos, MD, of the University of Basel in Switzerland, and colleagues, and by Jeffrey Cohen, MD, of the Cleveland Clinic, and other researchers, respectively. Some researchers worked on both studies.&lt;br&gt;
&lt;br&gt;Cladribine, an oral drug already marketed for hematologic cancers under the trade name Leustatin, was clearly more effective than placebo in a third trial called CLARITY reported by Gavin Giovannoni, MB, BCh, PhD, of Queen Mary University in London, and colleagues.&lt;p&gt;&lt;/p&gt;
&lt;p&gt;&quot;The studies in this issue of the [&lt;em&gt;NEJM&lt;/em&gt;] provide a new horizon for patients with relapsing-remitting multiple sclerosis and a welcome increase in the range of treatment options,&quot; William M. Carroll, MBBS, MD, of Sir Charles Gairdner Hospital in Perth, Australia, wrote in an accompanying editorial.&lt;/p&gt;
&lt;p&gt;Oral drugs for MS would not only improve patient acceptance of treatment, but also &quot;further support a change in treatment approach to directly prevent immune-mediated injury,&quot; Carroll wrote.&lt;/p&gt;
&lt;p&gt;Existing disease-modifying therapies  --  interferon, glatiramer acetate (Copaxone), and natalizumab (Tysabri)  --  are all injectable drugs.&lt;/p&gt;
&lt;p&gt;&quot;Patients hate the shots and have been waiting 17 years for an oral drug,&quot; John Corboy, MD, a neurologist of the University of Colorado in Denver who was not involved in the study, told &lt;em&gt;MedPage Today&lt;/em&gt; and ABC news when contacted for comment.&quot;&lt;/p&gt;
&lt;p&gt;The National Multiple Sclerosis Society also expressed delight at the reports.&lt;/p&gt;
&lt;p&gt;&quot;The published results ... are wonderful news for people with MS,&quot; wrote John Richert, MD, the group&apos;s executive vice president of research and clinical programs, in a report to local chapters.&lt;/p&gt;
&lt;p&gt;&quot;Having oral therapies in the MS pipeline is real progress, and it should increase the number of people who choose to begin therapy earlier and who stay on therapy, which our experts say is the best way to combat future disease activity.&quot;&lt;/p&gt;
&lt;p&gt;Most of the studies&apos; key results had been presented last spring at the American Academy of Neurology&apos;s annual meeting. (See &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/AAN/14013&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/AAN/14013&quot; target=&quot;_blank&quot;&gt;AAN: Oral MS Drug with Novel Mechanism Beats Interferon-Beta1a&lt;/a&gt; and &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/AAN/13996&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/AAN/13996&quot; target=&quot;_blank&quot;&gt;AAN: Cancer Drug Shows Promise as Oral MS Therapy&lt;/a&gt;)&lt;/p&gt;
&lt;p&gt;But the journal reports included additional details, especially on adverse effects, as well as peer review.&lt;/p&gt;
&lt;p&gt;The two drugs target different aspects of T-cell biology. These cells are key players in the autoimmune attack on the myelin sheaths surrounding nerve fibers, which, in turn, causes the slow loss of peripheral nerve function.&lt;/p&gt;
&lt;p&gt;Cladribine induces active T cells to undergo apoptosis, which explains its utility in hairy cell leukemia, lymphoma, and certain other hematologic malignancies.&lt;/p&gt;
&lt;p&gt;Fingolimod has a different mechanism. It causes the sphingosine-1-phosphatase receptor, which normally sits on the surface of T and B cells, to withdraw into the cell interior.&lt;/p&gt;
&lt;p&gt;The effect is to leave the cells unresponsive to signals that instruct them to exit lymph nodes and head toward sites of inflammation. Keeping T cells bottled up in lymph nodes prevents them from attacking nerves in MS.&lt;/p&gt;
&lt;p&gt;The two placebo-controlled studies of fingolimod and cladribine both showed that relapse rates and disease progression were reduced.&lt;/p&gt;
&lt;p&gt;In the 1,272-patient fingolimod study, annualized relapse rates were 0.40 in the placebo group, 0.18 with 0.5 mg of the drug daily, and 0.16 with a 1.25-mg dose over a two-year period (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001 for both doses versus placebo).&lt;/p&gt;
&lt;p&gt;The hazard ratios for disability progression relative to placebo at the two-year evaluation were 0.70 and 0.68 for the low and high doses of fingolimod, respectively (&lt;em&gt;P&lt;/em&gt;=0.02 for both comparisons).&lt;/p&gt;
&lt;p&gt;Cladribine, a more toxic drug, was given in short bursts of treatment over the 96-week study.&lt;/p&gt;
&lt;p&gt;Two dosing regimens were tested, delivering cumulative totals of 3.5 or 5.25 mg/kg, along with placebo. Patients took one or two 10-mg tablets daily for the first four or five days of either two or four monthly periods starting at week zero, followed by two additional monthly courses starting at week 48.&lt;/p&gt;
&lt;p&gt;Results for the primary outcome of annualized relapse rate were 0.33 for placebo, 0.14 for the low cladribine dose, and 0.15 for the higher dose (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001 for both doses versus placebo).&lt;/p&gt;
&lt;p&gt;Hazard ratios for disability progression at week 96 for cladribine versus placebo were 0.67 with the low dose (&lt;em&gt;P&lt;/em&gt;=0.02) and 0.69 with the high dose (&lt;em&gt;P&lt;/em&gt;=0.03).&lt;/p&gt;
&lt;p&gt;Perhaps more striking were the findings in the other fingolimod trial, in which the drug was tested head-to-head against the current standard of care.&lt;/p&gt;
&lt;p&gt;The same two doses of fingolimod were used. Patients assigned to interferon received the drug in weekly intramuscular injections of 30 &amp;#956;g.&lt;/p&gt;
&lt;p&gt;The annualized relapse rate with interferon was 0.33, whereas it was significantly lower with fingolimod: 0.16 with the 0.5-mg dose and 0.20 for the 1.25-mg dose (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001 versus interferon for both).&lt;/p&gt;
&lt;p&gt;But the risk of disease progression did not differ significantly between treatment groups.&lt;/p&gt;
&lt;p&gt;Moreover, two patients receiving the higher fingolimod dose died of herpes zoster infections, disseminated in one case and causing encephalopathy in the other. Increased rates of herpes zoster infections were also seen in the other fingolimod trial and with cladribine. In the cladribine trial, lymphocytopenia was seen in about 14% of patients taking the drug, compared with less than 2% of the placebo group.&lt;/p&gt;
&lt;p&gt;Fingolimod also seemed to be associated with cardiac rhythm disturbances, including bradycardia (2.7% with fingolimod, 0.7% placebo) and atrioventricular conduction block, though the latter was mostly confined to the higher drug dose (five cases versus two each for the low dose and placebo).&lt;/p&gt;
&lt;p&gt;Leukopenia and lymphocytopenia were also seen with fingolimod in the placebo-controlled study, though at lower rates than with cladribine  --  about 3% to 6%, compared with less than 1% in the control group.&lt;/p&gt;
&lt;p&gt;Lymphocytopenia was less frequent overall in the interferon-controlled study, seen in 0.2% of the low-dose group and 1.0% of the high-dose group, compared with no cases in the interferon-treated patients.&lt;/p&gt;
&lt;p&gt;Hillel Panitch, MD, of the University of Vermont in Burlington, Vt., told &lt;em&gt;MedPage Today&lt;/em&gt; and ABC News that the findings were actually reassuring.&lt;/p&gt;
&lt;p&gt;&quot;The adverse events including herpes infections, malignancies, and bradycardia are much less of an issue than expected for these drugs, and with the proper oversight should not delay their use,&quot; Panitch wrote in an e-mail.&lt;/p&gt;
&lt;p&gt;Richert of the National MS Society also indicated that the reported adverse effects were not especially worrisome.&lt;/p&gt;
&lt;p&gt;&quot;Herpes infections are likely to occur with many different immune-modulating therapies, including some already approved for MS,&quot; he wrote in an e-mail to &lt;em&gt;MedPage Today&lt;/em&gt; and ABC News, adding that these usually respond to treatment.&lt;/p&gt;
&lt;p&gt;&quot;They should be something patients and doctors keep a lookout for,&quot; he wrote.&lt;/p&gt;
&lt;p&gt;Similarly, he said, the cardiac effects of fingolimod appeared transient and asymptomatic. But he suggested it may be necessary to avoid combining fingolimod with anti-arrhythmic drugs in at least some patients.&lt;/p&gt;
&lt;p&gt;But Colorado&apos;s Corboy was more concerned by the side effect profile. He pointed to the issue of progressive multifocal leukoencephalopathy (PML) seen with natalizumab (Tysabri) in MS patients, which kept the drug off the market for a time.&lt;/p&gt;
&lt;p&gt;&quot;The price you may have to pay for greater efficacy is greater risk,&quot; he wrote in an e-mail. He said some in the MS community would avoid the new oral drugs because of the risks, should they be approved.&lt;/p&gt;
&lt;p&gt;The manufacturers of both drugs have filed for FDA approval. Merck Serono was first to file, for cladribine, but the FDA informed the company in late November that it considered the application incomplete and refused to accept it.&lt;/p&gt;
&lt;p&gt;Company officials promised at the time that they would submit additional information requested by the agency. They did not respond to requests for an update.&lt;/p&gt;
&lt;p&gt;Novartis, maker of fingolimod, announced in mid-December that its FDA filing was imminent and a company representative confirmed that it had been submitted.&lt;/p&gt;
&lt;p&gt;Although the FDA has given both drugs fast-track status, the possibility that the agency will want an advisory committee review may push their final approvals into 2011.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The two fingolimod studies were funded by Novartis. The study of cladribine was funded by Merck Serono.&lt;/p&gt;&lt;p&gt;Authors of the placebo-controlled study of fingolimod reported relationships other than research funding with Novartis and many other firms including Accorda, Actelion, Allergan, Allozyne, Bayer Schering, Biogen Idec, Biogen-Dompe, Boehringer Ingelheim, Genmab, GlaxoSmithKline, Medicinova, Merck Serono, Roche, sanofi aventis, Santhera, Teva, UCB, Wyeth, Helvea, and Mediservice. Several co-authors were employees of Novartis.&lt;/p&gt;&lt;p&gt;Authors of the study of fingolimod versus interferon reported relationships other than research funding with Novartis and other firms including Biogen Idec, EMD Serono, Teva, sanofi aventis, Waterfront Media, Bayer Schering, AstraZeneca, Genentech, Lundbeck, Talecris, Roche, Wyeth, Medicinova, Biogen-Dompe, Medtronic, Accorda, Actelion, Allergan, Allozyne, Boehringer Ingelheim, Genmab, GlaxoSmithKline, Santhera, and UCB. Several co-authors were employees of Novartis.&lt;/p&gt;&lt;p&gt;Authors of the cladribine study reported relationships other than research funding with Merck Serono or EMD Serono and with other firms including Bayer Schering, Biogen Idec, Novartis, Teva-Aventis, UCB, Vertex, sanofi-aventis, Biogen-Dompe, Pfizer, and Genentech. Several co-authors were employees of Merck Serono.&lt;/p&gt;&lt;p&gt;Carroll reported relationships other than research funding with Biogen Idec, Bayer Schering, Merck Serono, and sanofi-a ventis. He also reported agreeing to serve on a Novartis advisory board but did not attend meetings and received no compensation.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;&lt;p&gt;&lt;em&gt;This article was developed in collaboration with ABC News. &lt;/em&gt;&lt;img src=&quot;http://www.medpagetoday.com/upload/2009/10/1/14357_1.jpg&quot; mce_src=&quot;http://www.medpagetoday.com/upload/2009/10/1/14357_1.jpg&quot; alt=&quot;&quot;&gt;&lt;/p&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_184"
                     title="Higher Opioid Dose Linked to Greater Overdose Risk (CME/CE)"
                     score="-0.003"
                     href="http://www.medpagetoday.com/Psychiatry/PainManagement/tb/18025?impressionId=1265792173892"
                     
      Higher prescribed doses of opioids for chronic pain significantly increased the risk of overdose, data from a large retrospective study showed.&lt;br&gt;
&lt;br&gt;Patients prescribed opioid doses of 100 mg/d or more had almost nine times the overdose risk of patients prescribed daily doses of 1 to 20 mg.&lt;br&gt;
&lt;br&gt;Patients taking 50 to 99 mg/d had almost four times the risk of low-dose patients, investigators reported in the Jan. 19 issue of &lt;em&gt;Annals of Internal Medicine&lt;/em&gt;.&lt;br&gt;
&lt;br&gt;&quot;This study was the first to look at opioid overdose, nonfatal as well as fatal, among people who we know were getting opioids for chronic pain from a physician,&quot; Michael Von Korff, ScD, of the Group Health Research Institute in Seattle, said in an interview.&lt;br&gt;
&lt;br&gt;Although prescribed opioids had a low overall risk of overdose, patients who receive higher doses require careful monitoring. The findings have considerable clinical relevance, given evidence that higher opioid doses do not lead to better pain control, he added.&lt;p&gt;&lt;/p&gt;
&lt;p&gt;Increasingly, patients with chronic noncancer pain receive long-term opioid therapy, prescribed by healthcare providers. Previous studies of opioid overdose had focused on drug diversion and abuse, said Von Korff. The overdose risk associated with medically prescribed opioids had not been examined.&lt;/p&gt;
&lt;p&gt;To explore this risk, Von Korff and colleagues analyzed opioid prescription data from a large healthcare system. They identified patients who initiated opioid therapy for chronic noncancer pain from 1997 through 2005, who filled three or more prescriptions for opioids within the first 90 days of the pain episode, and who had no opioid prescriptions in the previous six months.&lt;/p&gt;
&lt;p&gt;The analysis identified 9,940 patients for inclusion. Follow-up from the initial 90-day prescription period averaged 42 months.&lt;/p&gt;
&lt;p&gt;The authors compared the average daily opioid dose over the prior 90 days with reported fatal and nonfatal overdoses. The analysis revealed 51 opioid-related overdoses, six of which were fatal.&lt;/p&gt;
&lt;p&gt;Patients prescribed daily opioid doses of 1 to 20 mg had an annual overdose rate of 0.2%. Patients taking 50 to 99 mg/d had an annual overdose rate of 0.7%, roughly 3.7 times greater than patients taking lower doses (95% CI 1.5 to 9.5). Daily opioid doses of 100 mg or greater were associated with an annual overdose risk of 1.8%, an 8.9-fold increase compared with patients taking 1 to 20 mg/d (95% CI 4.0 to 19.7).&lt;/p&gt;
&lt;p&gt;Patients who had not recently received opioids had less than one-third the overdose risk of patients who received the lowest daily doses of opioid drugs (HR 0.31).&lt;/p&gt;
&lt;p&gt;&quot;Observational studies suggest that many patients receiving opioids for chronic noncancer pain often continue to experience appreciable pain and activity limitations,&quot; the authors wrote.&lt;/p&gt;
&lt;p&gt;&quot;Because of uncertainties regarding effectiveness and risks, long-term opioid therapy should be prescribed with awareness of risk and close patient monitoring, which may not be happening consistently at present,&quot; they added.&lt;/p&gt;
&lt;p&gt;The findings make a case for user-friendly, real-time, prescription-drug monitoring programs that allow physicians to track all opioid prescriptions for a patient, A. Thomas McLellan, PhD, of the White House Office of National Drug Control Policy, wrote in an accompanying editorial. Promising systems have been designed, but none is satisfactory at this point.&lt;/p&gt;
&lt;p&gt;&quot;Frankly, we do not know how to increase clinical diligence without additional work, time, or money, although technology can facilitate some of these suggested practice changes,&quot; McLellan wrote. &quot;The threat to patient safety is too great to allow current pain management and opioid-prescribing practices to remain as they are.&quot;&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The study was funded by the National Institutes of Health.&lt;/p&gt;&lt;p&gt;Von Korff disclosed a relationship with Johnson &amp;amp; Johnson. Co-author Mark D. Sullivan disclosed relationships with Eli Lilly, ABT Bio-Pharma, Wyeth, Aetna, Johnson &amp;amp; Johnson, and Ortho-McNeil. Co-author Kathleen W. Saunders disclosed a relationship with Merck &amp;amp; Co.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20090101_1_349"
                     title="Imuran Stops New Brain Lesions in MS Patients"
                     score="-0.006"
                     href="