Pharmacy & Therapeutics - October 2008 - (Page 603)

Medical Management of Parkinson’s Disease administration of selegiline and serotonergic drugs with caution, and selegiline and SSRIs have been used in combination in PD patients without adverse reactions. Adverse effects. The most commonly obser ved Medication Available Doses Initial Dosing adverse events affecting 5% or more patients who were Selegiline 5 mg 5 mg twice daily receiving rasagiline as monotherapy and who were par(Eldepryl, Carbex) (maximum dose) ticipating in the double-blind, placebo-controlled trial occurred at least 1.5 times as often as in the placebo Selegiline HCl orally 1.25 mg 1.25 mg once daily group. These events included flu syndrome, arthraldisintegrating tablets 2.5 mg gia, depression, dyspepsia, and falls. (Zelapar) Treatment-emergent adverse events occurred in 2% Rasagiline 0.5 mg 0.5 mg once daily or more of patients who received rasagiline as mono(Agilect) 1 mg therapy and who were participating in a double-blind, placebo-controlled trial. These events occurred more frequently than in the placebo group and included headache, to week 72, and non-inferiority of early-start versus delayedarthralgia, dyspepsia, depression, falling down, flu syndrome, start slopes during weeks 48 to 72 of the active phase. The conjunctivitis, fever, gastroenteritis, rhinitis, arthritis, ecchyUPDRS is the most commonly used rating tool to assess dismosis, malaise, and neck pain.51 ease status. Patients who received rasagiline 1-mg tablets once daily upon entry into the trial experienced a significant improvement Anticholinergic Agents (Muscarinic Receptor compared with patients receiving the drug nine months later. Antagonists: Artane, Cogentin, Benadryl) The 1-mg dose met all three primary endpoints, as well as the Before the discovery of levodopa, antagonists of muscarinic secondary endpoint, with statistical significance.50 acetylcholine receptors were widely used to treat PD, although it is not clear why such anticholinergic agents were used. The primary analysis included three hierarchical endpoints They probably act within the neostriatum through the recepbased on total-UPDRS scores: tors that normally mediate the response to intrinsic cholinergic innervation of this structure, which arises primarily from • superiority of slopes in weeks 12 to 36 (–0.05; P = 0.013, cholinergic striatal interneurons. 95% confidence interval [CI], –0.08, –0.01) Several drugs with anticholinergic properties are currently • a change from baseline to week 72 (–1.7 units; P = 0.025, used in the treatment of PD. These are trihexyphenidyl (Ar95% [CI], –3.15, –0.21) tane, Wyeth), benztropine mesylate (Cogentin, Merck) and • non-inferiority of slopes (0.15 margin) in weeks 48 to 72 diphenhydramine (Benadryl, Pfizer). All have modest anti(0.0; 90% CI, –0.04, 0.04). parkinsonian activity that is useful in the treatment of early PD or as an adjunct to dopaminergic therapy. Anticholinergics The safety profile of rasagiline seen in ADAGIO was simiare better tolerated in younger patients and are useful in this lar to that observed in previous experience with this agent. All subgroup for tremor control. three primary endpoints were met with statistical significance Table 5 lists the muscarinic blocking agents and their initial and reinforce the quality of the data, supporting the potential for rasagiline to slow disease progression. Delaying disease dosing schedule. progression is the most important unmet need in the manageAdverse effects. The adverse events associated with the ment of PD.50 muscarinic receptor antagonists result from their anticholinergic properties. Most problematic are sedation and mental Table 4 depicts the MAO-B inhibitors and their initial dosconfusion. These drugs can also produce constipation, uriing schedule. nary retention, and blurred vision.52 Potential adverse effects and contraindications. Several drugs are contraindicated with rasagiline because of the risk of serotonin syndrome.51 Although there is little evidence to Amantadine (Symmetrel) suggest the combination is actually dangerous, the potential Amantadine (Symmetrel, Endo) is an antiviral agent used to adverse outcomes are so severe that the contraindication desprevent and treat influenza A, but it also has antiparkinsonian ignation was thought to be appropriate. activity. It appears to alter dopamine release in the striatum and Serotonergic antidepressants such as selective serotonin has anticholinergic properties. Its most significant action may be its ability to block N-methyl D-aspartate (NMDA) glutareuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SSNRIs), and tricyclic antimate receptors.53 depressants (TCAs) are not listed in the rasagiline product inInterestingly, the effects of amantadine in PD are modest. formation as contraindicated, but the concomitant use of It is used as initial therapy for mild PD, and it may be helpful rasagiline with these agents is not recommended.51 Hundreds as an adjunct in patients taking levodopa with dose-related fluctuations and dyskinesias. The antidyskinetic properties of of patients in clinical trials of rasagiline received concomitant amantadine have been attributed to actions at NMDA recepSSRIs or TCAs, apparently without adverse interactions, but tors, although the closely related NMDA receptor antagonist the FDA correctly noted that this does not rule out the possimemantine (Namenda, Forest) does not seem to have this bility of a rare, serious adverse outcome from these combinaeffect. tions.51 However, physicians are prescribing the concomitant Table 4 Monoamine Oxidase-B (MAO-B)–Inhibitors for the Treatment of Parkinson’s Disease Vol. 33 No. 10 • October 2008 • P&T® 603

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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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