Movement Disorders Spotlight

In Open-Label Extension Studies, Rotigotine Transdermal Patch Demonstrates Safety
and Efficacy in Treatment of Parkinson’s Disease

Parkinson’s disease (PD) is a common neurodegenerative disease that is difficult to treat because the clinical signs and symptoms change as the disease progresses. Levodopa has been considered the mainstay treatment for PD for decades; however, long-term therapy with levodopa has been associated with adverse effects, including motor response fluctuations and dyskinesias, which have been attributed to the drug’s short half-life. Nonergolinic dopamine agonists have shown significant treatment benefits in addition to good tolerability in both early and advanced PD, but only a handful of open-label studies have evaluated their safety and efficacy. Approved by the FDA in 2007, rotigotine is the first once-daily nonergolinic dopamine agonist patch that is indicated to treat symptoms of early and advanced PD as well as moderate to severe idiopathic restless legs syndrome. It is approved in 2-mg, 4-mg, or 6-mg doses to be taken once every 24 hours.

Approval for rotigotine was based on two clinical trials involving a total of 838 patients with PD. The CLEOPATRA-PD (Clinical Efficacy of Pramipexole and Transdermal Rotigotine in Advanced PD) trial assessed the efficacy of adjunct treatment with rotigotine compared with placebo and with pramipexole in levodopa-treated patients with advanced PD; it also assessed the potential of rotigotine to decrease “off” times, which refer to a state of decreased mobility in between periods when the medication is working. The trial found that continuous delivery of rotigotine via transdermal patch could offer similar efficacy to that of oral pramipexole in patients with fluctuating PD symptoms over 6 months of treatment. The PREFER (Prospective Randomized Evaluation of a New Formulation: Efficacy of Rotigotine) trial assessed the efficacy and safety of two targeted transdermal doses of rotigotine in patients with advanced PD with 2.5 hours or more of daily “off” time. Compared with placebo, rotigotine significantly improved “off” time in participants with PD not optimally controlled with levodopa. Overall at 6 months, patients in both trials receiving rotigotine showed significant improvement in motor function and in activities of daily living compared with the placebo group.

In a follow-up open-label extension study of CLEOPATRA-PD and PREFER, the results of which were published in July in the Journal of Neural Transmission, patients had their dose of rotigotine de-escalated in a blinded fashion to 4 mg every 24 hours over a 6-day period (CLEOPATRA-PD) or an 8-day period (PREFER). Dose de-escalation was followed by up-titration in 2-mg increments daily every 7 days to reach the patient’s optimal dose (up to a maximum dose of 16 mg every 24 hours). Titration periods lasted up to 7 weeks. The dose was increased or decreased as needed to maintain the effects of the optimal dose while minimizing adverse effects (somnolence, insomnia, dyskinesias, and hallucinations). Measures of activities of daily living and motor function improved from the double-blind baseline during dose titration, then gradually declined over the maintenance period. As treating physicians had the option of adding to the anti-PD medication regimen used in CLEOPATRA-PD and PREFER, an average of 17% of study participants in the open-label extension were receiving another dopaminergic agonist in addition to rotigotine, and the dose of concomitant levodopa increased over time in both studies. The investigators noted, “This combination anti-PD treatment regimen may have contributed to both the efficacy and adverse effects outcomes in the two extension studies reported here,” leading to their conclusion that, “In these open-label studies, adjunctive rotigotine was efficacious with an acceptable safety and tolerability profile in patients with advanced PD for up to 6 years.”

The open-label extensions were conducted by Peter LeWitt, MD, Department of Neurology, Henry Ford Hospital and Wayne State University School of Medicine, Detroit, MI, and associates. Read the full study on PubMed.

The Use of Clobazam in Treatment of Lennox-Gastaut Syndrome in Older Adults

Lennox-Gastaut Syndrome (LGS) is an uncommon type of epileptic encephalopathy that is typically diagnosed in children before the age of 8 years. However, more than 80% of affected individuals continue to experience seizures as adults. Treatment of LGS in older adults is a challenge because there is a lack of available data assessing various antiepileptic drugs in this patient population, LGS is often refractory to many antiepileptic drugs, and the type and frequency of seizures tend to change with advancing age. Furthermore, identifying the appropriate treatment of LGS is challenging because clinical trials have not evaluated these agents directly. In a new study published in Acta Neurologica Scandinavica, Joyce Cramer, formerly president and chief scientific officer, Epilepsy Therapy Project, and associate research scientist, Yale University School of Medicine, and colleagues indirectly compared the relative efficacies of clobazam, felbamate, lamotrigine, topiramate, and rufinamide as adjunctive treatments for LGS.

Cramer and colleagues reviewed clinical studies of LGS patients, including five randomized controlled trials in the United States and Europe. Because each of the trials measured safety and efficacy outcomes differently, the researchers calculated the primary efficacy end point from each trial as a Cohen’s d effect size. A Cohen’s d is defined as the difference between two means divided by a standard deviation for the data (d<0.2 indicates change not detectable; 0.2≤d<0.5 indicates small change; 0.5≤d<0.8 indicates moderate change; and 0.8≤d indicates large change). Using this method, Cramer and colleagues found that high-dosage clobazam (1 mg/kg per day) has the strongest treatment effect compared with placebo (effect size, 0.80), and medium-dosage clobazam (0.5 mg/kg per day) has a moderate treatment effect (effect size, >0.50). Similar to medium-dosage clobazam, rufinamide also had a moderate treatment effect. Felbamate, lamotrigine, and topiramate had low effect sizes. Both clobazam dosages demonstrated superiority over all other agents in reducing the number of total seizures and tonic-atonic seizures (“drop attacks”). “We were not surprised by this finding at all,” said Cramer in an interview with Annals of Long-Term Care^®. “European doctors have been using clobazam for more than 20 years, but it was only approved just recently in the United States. It’s long been known to be effective, particularly in treating drop attacks that we see in LGS patients and also for total seizure frequency. One concern in early use was whether the effects of the medication would wear off quickly because it is a benzodiazepine, but this was not the case. We cannot say clobazam will work for everybody with LGS, but it seems much more likely to work in some patients, including those in older ages, than other options.”

Ask the Expert: Safe Prescribing of Anticonvulsants in Older Patients With Epilepsy

The incidence of epilepsy is growing faster in the elderly population than in any other age group. While many individuals can eliminate or significantly reduce the recurrence of seizures with anticonvulsants, pharmacologic treatment of epilepsy in the elderly poses a challenge because elderly persons tend to have more comorbidities and take more medications than younger persons. According to the National Institutes of Health, there are 20 antiepileptic drugs approved for use in the United States. Despite the advantages of having more treatment options for epilepsy than ever before, there is a paucity of data to guide appropriate prescribing of anticonvulsants in elderly patients. Annals of Long-Term Care^® (ALTC) discussed this quandary with James W. Cooper, RPh, PhD, BCPS, emeritus professor of clinical and administrative pharmacy and consultant pharmacist, University of Georgia College of Pharmacy, Athens, GA.

ALTC: How do healthcare providers decide upon which anticonvulsant to prescribe to older adults to achieve treatment goals while minimizing the risk of severe drug-drug interactions?

Cooper: The best way is to carefully consider the patient’s neurologic findings and total medication regimen as well as diagnoses—both past and new—such as acute stroke, and any newly started or stopped medications. Neurologic consultation should be available to determine risk versus benefit of new medications. One must consider the total psychoactive drug load, all drug interactions, and how the anticipated medication will add to the interaction. A high total psychoactive load has been shown to increase risk of falls, emergency visits, and hospitalizations.

Many of the newer antiepileptic drugs, such as lacosamide, are FDA-approved as adjunctive therapy for epilepsy, but there are many studies underway testing the safety and efficacy of these drugs as monotherapy. What does the evidence show with regard to the efficacy of new antiepileptic drugs as monotherapy?

Monotherapy should be tried first, but sometimes the clinician must experiment with careful changes, such as tapering suspect drugs that may have contributed to the seizure and/or abnormal movement activity. The key concern is to determine whether or not one is treating the adverse effect of another medication or its withdrawal before using multiple medications for a problem. An underlying problem in the frail, malnourished older adult may be the ability of the body to make sufficient serum albumin (>3.5 g/dL) to bind the drug (eg, phenytoin), and that what may be a seemingly “normal drug level” may in fact be a toxic level due to an excessive amount of the unbound drug, which may not be apparent with most drug level determinations.

When should the anticonvulsant agent be discontinued?

Always taper carefully rather than suddenly withdraw it when there is suspected or apparent toxicity from the medication, if the dose appears to be excessive, or if the blood lead level is elevated and/or serum albumin is decreased (<3.0 g/dL). Another consideration is to determine if there was an adverse drug reaction sequence (ie, if one medication increases abnormal involuntary movements or lowers seizure threshold). Finally, a medication reconciliation team that includes a pharmacist, nurse, and the patient’s primary care physician should carefully determine if the patient has been complying with the prescription and whether he or she has been taking any muscle relaxant, benzodiazepine, all antipsychotics, metoclopramide hypnotic, sleep aide, tramadol, bupropion, selective-serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor, tricyclic antidepressant, fluoroquinolone, or other medications on an irregular basis. This process could help determine if what is being observed is a primary or new seizure activity, tremor, abnormal involuntary movement, added medication adverse effect, and/or simply a drug withdrawal effect.

Dr. Cooper is a member of the ALTC Editorial Advisory Board. He is a past speaker and advisory board member for valproic acid and topiramate.