Neupro (rotigotine transdermal system) - 2 indications

Scroll down for more information on each indication:

• for the treatment of Parkinson's disease; approved May 2007
• for the treatment of Restless Legs Syndrome; approved April 2012 

General Information

Neupro is a transdermal system that provides continuous delivery of rotigotine, a non-ergoline dopamine agonist, for 24 hours following application to intact skin.

Neupro is specifically approved for:

• the treatment of moderate-to-severe primary restless legs syndrome
• the treatment of the signs and symptoms of early-stage idiopathic Parkinson's disease.

Neupro is supplied as a transdermal formula for topical administration. Scroll down for the recommended dosing/administration for each indicaiton.

Mechanism of Action

Neupro is a transdermal system that provides continuous delivery of rotigotine, a non-ergoline dopamine agonist, for 24 hours following application to intact skin.The precise mechanism of action of rotigotine as a treatment for Restless Legs Syndrome is unknown but is thought to be related to its ability to stimulate dopamine receptors. The exact mechanism of action of rotigotine in the treatment of Parkinson's disease is unknown. However, it is thought to be related to its ability to stimulate dopamine D2 receptors within the caudate-putamen in the brain.

Side Effects

Adverse events associated with the use of Neupro for Restless Legs Syndrome may include, but are not limited to, the following:

• application site reactions
• nausea
• somnolence
• headache

Adverse events associated with the use of Neupro for PD may include, but are not limited to, the following:

• Somnolence
• Nausea
• Application site reactions
• Dizziness
• Headache
• Fatigue
• Extremity edema
• Insomnia

Indication 1 - for the treatment of Parkinson's disease

approved May 2007

Dosing/Administration

Neupro is supplied as a patch in 2, 4, and 6 mg strengths designed for transdermal administration. The recommended initial dose of the drug is 2 mg/24 hours. Based on individual response and tolerability, the dosage may be increased weekly by 2 mg/24 hours if tolerated and additional therapeutic effect is needed. The lowest effective dose was found to be 4 mg/24 hours. The highest recommended dose is 6 mg/24 hours. The discontinuation of Neupro should be done gradually. The daily dose should be reduced by 2 mg/24 hours with a dose reduction preferably every other day, until complete withdrawal.

Clinical Trial Results

FDA approval of Neupro was based on the results of three clinical studies. These parallel group, randomized, double-blind, placebo controlled studies enrolled subjects internationally. All subjects were not receiving concomitant dopamine agonist therapy and were either L-dopa naïve or off L-dopa for at least 28 days prior to baseline and were never on L-dopa for more than 6 months. The primary endpoint was the change from baseline for the combined scores for Part II (activities of daily living component) plus part III (motor component) of the Unified Parkinson’s Disease Rating Scale (UPDRS).

Dose Response Study
This randomized, double-blind, dose-response trial enrolled 316 early stage Parkinson's subjects. Subjects received either placebo or one of several fixed doses (2 mg/24 hours, 4 mg/24 hours, 6 mg/24 hours, or 8 mg/24 hours) of Neupro, given as 1, 2, 3, or 4 2-mg patches for a period up to 11 weeks. Subjects underwent a weekly titration over four weeks. They then continued on treatment for a 7 week maintenance phase followed by a down titration during the last week. Mean baseline combined UPDRS scores were similar among all treatment groups, between 27.1 and 28.5. Subjects experienced a mean improvement in the combined UPDRS from baseline to end of treatment of -3.5, -4.5, -6.3, and -6.3 for the 2 mg/24 hours, 4 mg/24 hours, 6 mg/24 hours, and 8 mg/24 hours Neupro groups respectively and -1.4 for the placebo group. Statistical significance was observed at the three highest doses.

North American Study
This randomized, double-blind trial enrolled 277 early stage, idiopathic Parkinson's Disease subjects who were randomized in a 2:1 ratio to receive Neupro (2, 4, or 6 mg/24 hours) or placebo for 28 weeks. Subjects underwent a weekly titration over 3 weeks to a maximal dose of 6 mg/24 hours depending on efficacy and tolerability, and then received treatment over a 24 week maintenance phase followed by a de-escalation over a period up to 4 days. Mean baseline combined UPDRS was similar in both groups, 29.9 for the Neupro group and 30.0 for placebo. Statistical significance was reached in the Neupro treated subjects versus placebo in the mean change in the combined UPDRS from baseline to end of treatment ( -4.0 versus +1.39, respectively).

Foreign Multinational Study
This randomized, double-blind trial, three arm, parallel group, double-dummy trial enrolled 561 subjects with early stage Parkinson's Disease. Subjects were assigned to treatment with either placebo, Neupro (2 mg/24 hours, 218 4 mg/2 hours, 6 mg/24 hours, or 8 mg/24 hours) or active oral comparator in a ratio of 1: 2: 2 for a period of up to 39 weeks. Subjects underwent a weekly dose escalation of patch (consisting of 2 mg/24 hours increments of Neupro or placebo) and a dose escalation of capsules of comparator or placebo over 13 weeks up to a maximal dose of 8 mg/24 hours of Neupro. Subjects randomized to Neupro achieved the maximal dose of 230 mg/24 hours after a 4 week titration if maximal efficacy and intolerability had not occurred over a 4 week titration period. Subjects then received treatment over a 24 week maintenance phase followed by a de-escalation over a period up to 12 days. Mean baseline combined UPDRS was similar across all groups (33.2 Neupro, 245 31.3 placebo, 32.2 comparator). Neupro treated subjects experienced a mean change in the combined UPDRS from baseline to end of treatment of - 6.83, and placebo treated subjects showed a mean change from baseline of - 2.33, a statistically significant difference.

Indication 2 - for the treatment of Restless Legs Syndrome

approved April 2012 

Dosing/Administration

The recommended initial dose is 1 mg/24 hours. Based upon individual response and tolerability, Neupro dosage may be increased weekly by 1 mg/24 hours if tolerated and if additional therapeutic effect is needed. The highest recommended dose is 3 mg/24 hours. Neupro is applied once a day. The adhesive side of the transdermal system should be applied to clean, dry, intact healthy skin on the front of the abdomen, thigh, hip, flank, shoulder, or upper arm. The application site for Neupro should be moved on a daily basis. Neupro should not be applied to the same application site more than once every 14 days.

Clinical Trial Results

The FDA approval of Neupro for Restless Legs Syndrome was based on two fixed-dose, randomized, double-blind, placebo-controlled trials. The co-primary efficacy endpoints were changes on the International RLS Rating Scale (IRLS Scale) and a Clinical Global Impression - Improvement (CGI-I) assessment. The IRLS Scale contains 10 items designed to assess a variety of RLS symptoms. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. The CGI-I is designed to assess clinical progress (global improvement) on a 7-point scale.
Study One
This U.S-based, multicenter, 5-arm, parallel-group, fixed-dose trial enrolled 505 subjects with moderate-to-severe RLS. Subjects received placebo or Neupro (0.5 mg/24 hours, 1 mg/24 hours, 2 mg/24 hours, 3 mg/24 hours). Subjects began treatment at a daily dosage of 0.5 mg/24 hours Neupro and were titrated over a four week period to their assigned daily dose followed by a six month maintenance period and 7 day down titration period. Each of the four Neupro arms resulted in a mean change in the IRLS sum score from baseline to the end of treatment. The difference between the two highest treatment groups (2 mg/24 hours and 3 mg/24 hours) and placebo were statistically significant. Of the Neupro-treated arm, 23% had an IRLS score of 0 compared to 9.1% of the placebo arm at the end of the maintenance period. Onset of treatment benefit was seen with the 1 mg/24 hours dose.
Study Two
This European-based multicenter, 4-arm, parallel-group trial enrolled 458 subjects with moderate-to-severe RLS. The subjects received placebo or Neupro (1 mg/24 hours, 2 mg/24 hours, 3 mg/24 hours). Subjects began treatment at a daily dosage of 1 mg/24 hours Neupro and were titrated over a three week period to their assigned daily dose followed by a six month maintenance period and 7 day down-titration period. Each of the three Neupro dose groups showed a mean change in the IRLS sum score from baseline to the end of treatment. The difference between all three treatment groups and placebo was statistically significant. Of the Neupro-treated arm, 24% had an IRLS score of 0 compared to 12% of the placebo arm at the end of the maintenance period. Onset of treatment benefit was seen with the 1 mg/24 hours dose.