Trials Rising Codes

[Channing Rupnick]

Mark Earnest has spent more than 15 years advocating for employers in complex, high-stakes litigation matters with a focus on class actions and representative actions under California's Private Attorneys General Act (PAGA). He is an accomplished trial lawyer who has prevailed in multiple bench and jury trials and arbitrations and has extensive experience in all aspects of litigation, motion practice, and alternative dispute resolution. He represents corporate clients throughout the United States and is particularly adept at defending against claims alleging wage and hour violations (including reporting time, meal and rest breaks, overtime, waiting time, and employee misclassification) and trade secret misappropriation. Clients praise Mark for his ability to appreciate their business needs and his strategic approach to accomplishing their litigation goals.

In addition to representing employers in all aspects of employment law, Mark has litigated class and individual lawsuits involving the alleged inaccessibility of websites, facilities, programs, and services offered by public and private entities filed under the Americans with Disabilities Act (ADA), California's Unruh Civil Rights Act, and various federal and state regulations and building codes. He also counsels and aids retail and other businesses in implementing facility accessibility plans and audits.

Mark is a longtime member of the Orange County Bar Association, the Association of Business Trial Lawyers, and the J. Reuben Clark Law Society and currently sits on the board for the Constitutional Rights Foundation, Orange County chapter. He presents to employers on issues related to employment litigation and legislation.

Maintenance Treatment

Pramipexole dihydrochloride tablets were effective and well tolerated over a dosage range of 1.5 to 4.5 mg/day administered in equally divided doses three times per day with or without concomitant levodopa (approximately 800 mg/day).

In a fixed-dose study in early Parkinson's disease patients, doses of 3 mg, 4.5 mg, and 6 mg per day of pramipexole dihydrochloride tablets were not shown to provide any significant benefit beyond that achieved at a daily dose of 1.5 mg/day. However, in the same fixed-dose study, the following adverse events were dose related: postural hypotension, nausea, constipation, somnolence, and amnesia. The frequency of these events was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence reported with pramipexole at a dose of 1.5 mg/day was comparable to placebo.

When pramipexole dihydrochloride tablets are used in combination with levodopa, a reduction of the levodopa dosage should be considered. In a controlled study in advanced Parkinson's disease, the dosage of levodopa was reduced by an average of 27% from baseline.

Dosing in Patients with Renal Impairment

The recommended dosing of pramipexole dihydrochloride tablets in Parkinson's disease patients with renal impairment is provided in Table 2.

Discontinuation of Treatment

Pramipexole dihydrochloride tablets may be tapered off at a rate of 0.75 mg per day until the daily dose has been reduced to 0.75 mg. Thereafter, the dose may be reduced by 0.375 mg per day [see Warnings and Precautions (5.10,5.11)].

The duration between titration steps should be increased to 14 days in RLS patients with moderate and severe renal impairment (creatinine clearance 20 to 60 mL/min) [see Clinical Pharmacology (12.3)].

In clinical trials of patients being treated for RLS with doses up to 0.75 mg once daily, pramipexole dihydrochloride tablets were discontinued without a taper. In a 26 week placebo-controlled clinical trial, patients reported a worsening of RLS symptom severity as compared to their untreated baseline when pramipexole dihydrochloride tablets treatment was suddenly withdrawn [see Warnings and Precautions (5.10)].

Age appears to increase the risk of hallucinations attributable to pramipexole. In the early Parkinson's disease patients, the risk of hallucinations was 1.9 times greater than placebo in patients younger than 65 years and 6.8 times greater than placebo in patients older than 65 years. In the advanced Parkinson's disease patients, the risk of hallucinations was 3.5 times greater than placebo in patients younger than 65 years and 5.2 times greater than placebo in patients older than 65 years.

Animal Data
Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-year carcinogenicity study. While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls. Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar 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 [see Nonclinical Toxicology (13.2)].

Although not reported with pramipexole in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. If possible, avoid sudden discontinuation or rapid dose reduction in patients taking pramipexole dihydrochloride tablets. If the decision is made to discontinue pramipexole dihydrochloride tablets, the dose should be tapered to reduce the risk of hyperpyrexia and confusion [see Dosage and Administration (2.2)].

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Cases of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis have been reported in the postmarketing experience with pramipexole dihydrochloride tablets. While the evidence is not sufficient to establish a causal relationship between pramipexole dihydrochloride tablets and these fibrotic complications, a contribution of pramipexole dihydrochloride tablets cannot be completely ruled out.

Reports in the literature indicate treatment of RLS with dopaminergic medications can result in rebound: a worsening of symptoms following treatment cessation with greater intensity than described before starting treatment. In a 26 week placebo-controlled clinical trial in patients with RLS, a worsening of symptoms scores (IRLS) beyond their untreated baseline levels was reported more frequently by patients suddenly withdrawn from pramipexole dihydrochloride (up to 0.75 mg once daily) compared to the group assigned to placebo (10% vs. 2%, respectively). The worsening of RLS symptoms was considered generally mild.

Augmentation has also been described during therapy for RLS. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. In a 26 week placebo-controlled clinical trial in patients with RLS, augmentation was reported with greater frequency by patients treated with pramipexole dihydrochloride (up to 0.75 mg once daily) compared to patients who received placebo (12% vs. 9%, respectively). The incidence of augmentation increased with increasing duration of exposure to pramipexole dihydrochloride and to placebo.

The frequency and severity of augmentation and/or rebound after longer-term use of pramipexole dihydrochloride tablets and the appropriate management of these events have not been adequately evaluated in controlled clinical trials.

During the premarketing development of pramipexole, patients with either early or advanced Parkinson's disease were enrolled in clinical trials. Apart from the severity and duration of their disease, the two populations differed in their use of concomitant levodopa therapy. Patients with early disease did not receive concomitant levodopa therapy during treatment with pramipexole; those with advanced Parkinson's disease all received concomitant levodopa treatment. Because these two populations may have differential risks for various adverse reactions, this section will, in general, present adverse-reaction data for these two populations separately.

Because the controlled trials performed during premarketing development all used a titration design, with a resultant confounding of time and dose, it was impossible to adequately evaluate the effects of dose on the incidence of adverse reactions.

In the three double-blind, placebo-controlled trials of patients with early Parkinson's disease, the most common adverse reactions (>5%) that were numerically more frequent in the group treated with pramipexole dihydrochloride tablets were nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations.

Approximately 12% of 388 patients with early Parkinson's disease and treated with pramipexole dihydrochloride tablets who participated in the double-blind, placebo-controlled trials discontinued treatment due to adverse reactions compared with 11% of 235 patients who received placebo. The adverse reactions most commonly causing discontinuation of treatment were related to the nervous system (hallucinations [3.1% on pramipexole dihydrochloride tablets vs 0.4% on placebo]; dizziness [2.1% on pramipexole dihydrochloride tablets vs 1% on placebo]; somnolence [1.6% on pramipexole dihydrochloride tablets vs 0% on placebo]; headache and confusion [1.3% and 1.0%, respectively, on pramipexole dihydrochloride tablets vs 0% on placebo]) and gastrointestinal system (nausea [2.1% on pramipexole dihydrochloride tablets vs 0.4% on placebo]).

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