Pramipexole Dihydrochloride (Page 6 of 8)

14 CLINICAL STUDIES

14.1 Parkinson’s Disease


The effectiveness of pramipexole dihydrochloride tablets in the treatment of Parkinson’s disease was evaluated in a multinational drug development program consisting of seven randomized, controlled trials. Three were conducted in patients with early Parkinson’s disease who were not receiving concomitant levodopa, and four were conducted in patients with advanced Parkinson’s disease who were receiving concomitant levodopa. Among these seven studies, three studies provide the most persuasive evidence of pramipexole’s effectiveness in the management of patients with Parkinson’s disease who were and were not receiving concomitant levodopa. Two of these three trials enrolled patients with early Parkinson’s disease (not receiving levodopa), and one enrolled patients with advanced Parkinson’s disease who were receiving maximally tolerated doses of levodopa.
In all studies, the Unified Parkinson’s Disease Rating Scale (UPDRS), or one or more of its subparts, served as the primary outcome assessment measure. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (part I), Activities of Daily Living (ADL) (part II), motor performance (part III), and complications of therapy (part IV).
Part II of the UPDRS contains 13 questions relating to ADL, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 27 questions (for 14 items) and is scored as described for part II. It is designed to assess the severity of the cardinal motor findings in patients with Parkinson’s disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions, and has a maximum (worst) score of 108.
Studies in Patients with Early Parkinson’s Disease
Patients (N=599) in the two studies of early Parkinson’s disease had a mean disease duration of 2 years, limited or no prior exposure to levodopa (generally none in the preceding 6 months), and were not experiencing the “on-off” phenomenon and dyskinesia characteristic of later stages of the disease.
One of the two early Parkinson’s disease studies (N=335) was a double-blind, placebo-controlled, parallel trial consisting of a 7-week dose-escalation period and a 6-month maintenance period. Patients could be on selegiline, anticholinergics, or both, but could not be on levodopa products or amantadine. Patients were randomized to pramipexole dihydrochloride tablets or placebo. Patients treated with pramipexole dihydrochloride tablets had a starting daily dose of 0.375 mg and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS part II (ADL) total score was 1.9 in the group receiving pramipexole dihydrochloride tablets and -0.4 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5 in the group receiving pramipexole dihydrochloride tablets and -0.8 in the placebo group, a difference that was also statistically significant. A statistically significant difference between groups in favor of pramipexole dihydrochloride tablets was seen beginning at week 2 of the UPDRS part II (maximum dose 0.75 mg/day) and at week 3 of the UPDRS part III (maximum dose 1.5 mg/day).
The second early Parkinson’s disease study (N=264) was a double-blind, placebo-controlled, parallel trial consisting of a 6-week dose-escalation period and a 4-week maintenance period. Patients could be on selegiline, anticholinergics, amantadine, or any combination of these, but could not be on levodopa products. Patients were randomized to 1 of 4 fixed doses of pramipexole dihydrochloride tablets (1.5 mg, 3 mg, 4.5 mg, or 6 mg per day) or placebo. At the end of the 4-week maintenance period, the mean improvement from baseline on the UPDRS part II total score was 1.8 in the patients treated with pramipexole dihydrochloride tablets, regardless of assigned dose group, and 0.3 in placebo-treated patients. The mean improvement from baseline on the UPDRS part III total score was 4.2 in patients treated with pramipexole dihydrochloride tablets and 0.6 in placebo-treated patients. No dose-response relationship was demonstrated. The between-treatment differences on both parts of the UPDRS were statistically significant in favor of pramipexole dihydrochloride tablets for all doses.
No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race. Patients receiving selegiline or anticholinergics had responses similar to patients not receiving these drugs.
Studies in Patients with Advanced Parkinson’s Disease
In the advanced Parkinson’s disease study, the primary assessments were the UPDRS and daily diaries that quantified amounts of “on” and “off” time.
Patients in the advanced Parkinson’s disease study (N=360) had a mean disease duration of 9 years, had been exposed to levodopa for long periods of time (mean 8 years), used concomitant levodopa during the trial, and had “on-off” periods.
The advanced Parkinson’s disease study was a double-blind, placebo-controlled, parallel trial consisting of a 7-week dose-escalation period and a 6-month maintenance period. Patients were all treated with concomitant levodopa products and could additionally be on concomitant selegiline, anticholinergics, amantadine, or any combination. Patients treated with pramipexole dihydrochloride tablets had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At selected times during the 6-month maintenance period, patients were asked to record the amount of “off,” “on,” or “on with dyskinesia” time per day for several sequential days. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS part II total score was 2.7 in the group treated with pramipexole dihydrochloride tablets and 0.5 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5.6 in the group treated with pramipexole dihydrochloride tablets and 2.8 in the placebo group, a difference that was statistically significant. A statistically significant difference between groups in favor of pramipexole dihydrochloride tablets was seen at week 3 of the UPDRS part II (maximum dose 1.5 mg/day) and at week 2 of the UPDRS part III (maximum dose 0.75 mg/day). Dosage reduction of levodopa was allowed during this study if dyskinesia (or hallucinations) developed; levodopa dosage reduction occurred in 76% of patients treated with pramipexole dihydrochloride tablets versus 54% of placebo patients. On average, the levodopa dose was reduced 27%.
The mean number of “off” hours per day during baseline was 6 hours for both treatment groups. Throughout the trial, patients treated with pramipexole dihydrochloride tablets had a mean of 4 “off” hours per day, while placebo-treated patients continued to experience 6 “off” hours per day.
No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Pramipexole Dihydrochloride tablets are available as follows:

Pramipexole Dihydrochloride Tablets, 0.125 mg are white to off-white, round, flat, beveled edge uncoated tablets, debossed with ‘Y’ on one side ‘41’ on other side.
Bottles of 90 NDC 57237-180-90
Bottles of 1,000 NDC 57237-180-99

Pramipexole Dihydrochloride Tablets, 0.25 mg are white to off-white, oval, biconcave, beveled edge uncoated tablets, debossed with ‘Y’ and ‘42’ separated by score line on one side and plain with score line on other side.
Bottles of 90 NDC 57237-181-90
Bottles of 1,000 NDC 57237-181-99

Pramipexole Dihydrochloride Tablets, 0.5 mg are white to off-white, oval, biconcave, beveled edge uncoated tablets, debossed with ‘Y’ and ‘43’ separated by score line on one side and plain with score line on other side.
Bottles of 90 NDC 57237-182-90
Bottles of 1,000 NDC 57237-182-99

Pramipexole Dihydrochloride Tablets, 0.75 mg are white to off-white, oval, biconcave, beveled edge uncoated tablets, debossed with ‘Y’ on one side and ‘44’ on other side.
Bottles of 90 NDC 57237-183-90
Bottles of 1,000 NDC 57237-183-99

Pramipexole Dihydrochloride Tablets, 1 mg are white to off-white, round, flat, beveled edge uncoated tablets, debossed with ‘Y’ and ‘45’ separated by score line on one side and plain with score line on other side.
Bottles of 90 NDC 57237-184-90
Bottles of 1,000 NDC 57237-184-99

Pramipexole Dihydrochloride Tablets, 1.5 mg are white to off-white, round, flat, beveled edge uncoated tablets, debossed with ‘Y’ and ‘46’ separated by score line on one side and plain with score line on other side.
Bottles of 90 NDC 57237-185-90
Bottles of 1,000 NDC 57237-185-99

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