Pharmacy & Therapeutics - October 2008 - (Page 600)

Medical Management of Parkinson’s Disease tion and release, thereby diminishing oxidative stress. It takes several weeks to achieve clinically significant maintenance doses of ropinirole and pramipexole.12 These agents generally evoke less disturbance of the GI tract than bromocriptine, but they can elicit nausea and somnolence. The somnolence may be severe, and sudden attacks of irresistible sleepiness leading to motor vehicle accidents have been reported.33 The introduction of pramipexole and ropinirole has led to a substantial change in the clinical use of dopamine agonists in PD. Because these selective agonists are well tolerated, they are used increasingly as an initial treatment for PD rather than as adjuncts to levodopa. This change has been driven by two factors: (1) dopamine agonists have a longer duration of action and may be less likely than levodopa to evoke on/off effects and dyskinesias, and (2) levodopa may contribute to oxidative stress, thereby accelerating the loss of dopaminergic neurons. In two large controlled clinical trials comparing levodopa with pramipexole or ropinirole as an initial therapy for PD, a reduced rate of motor fluctuation in patients receiving these agonists was evident.34,35 However, this benefit was accompanied by an increased rate of adverse events in both studies, especially somnolence and hallucinations.34,35 Many specialists now favor dopamine agonists as an initial treatment as monotherapy in patients with early PD and in younger patients to reduce motor fluctuations and dyskinesia. Levodopa should be used as the initial treatment in older patients, who might be more vulnerable to the adverse cognitive effects of the dopamine agonists. Adverse effects (ropinirole). In early PD trials, the most commonly observed adverse events associated with ropinirole affecting more than 5% of patients were, in order of decreasing incidence, as follows: nausea, dizziness, somnolence, headache, vomiting, syncope, fatigue, dyspepsia, viral infection, constipation, pain, increased sweating, asthenia, dependent or leg edema, orthostatic symptoms, abdominal pain, pharyngitis, confusion, hallucinations, urinary tract infections, and abnormal vision.36 In advanced PD trials, the most commonly observed adverse events associated with ropinirole as an adjunct to levodopa in more than 5% of patients were, in order of decreasing incidence, as follows: dyskinesias, nausea, dizziness, aggravated parkinsonism, somnolence, headache, insomnia, injury, hallucinations, falls, abdominal pain, upper respiratory infection, confusion, increased sweating, vomiting, viral infection, an elevated drug level, arthralgia, tremor, anxiety, urinary tract infection, constipation, dry mouth, pain, hypokinesia, and paresthesia. 36 Adverse effects (pramipexole): In placebo-controlled trials of early PD, the most commonly observed adverse events that were more numerous with pramipexole in more than 5% of patients were nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations. The adverse events most commonly causing discontinuation of treatment were related to the nervous system (hallucinations, dizziness, somnolence, extrapyramidal syndrome, headache and confusion), and gastrointestinal symptoms (e.g., nausea).37 In placebo-controlled trials of advanced PD, the most commonly observed adverse events that were more frequent with pramipexole and concomitant levodopa in more than 5% of patients were postural hypotension, dyskinesia, extrapyramidal syndrome, insomnia, dizziness, hallucinations, accidental injury, dream abnormalities, confusion, constipation, asthenia, somnolence, dystonia, gait abnormality, hypertonia, dr y mouth, amnesia, and urinary frequency.37 An Injectable Medication Apomorphine (Apokyn). Motor fluctuations are distressing for patients with advanced PD. Subcutaneous apomorphine injections can be a valuable adjunctive therapy.38 Apomorphine HCl (Mylan/Bertek) is a fast-acting dopaminergic agonist after it is injected subcutaneously. It has high affinity for D4 receptors; moderate affinity for D2, D3, D5, and adrenergic α1D, α2B, and α2C receptors; and low affinity for D1 receptors. It is approved as a rescue therapy for the acute intermittent treatment of “off” episodes in patients with a fluctuating response to dopaminergic therapy. Apomorphine can be injected when muscles become frozen and the patient cannot rise from a chair or perform daily activities. Treatment with as-needed injections may make it possible to decrease the doses of other anti-PD medications. This may reduce the risk of side effects, such as twitching and other uncontrolled movements. Apomorphine can be taken with an antinausea drug to prevent side effects of severe nausea and vomiting. Apomorphine is available only from selected pharmacy distribution centers, and an office or clinic-based test dose with monitoring for blood pressure (BP) and tolerability is required. Table 2 lists some dopamine agonists and the initial dosing schedule. Adverse effects. In addition to all the other potential adverse effects associated with dopamine receptor agonists, apomorphine is highly emetogenic and can cause QT prolongation, injection-site reactions, hallucinations, dyskinesia, and abnormal behavior.16 It is recommended that trimethobenzamide (Tigan, King), an oral antinauseant and antiemetic agent, be started at a dose of 300 mg three times daily three days before the initial apomorphine dose and continued at least during the first two months of therapy. The use of apomorphine with antiemetic drugs of the serotonin (5-HT3) antagonist class is contraindicated because of reports of profound hypotension and loss of consciousness when ondansetron (Zofran, GlaxoSmithKline) and apomorphine are taken together.39 A Transdermal Patch Rotigotine Transdermal System (Neupro). The Neupro patch (UCB/Schwarz) was approved in 2007 to treat the signs and symptoms of early-stage idiopathic PD.40 Neupro is the first once-daily, non-ergolinic, dopamine agonist patch to provide stable, continuous drug delivery 24 hours per day.16 Therapeutic benefits are independent of age, sex, and race. Available in three strengths (2 mg every 24 hours, 4 mg every 24 hours, and 6 mg every 24 hours), the patch is designed to mimic the action of dopamine. Multinational clinical studies in patients with early-stage PD were completed at the end of 2003. In 15 clinical trials, more than 1,500 patients used the patch. Rotigotine exhibits a low potential of pharmaco- 600 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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