FDA Okays Carbidopa/Levodopa ER (Rytary) in Parkinson's

Megan Brooks

January 08, 2015

The US Food and Drug Administration (FDA) has approved an extended-release capsule formulation of carbidopa-levodopa (Rytary, IPX066, Impax Pharmaceuticals) for the treatment of Parkinson's disease (PD), postencephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication.

The product contains immediate-release and extended-release beads, with a specific amount of carbidopa and levodopa in a 1:4 ratio, and provides both initial and extended levodopa plasma concentrations after a single dose, the company said in a statement. The capsule may be swallowed whole or, for patients who have trouble swallowing, the capsule may be opened and the beads sprinkled on applesauce and consumed immediately.

Impax expects this formulation to be available beginning next month in four strengths: 23.75 mg/95 mg, 36.25 mg/145 mg, 48.75 mg/195 mg, and 61.25 mg/245 mg (carbidopa/levodopa).

The company received a complete response letter on their New Drug Application in January 2013. A statement from the company at that time said the FDA required a "satisfactory re-inspection" of the company's Hayward, California, facility.

The approval was based on positive results in a trio of phase 3 studies involving patients with early and advanced PD in the United States and in Europe.

In the APEX-PD study of 381 levodopa-naive patients, the extended-release formulation met its primary efficacy endpoint of change from baseline in the sum of Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III scores, reflecting improvements in activities of daily living and motor symptoms of PD. The mean sum of the Parts II and III UPDRS score on treatment improved 13.2 units (36%) vs 0.6 units (2%) with placebo.

Treatment was also associated with mean improvements of 72% in both Clinician Global Impression of change (CGI) and Patient Global Impression of change (PGI) compared with 27% and 34% for placebo in CGI and PGI, respectively (P < .0001). Quality of life also improved over placebo as measured by the Parkinson's Disease Questionnaire at week 30 (P < .02).

In the ADVANCE-PD study of 393 patients with advanced PD and "off" time, Dr. Rytary showed a 37% improvement in "off" time during waking hours compared with baseline vs a 17% improvement for patients taking immediate-release carbidopa-levodopa (P < .0001). Treatment also increased "on" time without troublesome dyskinesia during waking hours by 1.8 hours. Less "off" time was primarily related to more "on" time without troublesome dyskinesia.

In the ASCEND-PD study, also in advanced patients, "offtime" improved by 84 minutes and a corresponding increase occurred in "on" time without dyskinesias, compared with patients receiving carbidopa-levodopa plus entacapone.

The most common adverse reactions in clinical trials were nausea, dizziness, headache, insomnia, abnormal dreams, dry mouth, dyskinesia, anxiety, constipation, vomiting, and orthostatic hypotension. This product is not for use in patients taking nonselective monoamine oxidase inhibitors. Hypertension can occur if these drugs are used concurrently.

Rytary is designed to address "one of the most significant unmet needs for patients living with Parkinson's disease, which is to reduce the amount of time during the day when their symptoms are not adequately controlled," Fred Wilkinson, president and CEO, Impax Laboratories, said in the company news release.


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