Pramipexole Dihydrochloride (Page 6 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Two-year carcinogenicity studies with pramipexole have been conducted in mice and rats. Pramipexole was administered in the diet to mice at doses up to 10 mg/kg/day [or approximately 10 times the maximum recommended human dose (MRHD) of 1.5 mg TID on a mg/m2 basis]. Pramipexole was administered in the diet to rats at doses up to 8 mg/kg/day. These doses were associated with plasma AUCs up to approximately 12 times that in humans at the MRHD. No significant increases in tumors occurred in either species.

Pramipexole was not mutagenic or clastogenic in a battery of in vitro (bacterial reverse mutation, V79/HGPRT gene mutation, chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) assays.

In rat fertility studies, pramipexole at a dose of 2.5 mg/kg/day (5 times the MRHD on a mg/m2 basis) prolonged estrus cycles and inhibited implantation. These effects were associated with reductions in serum levels of prolactin, a hormone necessary for implantation and maintenance of early pregnancy in rats.

13.2 Animal Toxicology and/or Pharmacology

Retinal Pathology in Albino Rats

Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2 year carcinogenicity study with pramipexole. These findings were first observed during week 76 and were dose-dependent in animals receiving 2 or 8 mg/kg/day (plasma AUCs equal to 2.5 and 12.5 times that in humans at the MRHD of 1.5 mg TID). In a similar study of pigmented rats with 2 years exposure to pramipexole at 2 or 8 mg/kg/day, retinal degeneration was not observed. Animals given drug had thinning in the outer nuclear layer of the retina that was only slightly greater than that seen in control rats.

Investigative studies demonstrated that pramipexole reduced the rate of disk shedding from the photoreceptor rod cells of the retina in albino rats, which was associated with enhanced sensitivity to the damaging effects of light. In a comparative study, degeneration and loss of photoreceptor cells occurred in albino rats after 13 weeks of treatment with 25 mg/kg/day of pramipexole (54 times the highest clinical dose on a mg/m2 basis) and constant light (100 lux), but not in pigmented rats exposed to the same dose and higher light intensities (500 lux). Thus, the retina of albino rats is considered to be uniquely sensitive to the damaging effects of pramipexole and light. Similar changes in the retina did not occur in a 2 year carcinogenicity study in albino mice treated with 0.3, 2, or 10 mg/kg/day (0.3, 2.2, and 11 times the highest clinical dose on a mg/m2 basis). Evaluation of the retinas of monkeys given 0.1, 0.5, or 2 mg/kg/day of pramipexole (0.4, 2.2, and 8.6 times the highest clinical dose on a mg/m2 basis) for 12 months and minipigs given 0.3, 1, or 5 mg/kg/day of pramipexole for 13 weeks also detected no changes.

The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved.

Fibro-osseous Proliferative Lesions in Mice

An increased incidence of fibro-osseous proliferative lesions occurred in the femurs of female mice treated for 2 years with 0.3, 2, or 10 mg/kg/day (0.3, 2.2, and 11 times the highest clinical dose on a mg/m2 basis). Lesions occurred at a lower rate in control animals. Similar lesions were not observed in male mice or rats and monkeys of either sex that were treated chronically with pramipexole. The significance of this lesion to humans is not known.

14 CLINICAL STUDIES

The effectiveness of pramipexole dihydrochloride extended-release tablets in the treatment of Parkinson’s disease was supported by clinical pharmacokinetic data [see Clinical Pharmacology (12.3)] and two randomized, double-blind, placebo-controlled, multicenter clinical trials in early and advanced Parkinson’s disease. In both randomized studies, the Unified Parkinson’s Disease Rating Scale (UPDRS) served as a primary outcome assessment measure. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor performance (Part III), and complications of therapy (Part IV).

Part II of the UPDRS contains 13 questions related to activities of daily living, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 14 items 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.

Early Parkinson’s Disease

The effectiveness of pramipexole dihydrochloride extended-release tablets in early Parkinson’s disease patients (Hoehn & Yahr Stages I-III) who were not on levodopa therapy was established in a randomized, double-blind, placebo-controlled, 3-parallel-group clinical study. Patients were treated with pramipexole dihydrochloride extended-release tablets, immediate-release pramipexole tablets, or placebo; those treated with pramipexole extended-release tablets or immediate-release pramipexole tablets had a starting dose of 0.375 mg/day followed by a flexible up-titration, based on efficacy and tolerability, up to 4.5 mg/day. Levodopa was permitted during the study as rescue medication. Stable doses of concomitant MAO-B inhibitors, anticholinergics, or amantadine, individually or in combination, were allowed. The primary efficacy endpoint was the mean change from baseline in the UPDRS Parts II+III score for pramipexole dihydrochloride extended-release tablets versus placebo following 18 weeks of treatment.

At 18 weeks of treatment, the mean change from baseline UPDRS Parts II+III score was –8.1 points in patients receiving pramipexole dihydrochloride extended-release tablets (n=102) and –5.1 points in patients receiving placebo (n=50), a difference that was statistically significant (p<0.03). Seven patients treated with placebo (14%) and 3 patients treated with pramipexole dihydrochloride extended-release tablets (3%) received levodopa rescue medication. At 18 weeks, the mean dose of pramipexole dihydrochloride extended-release was 3 mg/day.

At 33-weeks the adjusted mean improvement from baseline UPDRS Parts II+III score was –8.6 points in patients receiving pramipexole dihydrochloride extended-release tablets (n=213), compared to –3.8 points in patients receiving placebo (n=103).

At 18 and 33 weeks, the mean dose of pramipexole dihydrochloride extended-release tablets was approximately 3 mg/day. Twenty-two patients treated with placebo (21%) and 15 patients treated with pramipexole dihydrochloride extended-release tablets (7%) received levodopa rescue medication before the final assessment

No differences in effectiveness based on age or gender were detected. Patients receiving MAOB-I, anticholinergics, or amantadine had responses similar to patients not receiving these drugs.

Advanced Parkinson’s Disease

The effectiveness of pramipexole dihydrochloride extended-release tablets in advanced Parkinson’s disease patients (Hoehn & Yahr Stages II-IV at “on” time) who were on concomitant levodopa therapy (at an optimized dose) and who had motor fluctuations (at least 2 cumulative hours of “off” time per day) was established in a randomized, double-blind, placebo-controlled, 3-parallel-group clinical study. Patients were treated with pramipexole extended-release tablets, immediate-release pramipexole tablets, or placebo; those treated with pramipexole extended-release tablets or immediate-release pramipexole tablets had a starting dose of 0.375 mg/day followed by a flexible up-titration over 7 weeks, based on efficacy and tolerability, up to 4.5 mg/day, followed by a 26 week maintenance period. Levodopa dosage reduction was permitted only in the case of dopaminergic adverse events. The primary efficacy endpoint was the adjusted mean change from baseline in the UPDRS Parts II+III score for pramipexole dihydrochloride extended-release tablets versus placebo following 18 weeks of treatment.

At 18 weeks of treatment, the adjusted mean improvement from baseline UPDRS Parts II+III score was – 11 points in patients receiving pramipexole dihydrochloride extended-release tablets (n=161) and – 6.1 points in patients receiving placebo (n=174), (p=0.0001). At week 18, the adjusted mean improvement from baseline in “off” time was -2.1 hours for pramipexole dihydrochloride extended-release and -1.4 hours for placebo (p=0.0199).

At 33-weeks the adjusted mean improvement from baseline UPDRS Parts II+III score was –11.1 points in patients receiving pramipexole dihydrochloride extended-release tablets (n=117) and –6.8 points in patients receiving placebo (n=136) (p=0.0135).

At both 18 and 33 weeks the mean daily dose of pramipexole dihydrochloride extended-release was 2.6 mg/day. At week 18, 4 patients (3%) in the placebo group and 14 patients (11%) in the pramipexole dihydrochloride extended-release tablets group had decreased their levodopa daily dose compared to baseline due to dopaminergic adverse events. No clinically relevant difference in effectiveness was observed in the sub-group analyses based on gender, age, race (White vs. Asian), or concomitant use of antiparkinsonian treatment (MAOB-I, amantadine or anticholinergics).

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