Pramipexole Dihydrochloride Extended-Release Tablets

Mechanism Of Action

Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.

The precise mechanism of action of pramipexole as a treatment for Parkinson's disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum. The relevance of D3 receptor binding in Parkinson's disease is unknown.

Pharmacodynamics

The effect of pramipexole on the QT interval of the ECG was investigated in a clinical study in 60 healthy male and female volunteers. All subjects initiated treatment with 0.375 mg MIRAPEX ER tablets administered once daily, and were up-titrated every 3 days to 2.25 mg and 4.5 mg daily, a faster rate of titration than recommended in the label. No dose-or exposure-related effect on mean QT intervals was observed; however, the study did not have a valid assessment of assay sensitivity. The effect of pramipexole on QTc intervals at higher exposures achieved either due to drug interactions (e.g., with cimetidine), renal impairment, or at higher doses has not been systematically evaluated.

Although mean values remained within normal reference ranges throughout the study, supine systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate for subjects treated with pramipexole generally increased during the rapid up-titration phase, by 10 mmHg, 7 mmHg, and 10 bpm higher than placebo, respectively. Higher SBP, DBP, and pulse rates compared to placebo were maintained until the pramipexole doses were tapered; values on the last day of tapering were generally similar to baseline values. Such effects have not been observed in clinical studies with Parkinson's disease patients, who were titrated according to labeled recommendations.

Pharmacokinetics

MIRAPEX ER tablets, like immediate-release pramipexole tablets, display linear pharmacokinetics over the entire clinical dosage range. Slow release of pramipexole from MIRAPEX ER tablets with once-daily administration results in the same daily maximum and minimum pramipexole plasma concentrations (Cmax, Cmin) as three times daily administration of immediate-release pramipexole tablets.

The absolute bioavailability of pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic metabolism.

Increase in systemic exposure of pramipexole following oral administration of 0.375 mg to 4.5 mg of MIRAPEX ER tablets was dose-proportional. For MIRAPEX ER tablets, steady state of exposure is reached within 5 days of continuous dosing.

Relative bioavailability of MIRAPEX ER tablets compared with immediate-release tablets was approximately 100%. In a repeat-dose study in healthy, normal volunteers, MIRAPEX ER tablets 4.5 mg administered once daily was bioequivalent with regard to Cmax and AUC over 24 hours to immediate-release pramipexole tablets 1.5 mg administered three times daily. The average time-to-peak concentration for MIRAPEX ER tablets is 6 hours. Administration of MIRAPEX ER tablets with food (i.e., high-fat meal) did not affect AUC but increased Cmax by approximately 20% and delayed Tmax by approximately 2 hours compared with dosing under fasted conditions; these differences are not considered to be clinically relevant [see DOSAGE AND ADMINISTRATION].

Pramipexole is extensively distributed, having a volume of distribution of about 500 L (coefficient of variation [CV] = 20%). It is about 15% bound to plasma proteins. Pramipexole distributes into red blood cells as indicated by an erythrocyte-to-plasma ratio of approximately 2.

Pramipexole is metabolized only to a negligible extent ( < 10%). No specific active metabolite has been identified in human plasma or urine.

Urinary excretion is the major route of pramipexole elimination, with 90% of a pramipexole dose recovered in urine, almost all as unchanged drug. The renal clearance of pramipexole is approximately 400 mL/min (CV=25%), approximately three times higher than the glomerular filtration rate. Thus, pramipexole is secreted by the renal tubules, probably by the organic cation transport system.

Pharmacokinetics in Specific Populations

Because therapy with MIRAPEX ER tablets is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, race, or age is not necessary. However, renal insufficiency causes a large decrease in the ability to eliminate pramipexole. This will necessitate dosage adjustment in patients with moderate to severe renal impairment [see DOSAGE AND ADMINISTRATION].

Pramipexole clearance is about 30% lower in women than in men, but this difference can be accounted for by differences in body weight. There is no difference in plasma half-life between males and females.

Pramipexole clearance is reduced by approximately 30% in the elderly (aged 65 years or older) compared with young, healthy volunteers (aged less than 40 years). This difference is most likely due to the reduction in renal function with age, since pramipexole clearance is correlated with renal function, as measured by creatinine clearance.

No racial differences in metabolism and elimination have been identified.

The influence of hepatic insufficiency on pramipexole pharmacokinetics has not been evaluated. Because approximately 90% of the recovered dose is excreted in the urine as unchanged drug, hepatic impairment would not be expected to have a significant effect on pramipexole elimination.

Clearance of immediate-release pramipexole was about 75% lower in patients with severe renal impairment (creatinine clearance approximately 20 mL/min) and about 60% lower in patients with moderate impairment (creatinine clearance approximately 40 mL/min) compared with healthy volunteers [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. In patients with varying degrees of renal impairment, pramipexole clearance correlates well with creatinine clearance. Therefore, creatinine clearance can be used as a predictor of the extent of decrease in pramipexole clearance.

Drug Interactions

No specific pharmacokinetic drug interaction trials were conducted with MIRAPEX ER tablets since the potential for drug interactions mainly depends on the active drug substance pramipexole and not the formulation. The following interaction data were obtained using immediate-release pramipexole tablets.

Carbidopa/levodopa: Carbidopa/levodopa did not influence the pharmacokinetics of pramipexole in healthy volunteers (N=10). Pramipexole did not alter the extent of absorption (AUC) or the elimination of carbidopa/levodopa, although it caused an increase in levodopa Cmax by about 40% and a decrease in Tmax from 2.5 to 0.5 hours.

Selegiline: In healthy volunteers (N=11), selegiline did not influence the pharmacokinetics of pramipexole.

Amantadine: Population pharmacokinetic analyses suggest that amantadine may slightly decrease the oral clearance of pramipexole.

Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N=12).

Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence pramipexole pharmacokinetics (N=12).

Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. Other known organic cation transport substrates and/or inhibitors (e.g., cisplatin and procainamide) may also decrease the clearance of pramipexole.

CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 μM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the clinical dose of 4.5 mg/day.

Drugs affecting gastrointestinal motility or gastric pH: Population pharmacokinetic analysis suggests that co-administration of antacids (N=6) decreased the oral clearance of pramipexole by about 25%, while H2-blockers (N=5), anticholinergics (N=27), propulsive (N=7), and proton pump inhibitors (N=16) are likely to have little effect on the oral clearance of pramipexole.

Animal Toxicology And/Or Pharmacology

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 2.0 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.

An increased incidence of fibro-osseous proliferative lesions occurred in the femurs of female mice treated for 2 years with 0.3, 2.0, 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.

Clinical Studies

The effectiveness of MIRAPEX ER tablets in the treatment of Parkinson's disease was supported by clinical pharmacokinetic data [see CLINICAL PHARMACOLOGY] 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.

The effectiveness of MIRAPEX ER 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, 3parallel-group clinical study. Patients were treated with MIRAPEX ER tablets, immediate-release pramipexole tablets, or placebo; those treated with MIRAPEX ER 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 MIRAPEX ER 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 MIRAPEX ER 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 MIRAPEX ER tablets (3%) received levodopa rescue medication. At 18 weeks, the mean dose of MIRAPEX ER 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 MIRAPEX ER tablets (n=213), compared to –3.8 points in patients receiving placebo (n=103).

At 18 and 33 weeks, the mean dose of MIRAPEX ER tablets was approximately 3 mg/day. Twenty-two patients treated with placebo (21%) and 15 patients treated with MIRAPEX ER 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.

The effectiveness of MIRAPEX ER tablets in advanced Parkinson's disease patients (Hoehn & Yahr Stages IIIV 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 MIRAPEX ER tablets, immediate-release pramipexole tablets, or placebo; those treated with MIRAPEX ER 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 MIRAPEX ER 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 –11.0 points in patients receiving MIRAPEX ER 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 MIRAPEX ER 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 MIRAPEX ER 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 MIRAPEX ER was 2.6 mg/day. At week 18, 4 patients (3%) in the placebo group and 14 patients (11%) in the MIRAPEX ER 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).

You should not use pramipexole if you are allergic to it.

Some people taking pramipexole have fallen asleep during normal daytime activities such as working, talking, eating, or driving. You may fall asleep suddenly, even after feeling alert. Tell your doctor if you have any problems with daytime sleepiness or drowsiness. If you are unsure of how this medicine will affect you, be careful if you drive or do anything that requires you to be awake and alert.

To make sure you can safely take pramipexole, tell your doctor if you have any of these other conditions:

• low blood pressure;
• kidney disease; or
• tremors (dyskinesia) or uncontrolled muscle movements.

You may have increased sexual urges, unusual urges to gamble, or other intense urges while taking pramipexole. It is not known whether the medicine actually causes this effect. Talk with your doctor if you believe you have any intense or unusual urges while taking pramipexole.

Some people taking Parkinson's disease medications have developed skin cancer (melanoma). However, people with Parkinson's disease may have a higher risk of melanoma. Talk to your doctor about this risk and what skin symptoms to watch for. You may need to have regular skin exams.

FDA pregnancy category C. It is not known whether pramipexole will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether pramipexole passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Pramipexole may cause hallucinations (the sensation of hearing or seeing something that is not there), most commonly among elderly people. Call your doctor if you have hallucinations.

Pramipexole may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Drinking alcohol can increase certain side effects of pramipexole.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

• Parkinson's Disease