Pramipexole ER Tablets

Pramipexole Dihydrochloride Extended-Release Tablets are indicated for the treatment of Parkinson's disease.

Pregnancy

Risk Summary

There are no adequate data on the development risk associated with the use of pramipexole dihydrochloride extended-release tablets in pregnant women. No adverse development effects were observed in animal studies in which pramipexole was administered to rabbits during pregnancy. Effects on embryofetal development could not be adequately assessed in pregnant rats; however, postnatal growth was inhibited at clinically relevant exposures [see Data].

In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

Oral administration of pramipexole (0.1, 0.5, or 1.5 mg/kg/day) to pregnant rats during the period of organogenesis resulted in a high incidence of total resorption of embryos at the highest dose tested. This increase in embryolethality is thought to result from the prolactin-lowering effect of pramipexole; prolactin is necessary for implantation and maintenance of early pregnancy in rats but not in rabbits or humans. Because of pregnancy disruption and early embryonic loss in this study, the teratogenic potential of pramipexole could not be adequately assessed in rats. The highest no-effect dose for embryolethality in rats was associated with maternal plasma drug exposures (AUC) approximately equal to those in humans receiving the maximum recommended human dose (MRHD) of 4.5 mg/day. There were no adverse effects on embryo-fetal development following oral administration of pramipexole (0.1, 1, or 10 mg/kg/day) to pregnant rabbits during organogenesis (plasma AUC up to approximately 70 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with pramipexole (0.1, 0.5, or 1.5 mg/kg/day) during the latter part of pregnancy and throughout lactation. The no-effect dose for adverse effects on offspring growth (0.1 mg/kg/day) was associated with maternal plasma drug exposure lower than that in humans at the MRHD.

Lactation

Risk Summary

There are no data on the presence of pramipexole in human milk, the effects of pramipexole on the breastfed infant, or the effects of pramipexole on milk production. However, inhibition of lactation is expected because pramipexole inhibits secretion of prolactin in humans. Pramipexole or metabolites, or both, are present in rat milk [see Data].

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for pramipexole dihydrochloride extended-release tablets and any potential adverse effects on the breastfed infant from pramipexole dihydrochloride extended-release tablets or from the underlying maternal condition.

Data

In a study of radiolabeled pramipexole, pramipexole or metabolites, or both, were present in rat milk at concentrations three to six times higher than those in maternal plasma.

Pediatric Use

Safety and effectiveness of pramipexole dihydrochloride extended-release tablets in pediatric patients have not been evaluated.

Geriatric Use

Pramipexole total oral clearance is approximately 30% lower in subjects older than 65 years compared with younger subjects, because of a decline in pramipexole renal clearance due to an age-related reduction in renal function. This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours. In a placebo-controlled clinical trial of pramipexole dihydrochloride extended-release tablets in early Parkinson’s disease, 47% of the 259 patients were ≥ 65 years of age. Among patients receiving pramipexole dihydrochloride extended-release tablets, hallucinations were more common in the elderly, occurring in 13% of the patients ≥ 65 years of age compared to 2% of the patients < 65 years of age.

Renal Impairment

The elimination of pramipexole is dependent upon renal function. Pramipexole clearance is extremely low in dialysis patients, as a negligible amount of pramipexole is removed by dialysis [see Dosage and Administration (2.2), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)].

There is no clinical experience with significant overdosage. One patient took 11 mg/day of pramipexole for 2 days in a clinical trial for an investigational use. Blood pressure remained stable, although pulse rate increased to between 100 and 120 beats/minute. No other adverse reactions were reported related to the increased dose.

There is no known antidote for overdosage of a dopamine agonist. If signs of central nervous system stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdosage has not been assessed. Management of overdose may require general supportive measures along with gastric lavage, intravenous fluids, and electrocardiogram monitoring.

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 dihydrochloride 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 tablets 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 dihydrochloride extended-release tablets, immediate-release pramipexole tablets, or placebo; those treated with pramipexole dihydrochloride 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 tablets 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 tablets 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).

 Advise the patient to read the FDA-approved patient labeling (Patient Information).

Dosing Instructions

Instruct patients to take pramipexole dihydrochloride extended-release tablets only as prescribed. If a dose is missed, pramipexole dihydrochloride extended-release tablets should be taken as soon as possible, but no later than 12 hours after the regularly scheduled time. After 12 hours, the missed dose should be skipped and the next dose should be taken on the following day at the regularly scheduled time.

Pramipexole dihydrochloride extended-release tablets can be taken with or without food. If patients develop nausea, advise that taking pramipexole dihydrochloride extended-release tablets with food may reduce the occurrence of nausea.

Pramipexole dihydrochloride extended-release tablets should be swallowed whole. They should not be chewed, crushed, or divided [see Dosage and Administration (2.1)].

Inform patients that residue in stool which may resemble a swollen original pramipexole dihydrochloride extended-release tablet or swollen pieces of the original tablet have been reported [seeAdverse Reactions (6.2)]. Instruct patients to contact their physician if this occurs.

Pramipexole is the active ingredient that is in both pramipexole dihydrochloride extended-release tablets and immediate-release pramipexole tablets. Ensure that patients do not take both immediate-release pramipexole and pramipexole dihydrochloride extended-release tablets.

Sedating Effects

Alert patients to the potential sedating effects of pramipexole dihydrochloride extended-release tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse reaction with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with pramipexole dihydrochloride extended-release tablets to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., conversations or eating) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects, advise caution when patients are taking other sedating medications or alcohol in combination with pramipexole dihydrochloride extended-release tablets and when taking concomitant medications that increase plasma levels of pramipexole (e.g., cimetidine) [see Warnings and Precautions (5.1)].

Impulse Control Symptoms Including Compulsive Behaviors

Alert patients and their caregivers to the possibility that they may experience intense urges to spend money, intense urges to gamble, increased sexual urges, binge eating and/or other intense urges and the inability to control these urges while taking pramipexole dihydrochloride extended-release tablets [see Warnings and Precautions (5.3)].

Hallucinations and Psychotic-like Behavior

Inform patients that hallucinations and other psychotic-like behavior can occur and that the elderly are at a higher risk than younger patients with Parkinson's disease [see Warnings and Precautions (5.4)].

Postural (Orthostatic) Hypotension

Advise patients that they may develop postural (orthostatic) hypotension, with or without symptoms such as dizziness, nausea, fainting, or blackouts, and sometimes, sweating. Hypotension may occur more frequently during initial therapy. Accordingly, caution patients against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with pramipexole dihydrochloride extended-release tablets [see Warnings and Precautions (5.2)].

Pregnancy

Because the teratogenic potential of pramipexole has not been completely established in laboratory animals, and because experience in humans is limited, advise women to notify their physicians if they become pregnant or intend to become pregnant during therapy [see Use in Specific Populations (8.1)].

Lactation

Because of the possibility that pramipexole may be excreted in breast milk, advise women to notify their physicians if they intend to breast-feed or are breast-feeding an infant [see Use in Specific Populations (8.2)].