The recent approval of an irreversible monoamine oxidase inhibitor for treating Parkinson's disease includes an indication for patients with early disease as well as for those with more advanced disease who are already on levodopa.
The Food and Drug Administration approved rasagiline for treating the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa. Rasagiline, which will be marketed under the trade name Azilect by the Israel-based company Teva Pharmaceutical Industries Ltd., will be available sometime in July, according to the company. The recommended monotherapy dose is 1 mg once daily; for adjunctive therapy, the recommended starting dose is 0.5 mg once daily, increasing to 1 mg once daily if the clinical response is not adequate.
The approval comes with a warning about the need to restrict dietary tyramine and amines contained in medications in order to avoid the risk of a hypertensive crisis, as well as a precaution about monitoring patients for melanoma.
Rasagiline—a new molecular entity that was approved in Europe and Israel last year—inhibits monoamine oxidase type B (MAO-B). Whether it is selective for and inhibits only MAO-B and not MAO-A in humans has not been adequately studied yet, according to the drug's label. The label also states that its precise mechanism of action is unknown, but is believed to be “related to inhibition of MAO-B,” which results in increased extracellular levels of dopamine in the striatum.
FDA approval was based on three 18- to 26-week, randomized, placebo-controlled studies. In the monotherapy study of 404 patients with early Parkinson's disease, those treated with rasagiline experienced significantly less worsening in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS) at 6 months, when compared with those on placebo. The two other studies assessed the drug in more than 1,100 patients with more advanced disease. Study participants had had Parkinson's for an average of 9 years, were on chronic levodopa therapy, and were having motor fluctuations. Compared with those on placebo, subjects who received rasagiline had significantly less daily “off” time when their function and mobility were relatively poor.
Dr. Irene Litvan, the Raymond Lee Lebby Professor of Parkinson Disease Research at the University of Louisville (Ky.), described the approval as “great news” because the drug can be used both as monotherapy early in the course of the disease as well as an adjunct agent later in the disease's progression. In addition, the drug causes few side effects, is taken once a day, and does not need to be titrated.
Rasagiline is “an important new treatment … that can not only improve some of the symptoms of Parkinson's disease, but has the potential to slow the progression of the disease,” she said in an interview. This potential neuroprotective effect of the drug is the most exciting aspect of the approval and is what many patients have been waiting for, she added, noting that animal and in vitro data and some clinical evidence suggest rasagiline has some neuroprotective benefits.
Teva is currently recruiting patients with early idiopathic Parkinson's disease for a multinational trial to evaluate the effects of rasagiline on slowing the progression of the disease.
Even before approval, the 2006 American Academy of Neurology practice parameters had assigned the drug the highest level of evidence for having a significant beneficial effect, Dr. Litvan pointed out.
The FDA and the label warn that rasagiline may be associated with hypertensive crisis if patients consume tyramine-rich foods and beverages, such as aged cheese, tap beer, and red wine; dietary supplements; or amines contained in cough and cold medicines. A table of tyramine-rich food and beverages to avoid, as well as acceptable foods containing little or no tyramine, is included in the product label.
Dr. Litvan said she was surprised about the recommendation to restrict tyramine because of the selectivity of the drug. Rasagiline is more selective than selegiline (Eldepryl), which inhibits MAO-A in addition to MAO-B, she noted.
Rasagiline's label states that the drug's selectivity for inhibiting only MAO-B—not MAO-A—in humans, and a sensitivity to tyramine during treatment with rasagiline at any dose have “not been sufficiently characterized to avoid restriction of dietary tyramine and amines contained in medications.”
Dr. Litvan was not involved in clinical trials of the drug, and has no ties to the manufacturer, other than having received an education grant. Several of her patients who acquired the drug in Europe or Israel have done well on it, she said.
The FDA is also recommending that patients on the drug be checked regularly for signs of melanoma because people treated with rasagiline during its development were diagnosed with melanoma at a rate greater than that seen in the general population. However, the risk was comparable to that seen in some epidemiologic studies of Parkinson's disease patients; at this point, whether the greater melanoma rate is a result of the disease or the drug treatment is unclear. Teva will evaluate the relative risk of melanoma in a 6-month postmarketing study of rasagiline added to standard treatment, in about 5,000 patients.