Pharmacy & Therapeutics - October 2008 - (Page 602)

Medical Management of Parkinson’s Disease In placebo-controlled trials associated with entacapone, the most commonly observed adverse events affecting more than 5% of patients were dyskinesia and hyperkinesia, nausea, urine discoloration, diarrhea, and abdominal pain.44 and symptoms of PD, both as initial therapy alone and as an addition to levodopa later in the disease. The 1-mg formulation is available in 30 countries, including the U.S., Canada, Israel, Mexico, and most European countries. Rasagiline was approved for use as an initial single drug therapy in early PD, and as an addition to levodopa in patients with more advanced disease. Initially, rasagiline was said to be associated with hypertensive crisis if patients also consume tyramine-rich foods (e.g., aged cheeses, fermented bean curd) and beverages (e.g., some red wines, beer, ale) or dietary supplements or amines contained in many cough and cold medications. It was assumed that all nonselective MAO inhibitors were associated with dietary tyramine interactions that would result in hypertensive reactions. To test the safety of rasagiline, challenges with tyramine 50 to 75 mg were performed in 72 rasagiline-treated and 38 placebo-treated PD patients at the end of two double-blind, placebo-controlled trials (TEMPO and PRESTO; see page 604). An abnormal pressor response was prespecified as three consecutive measurements of systolic BP increases of 30 mm Hg or more and bradycardia of 40 beats/minute or less. In one substudy involving 55 patients with early PD receiving rasagiline monotherapy, no patients assigned to rasagiline (1 mg/2 mg; n = 38) or placebo (n = 17) developed systolic BP or heart rate changes indicative of a tyramine reaction.49 In the second substudy involving 55 levodopa-treated patients, 3 of 22 subjects receiving rasagiline 0.5 mg/day and one of 21 subjects receiving placebo developed asymptomatic, self-limiting systolic BP elevations of 30 mm Hg or greater on three measurements. None of the 12 patients receiving rasagiline 1 mg/day experienced significant BP or heart rate changes after ingesting tyramine. These data demonstrate that rasagiline 0.5 to 2 mg daily was not associated with clinically significant tyramine reactions and that it could be used as monotherapy or as an adjunct to levodopa in patients without specific dietary tyramine restrictions.49 As with most other medications for PD, rasagiline has the potential to cause involuntary movements (dyskinesias), hallucinations, and lowered BP. The ADAGIO Study. The Attenuation of Disease Progression with Agilect/Azilect Once Daily (ADAGIO) study, the first of its kind, was prospectively designed to demonstrate whether rasagiline could slow the progression of PD.50 Early treatment with once-daily rasagiline 1-mg tablets provided significant clinical benefits not obtained by those patients when the initiation of rasagiline therapy was delayed by nine months. ADAGIO, a randomized, multicenter, double-blind, placebocontrolled, parallel-group study, was prospectively conducted to examine rasagiline’s potential disease-modifying effects in 1,176 patients with early, untreated PD. Patients from 129 centers in 14 countries were randomly assigned to early treatment (72 weeks of rasagiline therapy 1 or 2 mg once daily) or delayed treatment (36 weeks of placebo, followed by 36 weeks of rasagiline 1 or 2 mg once daily, in the active-treatment phase). The primary analyses of the trial were based on a change in total scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) and included slope superiority of rasagiline over placebo in the placebo-controlled phase, change from baseline Selective Monoamine Oxidase-B Inhibitors (Selegiline and Rasagiline) Two isoenzymes of MAO oxidize monoamines. Although both isoenzymes (MAO-A and MAO-B) are present in the periphery and inactive monoamines of intestinal origin, the isoenzyme MAO-B is the predominant form in the striatum and is responsible for most of the oxidative metabolism of dopamine in the brain. Selegiline. At low-to-moderate doses (10 mg/day or less), selegiline (Eldepryl, Watson) is a selective inhibitor of MAOB, resulting in irreversible inhibition of the enzyme.45 Unlike nonspecific inhibitors of MAO (such as phenelzine, tranylcypromine and isocarboxazid), selegiline does not inhibit peripheral metabolism of catecholamines; therefore, it can be administered safely with levodopa. Selegiline also does not cause the lethal potentiation of catecholamine action when patients taking nonspecific MAO inhibitors ingest directly acting sympathomimetic amines, such as the tyramine found in aged or fermented cheeses and some red wines. Doses higher than 10 mg daily can elicit inhibition of MAO-A and should be avoided. Selegiline has been used for several years as a symptomatic treatment for PD, although its benefit is modest. The basis of the efficacy of selegiline is presumed to be its capacity to slow the metabolism of dopamine in the striatum. Selegiline is generally well tolerated in patients with early or mild PD. In patients with more advanced PD or underlying cognitive impairment, selegiline may accentuate the adverse motor and cognitive effects of levodopa therapy. Metabolites of selegiline include amphetamine and methamphetamine, which may cause anxiety, insomnia, and other adverse symptoms. Adverse effects. Experience with selegiline obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimates of adverse reaction rates. The following reactions that occurred with greater frequency among the 49 patients assigned to receive selegiline, compared with 50 patients assigned to receive placebo, in the only parallelgroup, placebo-controlled trial of patients with PD were nausea, dizziness, lightheadedness, and fainting; abdominal pain; confusion; hallucinations; dry mouth; vivid dreams; dyskinesias; and headache.45 Zydis selegiline. Zelapar (Valeant), an orally disintegrating tablet, includes a patented delivery system.46 Zydis technology allows the tablet to dissolve within seconds in the mouth upon contact with saliva. The active drug undergoes pregastric absorption through the oral mucosa and thus largely bypasses the intestine, obviating the need for first-pass hepatic metabolism. It can be taken once daily, up to 2.5 mg/day. Fewer amphetamine-like metabolites and possibly fewer adverse events are produced with a lower dose, typically 1.25 mg.47 Rasagiline. A related compound, rasagiline (Agilect, Azilect, Teva) is an oxidase type-B (MAO-B) inhibitor that also blocks the breakdown of dopamine,48 but it does not form undesirable metabolites. Rasagiline tablets are indicated for treating signs 602 P&T® • October 2008 • Vol. 33 No. 10

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Pharmacy & Therapeutics - October 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Medical Management of Parkinson’s Disease Why Is Health Care Regulation So Complex? The Next President’s Prescription for Action on Drugs Trends in Managing Multiple Sclerosis Product Profiler: Sancuso®

Pharmacy & Therapeutics - October 2008

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